PMID- 38093002 OWN - NLM STAT- In-Process LR - 20240103 IS - 1476-4687 (Electronic) IS - 0028-0836 (Linking) VI - 625 IP - 7993 DP - 2024 Jan TI - Cortical reactivations predict future sensory responses. PG - 110-118 LID - 10.1038/s41586-023-06810-1 [doi] AB - Many theories of offline memory consolidation posit that the pattern of neurons activated during a salient sensory experience will be faithfully reactivated, thereby stabilizing the pattern(1,2). However, sensory-evoked patterns are not stable but, instead, drift across repeated experiences(3-6). Here, to investigate the relationship between reactivations and the drift of sensory representations, we imaged the calcium activity of thousands of excitatory neurons in the mouse lateral visual cortex. During the minute after a visual stimulus, we observed transient, stimulus-specific reactivations, often coupled with hippocampal sharp-wave ripples. Stimulus-specific reactivations were abolished by local cortical silencing during the preceding stimulus. Reactivations early in a session systematically differed from the pattern evoked by the previous stimulus-they were more similar to future stimulus response patterns, thereby predicting both within-day and across-day representational drift. In particular, neurons that participated proportionally more or less in early stimulus reactivations than in stimulus response patterns gradually increased or decreased their future stimulus responses, respectively. Indeed, we could accurately predict future changes in stimulus responses and the separation of responses to distinct stimuli using only the rate and content of reactivations. Thus, reactivations may contribute to a gradual drift and separation in sensory cortical response patterns, thereby enhancing sensory discrimination(7). CI - © 2023. The Author(s), under exclusive licence to Springer Nature Limited. FAU - Nguyen, Nghia D AU - Nguyen ND AD - Program in Neuroscience, Harvard University, Boston, MA, USA. FAU - Lutas, Andrew AU - Lutas A AUID- ORCID: 0000-0002-6991-2898 AD - Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. AD - Diabetes, Endocrinology and Obesity Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. FAU - Amsalem, Oren AU - Amsalem O AUID- ORCID: 0000-0002-8070-0378 AD - Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. FAU - Fernando, Jesseba AU - Fernando J AUID- ORCID: 0000-0001-6776-947X AD - Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. FAU - Ahn, Andy Young-Eon AU - Ahn AY AD - Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. FAU - Hakim, Richard AU - Hakim R AD - Program in Neuroscience, Harvard University, Boston, MA, USA. AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Vergara, Josselyn AU - Vergara J AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - McMahon, Justin AU - McMahon J AUID- ORCID: 0000-0002-6388-1429 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Dimidschstein, Jordane AU - Dimidschstein J AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Program in Neuroscience, Harvard University, Boston, MA, USA. AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Andermann, Mark L AU - Andermann ML AUID- ORCID: 0000-0002-9882-933X AD - Program in Neuroscience, Harvard University, Boston, MA, USA. manderma@bidmc.harvard.edu. AD - Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. manderma@bidmc.harvard.edu. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. manderma@bidmc.harvard.edu. LA - eng PT - Journal Article DEP - 20231213 PL - England TA - Nature JT - Nature JID - 0410462 SB - IM EDAT- 2023/12/14 00:42 MHDA- 2023/12/14 00:42 CRDT- 2023/12/13 23:44 PHST- 2022/10/10 00:00 [received] PHST- 2023/10/31 00:00 [accepted] PHST- 2023/12/14 00:42 [pubmed] PHST- 2023/12/14 00:42 [medline] PHST- 2023/12/13 23:44 [entrez] AID - 10.1038/s41586-023-06810-1 [pii] AID - 10.1038/s41586-023-06810-1 [doi] PST - ppublish SO - Nature. 2024 Jan;625(7993):110-118. doi: 10.1038/s41586-023-06810-1. Epub 2023 Dec 13. PMID- 37986941 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231121 DP - 2023 Nov 9 TI - Striatum supports fast learning but not memory recall. LID - 2023.11.08.566333 [pii] LID - 10.1101/2023.11.08.566333 [doi] AB - Animals learn to carry out motor actions in specific sensory contexts to achieve goals. The striatum has been implicated in producing sensory-motor associations, yet its contribution to memory formation or recall is not clear. To investigate the contribution of striatum to these processes, mice were taught to associate a cue, consisting of optogenetic activation of striatum-projecting neurons in visual cortex, with forelimb reaches to access food pellets. As necessary to direct learning, striatal neural activity encoded both the sensory context and outcome of reaching. With training, the rate of cued reaching increased, but brief optogenetic inhibition of striatal activity arrested learning and prevented trial-to-trial improvements in performance. However, the same manipulation did not affect performance improvements already consolidated into short- (within an hour) or long-term (across days) memories. Hence, striatal activity is necessary for trial-to-trial improvements in task performance, leading to plasticity in other brain areas that mediate memory recall. FAU - Reinhold, Kimberly AU - Reinhold K AUID- ORCID: 0000-0001-9523-8967 FAU - Iadarola, Marci AU - Iadarola M FAU - Tang, Shi AU - Tang S FAU - Kuwamoto, Whitney AU - Kuwamoto W FAU - Sun, Senmiao AU - Sun S FAU - Hakim, Richard AU - Hakim R FAU - Zimmer, Joshua AU - Zimmer J FAU - Wang, Wengang AU - Wang W FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 LA - eng PT - Preprint DEP - 20231109 PL - United States TA - bioRxiv JT - bioRxiv : the preprint server for biology JID - 101680187 PMC - PMC10659398 EDAT- 2023/11/21 06:41 MHDA- 2023/11/21 06:42 CRDT- 2023/11/21 05:08 PHST- 2023/11/21 06:42 [medline] PHST- 2023/11/21 06:41 [pubmed] PHST- 2023/11/21 05:08 [entrez] AID - 2023.11.08.566333 [pii] AID - 10.1101/2023.11.08.566333 [doi] PST - epublish SO - bioRxiv. 2023 Nov 9:2023.11.08.566333. doi: 10.1101/2023.11.08.566333. Preprint. PMID- 37961214 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231121 DP - 2023 Nov 2 TI - A Cre-dependent reporter mouse for quantitative real-time imaging of Protein Kinase A activity dynamics. LID - 2023.10.31.565028 [pii] LID - 10.1101/2023.10.31.565028 [doi] AB - Intracellular signaling dynamics play a crucial role in cell function. Protein kinase A (PKA) is a key signaling molecule that has diverse functions, from regulating metabolism and brain activity to guiding development and cancer progression. We previously developed an optical reporter, FLIM-AKAR, that allows for quantitative imaging of PKA activity via fluorescence lifetime imaging microscopy and photometry. However, using viral infection or electroporation for the delivery of FLIM-AKAR is invasive, cannot easily target sparse or hard-to-transfect/infect cell types, and results in variable expression. Here, we developed a reporter mouse, FL-AK, which expresses FLIM-AKAR in a Cre-dependent manner from the ROSA26 locus. FL-AK provides robust and consistent expression of FLIM-AKAR over time. Functionally, the mouse line reports an increase in PKA activity in response to activation of both G(αs) and G(αq)-coupled receptors in brain slices. In vivo, FL-AK reports PKA phosphorylation in response to neuromodulator receptor activation. Thus, FL-AK provides a quantitative, robust, and flexible method to reveal the dynamics of PKA activity in diverse cell types. FAU - Tilden, Elizabeth I AU - Tilden EI AUID- ORCID: 0000-0001-6560-3863 AD - Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States. AD - Ph. D. Program in Neuroscience, Washington University in St. Louis. FAU - Maduskar, Aditi AU - Maduskar A AD - Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States. FAU - Oldenborg, Anna AU - Oldenborg A AD - Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, United States. FAU - Chen, Yao AU - Chen Y AUID- ORCID: 0000-0003-1509-6634 AD - Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States. LA - eng GR - F30 AG084271/AG/NIA NIH HHS/United States GR - R01 NS119821/NS/NINDS NIH HHS/United States PT - Preprint DEP - 20231102 PL - United States TA - bioRxiv JT - bioRxiv : the preprint server for biology JID - 101680187 PMC - PMC10635033 COIS- The authors declare no competing interests. EDAT- 2023/11/14 06:42 MHDA- 2023/11/14 06:43 CRDT- 2023/11/14 03:54 PHST- 2023/11/14 06:42 [pubmed] PHST- 2023/11/14 06:43 [medline] PHST- 2023/11/14 03:54 [entrez] AID - 2023.10.31.565028 [pii] AID - 10.1101/2023.10.31.565028 [doi] PST - epublish SO - bioRxiv. 2023 Nov 2:2023.10.31.565028. doi: 10.1101/2023.10.31.565028. Preprint. PMID- 37463580 OWN - NLM STAT- MEDLINE DCOM- 20231026 LR - 20231121 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 111 IP - 19 DP - 2023 Oct 4 TI - Synaptic and circuit functions of multitransmitter neurons in the mammalian brain. PG - 2969-2983 LID - S0896-6273(23)00438-5 [pii] LID - 10.1016/j.neuron.2023.06.003 [doi] AB - Neurons in the mammalian brain are not limited to releasing a single neurotransmitter but often release multiple neurotransmitters onto postsynaptic cells. Here, we review recent findings of multitransmitter neurons found throughout the mammalian central nervous system. We highlight recent technological innovations that have made the identification of new multitransmitter neurons and the study of their synaptic properties possible. We also focus on mechanisms and molecular constituents required for neurotransmitter corelease at the axon terminal and synaptic vesicle, as well as some possible functions of multitransmitter neurons in diverse brain circuits. We expect that these approaches will lead to new insights into the mechanism and function of multitransmitter neurons, their role in circuits, and their contribution to normal and pathological brain function. CI - Copyright © 2023 Elsevier Inc. All rights reserved. FAU - Wallace, Michael L AU - Wallace ML AD - Department of Anatomy and Neurobiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA. Electronic address: mlwall12@bu.edu. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. LA - eng GR - R00 NS105883/NS/NINDS NIH HHS/United States GR - R01 NS103226/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20230717 PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Neurotransmitter Agents) RN - 3KX376GY7L (Glutamic Acid) SB - IM MH - Animals MH - *Synaptic Transmission/physiology MH - *Neurons/physiology MH - Brain MH - Central Nervous System MH - Neurotransmitter Agents MH - Glutamic Acid MH - Mammals PMC - PMC10592565 MID - NIHMS1910420 OTO - NOTNLM OT - GABA OT - acetylcholine OT - co-packaging OT - corelease OT - cotransmission OT - dopamine OT - glutamate OT - multitransmitter OT - serotonin COIS- Declaration of interests The authors declare no competing interests. EDAT- 2023/07/19 01:06 MHDA- 2023/10/26 06:42 PMCR- 2024/10/04 CRDT- 2023/07/18 18:41 PHST- 2023/04/18 00:00 [received] PHST- 2023/05/31 00:00 [revised] PHST- 2023/06/08 00:00 [accepted] PHST- 2024/10/04 00:00 [pmc-release] PHST- 2023/10/26 06:42 [medline] PHST- 2023/07/19 01:06 [pubmed] PHST- 2023/07/18 18:41 [entrez] AID - S0896-6273(23)00438-5 [pii] AID - 10.1016/j.neuron.2023.06.003 [doi] PST - ppublish SO - Neuron. 2023 Oct 4;111(19):2969-2983. doi: 10.1016/j.neuron.2023.06.003. Epub 2023 Jul 17. PMID- 37557915 OWN - NLM STAT- MEDLINE DCOM- 20230925 LR - 20231208 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 621 IP - 7979 DP - 2023 Sep TI - Dopamine and glutamate regulate striatal acetylcholine in decision-making. PG - 577-585 LID - 10.1038/s41586-023-06492-9 [doi] AB - Striatal dopamine and acetylcholine are essential for the selection and reinforcement of motor actions and decision-making(1). In vitro studies have revealed an intrastriatal circuit in which acetylcholine, released by cholinergic interneurons (CINs), drives the release of dopamine, and dopamine, in turn, inhibits the activity of CINs through dopamine D2 receptors (D2Rs). Whether and how this circuit contributes to striatal function in vivo is largely unknown. Here, to define the role of this circuit in a living system, we monitored acetylcholine and dopamine signals in the ventrolateral striatum of mice performing a reward-based decision-making task. We establish that dopamine and acetylcholine exhibit multiphasic and anticorrelated transients that are modulated by decision history and reward outcome. Dopamine dynamics and reward encoding do not require the release of acetylcholine by CINs. However, dopamine inhibits acetylcholine transients in a D2R-dependent manner, and loss of this regulation impairs decision-making. To determine how other striatal inputs shape acetylcholine signals, we assessed the contribution of cortical and thalamic projections, and found that glutamate release from both sources is required for acetylcholine release. Altogether, we uncover a dynamic relationship between dopamine and acetylcholine during decision-making, and reveal multiple modes of CIN regulation. These findings deepen our understanding of the neurochemical basis of decision-making and behaviour. CI - © 2023. The Author(s). FAU - Chantranupong, Lynne AU - Chantranupong L AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, USA. FAU - Beron, Celia C AU - Beron CC AUID- ORCID: 0000-0003-4289-253X AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, USA. FAU - Zimmer, Joshua A AU - Zimmer JA AUID- ORCID: 0000-0003-4331-9831 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, USA. FAU - Wen, Michelle J AU - Wen MJ AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, USA. FAU - Wang, Wengang AU - Wang W AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, USA. bsabatini@hms.harvard.edu. LA - eng PT - Journal Article DEP - 20230809 PL - England TA - Nature JT - Nature JID - 0410462 RN - N9YNS0M02X (Acetylcholine) RN - VTD58H1Z2X (Dopamine) RN - 3KX376GY7L (Glutamic Acid) RN - 0 (Receptors, Dopamine D2) SB - IM MH - Animals MH - Mice MH - *Acetylcholine/metabolism MH - *Corpus Striatum/cytology/metabolism MH - *Dopamine/metabolism MH - *Glutamic Acid/metabolism MH - Neostriatum/cytology/metabolism MH - *Decision Making/physiology MH - Reward MH - Receptors, Dopamine D2/metabolism MH - Cholinergic Neurons/metabolism MH - Neural Pathways PMC - PMC10511323 COIS- The authors declare no competing interests. EDAT- 2023/08/10 00:42 MHDA- 2023/09/22 06:42 CRDT- 2023/08/09 19:13 PHST- 2022/09/09 00:00 [received] PHST- 2023/07/28 00:00 [accepted] PHST- 2023/09/22 06:42 [medline] PHST- 2023/08/10 00:42 [pubmed] PHST- 2023/08/09 19:13 [entrez] AID - 10.1038/s41586-023-06492-9 [pii] AID - 6492 [pii] AID - 10.1038/s41586-023-06492-9 [doi] PST - ppublish SO - Nature. 2023 Sep;621(7979):577-585. doi: 10.1038/s41586-023-06492-9. Epub 2023 Aug 9. PMID- 37609206 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230823 DP - 2023 Aug 10 TI - Thyroid hormone rewires cortical circuits to coordinate body-wide metabolism and exploratory drive. LID - 2023.08.10.552874 [pii] LID - 10.1101/2023.08.10.552874 [doi] AB - Animals adapt to varying environmental conditions by modifying the function of their internal organs, including the brain. To be adaptive, alterations in behavior must be coordinated with the functional state of organs throughout the body. Here we find that thyroid hormone- a prominent regulator of metabolism in many peripheral organs- activates cell-type specific transcriptional programs in anterior regions of cortex of adult mice via direct activation of thyroid hormone receptors. These programs are enriched for axon-guidance genes in glutamatergic projection neurons, synaptic regulators across both astrocytes and neurons, and pro-myelination factors in oligodendrocytes, suggesting widespread remodeling of cortical circuits. Indeed, whole-cell electrophysiology recordings revealed that thyroid hormone induces local transcriptional programs that rewire cortical neural circuits via pre-synaptic mechanisms, resulting in increased excitatory drive with a concomitant sensitization of recruited inhibition. We find that thyroid hormone bidirectionally regulates innate exploratory behaviors and that the transcriptionally mediated circuit changes in anterior cortex causally promote exploratory decision-making. Thus, thyroid hormone acts directly on adult cerebral cortex to coordinate exploratory behaviors with whole-body metabolic state. FAU - Hochbaum, Daniel R AU - Hochbaum DR AUID- ORCID: 0000-0001-6220-6651 FAU - Dubinsky, Alexandra C AU - Dubinsky AC FAU - Farnsworth, Hannah C AU - Farnsworth HC FAU - Hulshof, Lauren AU - Hulshof L FAU - Kleinberg, Giona AU - Kleinberg G FAU - Urke, Amanda AU - Urke A FAU - Wang, Wengang AU - Wang W FAU - Hakim, Richard AU - Hakim R FAU - Robertson, Keira AU - Robertson K FAU - Park, Canaria AU - Park C FAU - Solberg, Alyssa AU - Solberg A FAU - Yang, Yechan AU - Yang Y FAU - Baynard, Caroline AU - Baynard C FAU - Nadaf, Naeem M AU - Nadaf NM FAU - Beron, Celia C AU - Beron CC FAU - Girasole, Allison E AU - Girasole AE FAU - Chantranupong, Lynne AU - Chantranupong L FAU - Cortopassi, Marissa AU - Cortopassi M FAU - Prouty, Shannon AU - Prouty S FAU - Geistlinger, Ludwig AU - Geistlinger L FAU - Banks, Alexander AU - Banks A FAU - Scanlan, Thomas AU - Scanlan T FAU - Greenberg, Michael E AU - Greenberg ME FAU - Boulting, Gabriella L AU - Boulting GL FAU - Macosko, Evan Z AU - Macosko EZ AUID- ORCID: 0000-0002-2794-5165 FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng PT - Preprint DEP - 20230810 PL - United States TA - bioRxiv JT - bioRxiv : the preprint server for biology JID - 101680187 PMC - PMC10441422 EDAT- 2023/08/23 06:42 MHDA- 2023/08/23 06:43 CRDT- 2023/08/23 04:07 PHST- 2023/08/23 06:43 [medline] PHST- 2023/08/23 06:42 [pubmed] PHST- 2023/08/23 04:07 [entrez] AID - 2023.08.10.552874 [pii] AID - 10.1101/2023.08.10.552874 [doi] PST - epublish SO - bioRxiv. 2023 Aug 10:2023.08.10.552874. doi: 10.1101/2023.08.10.552874. Preprint. PMID- 37035505 OWN - NLM STAT- MEDLINE DCOM- 20230411 LR - 20230524 IS - 1662-5110 (Electronic) IS - 1662-5110 (Linking) VI - 17 DP - 2023 TI - Developmental regulation of GABAergic gene expression in forebrain cholinergic neurons. PG - 1125071 LID - 10.3389/fncir.2023.1125071 [doi] LID - 1125071 AB - Acetylcholine and GABA are often co-released, including from VIP-expressing neurons of the cortex, cortically-projecting neurons of the globus pallidus externus and basal forebrain, and hippocampal-projecting neurons of the medial septum. The co-release of the functionally antagonistic neurotransmitters GABA and acetylcholine (ACh) greatly expands the possible functional effects of cholinergic neurons and provides an additional exogenous source of inhibition to the cortex. Transgene expression suggests that nearly all forebrain cholinergic neurons in mice at some point in development express Slc32a1, which encodes the vesicular GABA transporter (VGAT). To determine the degree of co-expression of GABA and Ach handling proteins, we measured expression in adult mice of Slc32a1, Gad1 and Gad2 (which encode GAD67 and GAD65, respectively, the GABA synthetic enzymes) in cholinergic neurons using fluorescent in situ hybridization. We found that only a subset of cholinergic neurons express the necessary machinery for GABA release at a single time in adult mice. This suggests that GABA co-release from cholinergic neurons is dynamic and potentially developmentally regulated. By measuring expression of Slc32a1, Gad1, Gad2, and Chat in the basal forebrain and medial septum in mice from post-natal day 0 to 28, we noted abundant yet variable expressions of GABAergic markers across early development, which are subsequently downregulated in adulthood. This is in contrast with the forebrain-projecting pedunculopontine nucleus, which showed no evidence of co-expression of GABAergic genes. These results suggest that expression of GABA signaling machinery in the cortically-projecting cholinergic system peaks during early development before settling at a non-zero level that is maintained through adulthood. CI - Copyright © 2023 Granger, Mao, Saulnier, Hines and Sabatini. FAU - Granger, Adam J AU - Granger AJ AD - Department of Neurobiology, Harvard Medical School, Boston, MA, United States. FAU - Mao, Karen AU - Mao K AD - Department of Neurobiology, Harvard Medical School, Boston, MA, United States. FAU - Saulnier, Jessica L AU - Saulnier JL AD - Department of Neurobiology, Harvard Medical School, Boston, MA, United States. FAU - Hines, Morgan E AU - Hines ME AD - Department of Neurobiology, Harvard Medical School, Boston, MA, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Harvard Medical School, Boston, MA, United States. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - K99 NS102429/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230324 PL - Switzerland TA - Front Neural Circuits JT - Frontiers in neural circuits JID - 101477940 RN - N9YNS0M02X (Acetylcholine) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - EC 2.3.1.6 (Choline O-Acetyltransferase) SB - IM MH - Mice MH - Animals MH - *Acetylcholine/metabolism MH - In Situ Hybridization, Fluorescence MH - *gamma-Aminobutyric Acid MH - Cholinergic Neurons/physiology MH - Cerebral Cortex/metabolism MH - Gene Expression MH - Choline O-Acetyltransferase/metabolism PMC - PMC10080005 OTO - NOTNLM OT - GABA OT - GABAergic transmission OT - acetylcholine OT - cholinergic transmission OT - neurotransmitter co-transmission COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/04/11 06:00 MHDA- 2023/04/11 06:42 CRDT- 2023/04/10 04:22 PHST- 2022/12/15 00:00 [received] PHST- 2023/03/06 00:00 [accepted] PHST- 2023/04/11 06:42 [medline] PHST- 2023/04/10 04:22 [entrez] PHST- 2023/04/11 06:00 [pubmed] AID - 10.3389/fncir.2023.1125071 [doi] PST - epublish SO - Front Neural Circuits. 2023 Mar 24;17:1125071. doi: 10.3389/fncir.2023.1125071. eCollection 2023. PMID- 36993428 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231019 DP - 2023 Mar 13 TI - Sub-clinical triiodothyronine levels predict health, demographic, and socioeconomic outcomes. LID - 2023.03.09.531775 [pii] LID - 10.1101/2023.03.09.531775 [doi] AB - The Hypothalamic-Pituitary-Thyroid (HPT) axis is fundamental to human biology, exerting central control over energy expenditure, metabolic rate, and body temperature. However, the consequences of "normal" physiologic HPT-axis variation in non-clinical populations are poorly understood. Using nationally-representative data from the 2007-2012 NHANES, we explore relationships with demographics, mortality, and socio-economic factors. We find much larger variation across age in free T3 than other HPT-axis hormones. T3 and T4 have opposite effects on mortality: free T3 is inversely related and free T4 is positively related with likelihood of death. Free T3 and household income are negatively related, particularly at lower incomes. Finally, free T3 among older adults is associated with labor both on the extensive margin (unemployment) and intensive margin (hours worked). Physiologic TSH/T4 explain only 1% of T3 variation, and neither are appreciably correlated to socio-economic outcomes. Taken together, our data suggest an unappreciated complexity and non-linearity of the HPT-axis signaling cascade broadly such that TSH and T4 may not be accurate surrogates of free T3. Furthermore, we find that sub-clinical variation in the HPT-axis effector hormone T3 is an important and overlooked factor linking socio-economic forces, human biology, and aging. FAU - Lawton, Ralph I AU - Lawton RI AD - Harvard Medical School, Boston, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Harvard Medical School, Boston, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. AD - Howard Hughes Medical Institute, Chevy Chase, MD, USA. FAU - Hochbaum, Daniel R AU - Hochbaum DR AD - Harvard Medical School, Boston, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. LA - eng PT - Preprint DEP - 20230313 PL - United States TA - bioRxiv JT - bioRxiv : the preprint server for biology JID - 101680187 PMC - PMC10054950 EDAT- 2023/03/31 06:00 MHDA- 2023/03/31 06:01 CRDT- 2023/03/30 02:52 PHST- 2023/03/31 06:00 [pubmed] PHST- 2023/03/31 06:01 [medline] PHST- 2023/03/30 02:52 [entrez] AID - 2023.03.09.531775 [pii] AID - 10.1101/2023.03.09.531775 [doi] PST - epublish SO - bioRxiv. 2023 Mar 13:2023.03.09.531775. doi: 10.1101/2023.03.09.531775. Preprint. PMID- 36792830 OWN - NLM STAT- MEDLINE DCOM- 20230225 LR - 20230524 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 614 IP - 7949 DP - 2023 Feb TI - A NPAS4-NuA4 complex couples synaptic activity to DNA repair. PG - 732-741 LID - 10.1038/s41586-023-05711-7 [doi] AB - Neuronal activity is crucial for adaptive circuit remodelling but poses an inherent risk to the stability of the genome across the long lifespan of postmitotic neurons(1-5). Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is unknown. Here we identify an activity-dependent DNA repair mechanism in which a new form of the NuA4-TIP60 chromatin modifier assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex from the brain and demonstrate its functions in eliciting activity-dependent changes to neuronal transcriptomes and circuitry. By characterizing the landscape of activity-induced DNA double-strand breaks in the brain, we show that NPAS4-NuA4 binds to recurrently damaged regulatory elements and recruits additional DNA repair machinery to stimulate their repair. Gene regulatory elements bound by NPAS4-NuA4 are partially protected against age-dependent accumulation of somatic mutations. Impaired NPAS4-NuA4 signalling leads to a cascade of cellular defects, including dysregulated activity-dependent transcriptional responses, loss of control over neuronal inhibition and genome instability, which all culminate to reduce organismal lifespan. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental and autism spectrum disorders. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation, the disruption of which may contribute to developmental disorders, neurodegeneration and ageing. CI - © 2023. The Author(s). FAU - Pollina, Elizabeth A AU - Pollina EA AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. AD - Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA. FAU - Gilliam, Daniel T AU - Gilliam DT AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Landau, Andrew T AU - Landau AT AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. FAU - Lin, Cindy AU - Lin C AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Pajarillo, Naomi AU - Pajarillo N AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Davis, Christopher P AU - Davis CP AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Harmin, David A AU - Harmin DA AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Yap, Ee-Lynn AU - Yap EL AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Vogel, Ian R AU - Vogel IR AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Griffith, Eric C AU - Griffith EC AUID- ORCID: 0000-0003-0428-3215 AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Nagy, M Aurel AU - Nagy MA AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Ling, Emi AU - Ling E AUID- ORCID: 0000-0001-5287-0284 AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Duffy, Erin E AU - Duffy EE AUID- ORCID: 0000-0002-7519-5098 AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. FAU - Weitz, Charles J AU - Weitz CJ AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Greenberg, Michael E AU - Greenberg ME AUID- ORCID: 0000-0003-1380-2160 AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. meg@hms.harvard.edu. LA - eng GR - T32 GM007753/GM/NIGMS NIH HHS/United States GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - T32 NS007473/NS/NINDS NIH HHS/United States GR - K99 AG064042/AG/NIA NIH HHS/United States GR - F32 NS112455/NS/NINDS NIH HHS/United States GR - R01 NS028829/NS/NINDS NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230215 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Basic Helix-Loop-Helix Transcription Factors) RN - EC 2.3.1.48 (Lysine Acetyltransferase 5) RN - 0 (Multiprotein Complexes) SB - IM CIN - Mol Cell. 2023 Apr 20;83(8):1208-1209. PMID: 37084713 MH - Basic Helix-Loop-Helix Transcription Factors MH - *Brain/metabolism MH - DNA Breaks, Double-Stranded MH - *DNA Repair MH - Gene Expression Regulation MH - Lysine Acetyltransferase 5/metabolism MH - *Multiprotein Complexes/metabolism MH - *Neurons/metabolism MH - *Synapses/metabolism MH - Mutation MH - Longevity/genetics MH - Genome MH - Aging/genetics MH - Neurodegenerative Diseases PMC - PMC9946837 COIS- The authors declare no competing interests. EDAT- 2023/02/16 06:00 MHDA- 2023/02/25 06:00 CRDT- 2023/02/15 23:29 PHST- 2021/05/28 00:00 [received] PHST- 2023/01/05 00:00 [accepted] PHST- 2023/02/16 06:00 [pubmed] PHST- 2023/02/25 06:00 [medline] PHST- 2023/02/15 23:29 [entrez] AID - 10.1038/s41586-023-05711-7 [pii] AID - 5711 [pii] AID - 10.1038/s41586-023-05711-7 [doi] PST - ppublish SO - Nature. 2023 Feb;614(7949):732-741. doi: 10.1038/s41586-023-05711-7. Epub 2023 Feb 15. PMID- 36653449 OWN - NLM STAT- MEDLINE DCOM- 20230217 LR - 20230524 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 614 IP - 7946 DP - 2023 Feb TI - Spontaneous behaviour is structured by reinforcement without explicit reward. PG - 108-117 LID - 10.1038/s41586-022-05611-2 [doi] AB - Spontaneous animal behaviour is built from action modules that are concatenated by the brain into sequences(1,2). However, the neural mechanisms that guide the composition of naturalistic, self-motivated behaviour remain unknown. Here we show that dopamine systematically fluctuates in the dorsolateral striatum (DLS) as mice spontaneously express sub-second behavioural modules, despite the absence of task structure, sensory cues or exogenous reward. Photometric recordings and calibrated closed-loop optogenetic manipulations during open field behaviour demonstrate that DLS dopamine fluctuations increase sequence variation over seconds, reinforce the use of associated behavioural modules over minutes, and modulate the vigour with which modules are expressed, without directly influencing movement initiation or moment-to-moment kinematics. Although the reinforcing effects of optogenetic DLS dopamine manipulations vary across behavioural modules and individual mice, these differences are well predicted by observed variation in the relationships between endogenous dopamine and module use. Consistent with the possibility that DLS dopamine fluctuations act as a teaching signal, mice build sequences during exploration as if to maximize dopamine. Together, these findings suggest a model in which the same circuits and computations that govern action choices in structured tasks have a key role in sculpting the content of unconstrained, high-dimensional, spontaneous behaviour. CI - © 2023. The Author(s). FAU - Markowitz, Jeffrey E AU - Markowitz JE AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. AD - Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA. FAU - Gillis, Winthrop F AU - Gillis WF AUID- ORCID: 0000-0002-1659-8639 AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Jay, Maya AU - Jay M AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Wood, Jeffrey AU - Wood J AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Harris, Ryley W AU - Harris RW AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Cieszkowski, Robert AU - Cieszkowski R AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Scott, Rebecca AU - Scott R AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Brann, David AU - Brann D AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Koveal, Dorothy AU - Koveal D AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Kula, Tomasz AU - Kula T AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Weinreb, Caleb AU - Weinreb C AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Osman, Mohammed Abdal Monium AU - Osman MAM AUID- ORCID: 0000-0001-8606-6518 AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Pinto, Sandra Romero AU - Pinto SR AD - Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA. AD - Center for Brain Science, Harvard University, Cambridge, MA, USA. FAU - Uchida, Naoshige AU - Uchida N AUID- ORCID: 0000-0002-5755-9409 AD - Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA. AD - Center for Brain Science, Harvard University, Cambridge, MA, USA. FAU - Linderman, Scott W AU - Linderman SW AD - Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. AD - Department of Statistics, Stanford University, Stanford, CA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. AD - Howard Hughes Medical Institute, Chevy Chase, MD, USA. FAU - Datta, Sandeep Robert AU - Datta SR AUID- ORCID: 0000-0002-8068-3862 AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. Srdatta@hms.harvard.edu. LA - eng GR - F31 NS122155/NS/NINDS NIH HHS/United States GR - P30 EY026877/EY/NEI NIH HHS/United States GR - F31 NS113385/NS/NINDS NIH HHS/United States GR - P50 HD105351/HD/NICHD NIH HHS/United States GR - U19 NS113201/NS/NINDS NIH HHS/United States GR - P30 EY012196/EY/NEI NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - R01 NS114020/NS/NINDS NIH HHS/United States GR - RF1 AG073625/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230118 PL - England TA - Nature JT - Nature JID - 0410462 RN - VTD58H1Z2X (Dopamine) SB - IM CIN - Nature. 2023 Feb;614(7946):36-37. PMID: 36653602 MH - Animals MH - Mice MH - Corpus Striatum/metabolism MH - Dopamine/metabolism MH - *Reinforcement, Psychology MH - *Reward MH - *Behavior, Animal MH - Cues MH - Optogenetics MH - Photometry PMC - PMC9892006 COIS- S.R.D. sits on the scientific advisory boards of Neumora and Gilgamesh Therapeutics, which have licensed or sub-licensed the MoSeq technology. EDAT- 2023/01/19 06:00 MHDA- 2023/02/04 06:00 CRDT- 2023/01/18 23:19 PHST- 2022/04/20 00:00 [received] PHST- 2022/11/30 00:00 [accepted] PHST- 2023/01/19 06:00 [pubmed] PHST- 2023/02/04 06:00 [medline] PHST- 2023/01/18 23:19 [entrez] AID - 10.1038/s41586-022-05611-2 [pii] AID - 5611 [pii] AID - 10.1038/s41586-022-05611-2 [doi] PST - ppublish SO - Nature. 2023 Feb;614(7946):108-117. doi: 10.1038/s41586-022-05611-2. Epub 2023 Jan 18. PMID- 36711554 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230202 DP - 2023 Jan 20 TI - Neuronal-Activity Dependent Mechanisms of Small Cell Lung Cancer Progression. LID - 2023.01.19.524430 [pii] LID - 10.1101/2023.01.19.524430 [doi] AB - Neural activity is increasingly recognized as a critical regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth both through paracrine mechanisms and through electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses, while perisynaptic neurotransmitter signaling drives breast cancer brain metastasis growth. Outside of the CNS, innervation of tumors such as prostate, breast, pancreatic and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression. However, the extent to which the nervous system regulates lung cancer progression, either in the lung or when metastatic to brain, is largely unexplored. Small cell lung cancer (SCLC) is a lethal high-grade neuroendocrine tumor that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that, similar to glioma, metastatic SCLC cells in the brain co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Optogenetic stimulation of cortical neuronal activity drives proliferation and invasion of SCLC brain metastases. In the brain, SCLC cells exhibit electrical currents and consequent calcium transients in response to neuronal activity, and direct SCLC cell membrane depolarization is sufficient to promote the growth of SCLC tumors. In the lung, vagus nerve transection markedly inhibits primary lung tumor formation, progression and metastasis, highlighting a critical role for innervation in overall SCLC initiation and progression. Taken together, these studies illustrate that neuronal activity plays a crucial role in dictating SCLC pathogenesis in both primary and metastatic sites. FAU - Savchuk, Solomiia AU - Savchuk S FAU - Gentry, Kaylee AU - Gentry K FAU - Wang, Wengang AU - Wang W FAU - Carleton, Elana AU - Carleton E FAU - Yalçın, Belgin AU - Yalçın B FAU - Liu, Yin AU - Liu Y FAU - Pavarino, Elisa C AU - Pavarino EC FAU - LaBelle, Jenna AU - LaBelle J FAU - Toland, Angus M AU - Toland AM FAU - Woo, Pamelyn J AU - Woo PJ FAU - Qu, Fangfei AU - Qu F FAU - Filbin, Mariella G AU - Filbin MG FAU - Krasnow, Mark A AU - Krasnow MA FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Sage, Julien AU - Sage J FAU - Monje, Michelle AU - Monje M FAU - Venkatesh, Humsa S AU - Venkatesh HS LA - eng PT - Preprint DEP - 20230120 PL - United States TA - bioRxiv JT - bioRxiv : the preprint server for biology JID - 101680187 PMC - PMC9882339 EDAT- 2023/01/31 06:00 MHDA- 2023/01/31 06:01 CRDT- 2023/01/30 03:55 PHST- 2023/01/30 03:55 [entrez] PHST- 2023/01/31 06:00 [pubmed] PHST- 2023/01/31 06:01 [medline] AID - 2023.01.19.524430 [pii] AID - 10.1101/2023.01.19.524430 [doi] PST - epublish SO - bioRxiv. 2023 Jan 20:2023.01.19.524430. doi: 10.1101/2023.01.19.524430. Preprint. PMID- 36685083 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230524 IS - 1663-3563 (Print) IS - 1663-3563 (Electronic) IS - 1663-3563 (Linking) VI - 14 DP - 2022 TI - Analytical approaches to examine gamma-aminobutyric acid and glutamate vesicular co-packaging. PG - 1076616 LID - 10.3389/fnsyn.2022.1076616 [doi] LID - 1076616 AB - Multi-transmitter neurons, i.e., those that release more than one type of neurotransmitter, have been found in many organisms and brain areas. Given the peculiar biology of these cells, as well as the potential for diverse effects of each of the transmitters released, new tools, and approaches are necessary to parse the mechanisms and functions of synaptic co-transmission. Recently, we and others have studied neurons that project to the lateral habenula and release both gamma-aminobutyric acid (GABA) and glutamate, in some cases by packaging both transmitters in the same synaptic vesicles. Here, we discuss the main challenges with current electrophysiological approaches to studying the mechanisms of glutamate/GABA co-release, a novel statistical analysis that can identify co-packaging of neurotransmitters versus release from separate vesicle, and the implications of glutamate/GABA co-release for synapse function and plasticity. CI - Copyright © 2023 Kim and Sabatini. FAU - Kim, SeulAh AU - Kim S AD - Department of Neurobiology and Harvard Medical School, Howard Hughes Medical Institute, Boston, MA, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology and Harvard Medical School, Howard Hughes Medical Institute, Boston, MA, United States. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Review DEP - 20230104 PL - Switzerland TA - Front Synaptic Neurosci JT - Frontiers in synaptic neuroscience JID - 101548972 PMC - PMC9846491 OTO - NOTNLM OT - GABA OT - co-transmission OT - electrophysiology OT - glutamate OT - statistical analysis COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/01/24 06:00 MHDA- 2023/01/24 06:01 CRDT- 2023/01/23 04:31 PHST- 2022/10/21 00:00 [received] PHST- 2022/12/14 00:00 [accepted] PHST- 2023/01/23 04:31 [entrez] PHST- 2023/01/24 06:00 [pubmed] PHST- 2023/01/24 06:01 [medline] AID - 10.3389/fnsyn.2022.1076616 [doi] PST - epublish SO - Front Synaptic Neurosci. 2023 Jan 4;14:1076616. doi: 10.3389/fnsyn.2022.1076616. eCollection 2022. PMID- 36384944 OWN - NLM STAT- MEDLINE DCOM- 20221121 LR - 20230524 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 13 IP - 1 DP - 2022 Nov 16 TI - Ascertaining cells' synaptic connections and RNA expression simultaneously with barcoded rabies virus libraries. PG - 6993 LID - 10.1038/s41467-022-34334-1 [doi] LID - 6993 AB - Brain function depends on synaptic connections between specific neuron types, yet systematic descriptions of synaptic networks and their molecular properties are not readily available. Here, we introduce SBARRO (Synaptic Barcode Analysis by Retrograde Rabies ReadOut), a method that uses single-cell RNA sequencing to reveal directional, monosynaptic relationships based on the paths of a barcoded rabies virus from its "starter" postsynaptic cell to that cell's presynaptic partners. Thousands of these partner relationships can be ascertained in a single experiment, alongside genome-wide RNAs. We use SBARRO to describe synaptic networks formed by diverse mouse brain cell types in vitro, finding that different cell types have presynaptic networks with differences in average size and cell type composition. Patterns of RNA expression suggest that functioning synapses are critical for rabies virus uptake. By tracking individual rabies clones across cells, SBARRO offers new opportunities to map the synaptic organization of neural circuits. CI - © 2022. The Author(s). FAU - Saunders, Arpiar AU - Saunders A AUID- ORCID: 0000-0001-7540-7452 AD - Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. saundear@ohsu.edu. AD - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. saundear@ohsu.edu. AD - Vollum Institute, Oregon Health & Science University, Portland, OR, 97239, USA. saundear@ohsu.edu. FAU - Huang, Kee Wui AU - Huang KW AUID- ORCID: 0000-0003-2265-4550 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA. FAU - Vondrak, Cassandra AU - Vondrak C AUID- ORCID: 0000-0003-0774-5200 AD - Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. AD - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. FAU - Hughes, Christina AU - Hughes C AD - Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. AD - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. FAU - Smolyar, Karina AU - Smolyar K AD - Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. AD - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. FAU - Sen, Harsha AU - Sen H AUID- ORCID: 0000-0003-2267-7963 AD - Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. AD - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. FAU - Philson, Adrienne C AU - Philson AC AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA. FAU - Nemesh, James AU - Nemesh J AD - Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. AD - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. FAU - Wysoker, Alec AU - Wysoker A AD - Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. AD - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. FAU - Kashin, Seva AU - Kashin S AD - Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. AD - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA. FAU - McCarroll, Steven A AU - McCarroll SA AUID- ORCID: 0000-0002-6954-8184 AD - Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. mccarroll@genetics.med.harvard.edu. AD - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. mccarroll@genetics.med.harvard.edu. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221116 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 63231-63-0 (RNA) SB - IM MH - Mice MH - Animals MH - *Rabies virus/genetics MH - *Rabies MH - Synapses/physiology MH - Neurons/physiology MH - RNA PMC - PMC9668842 COIS- A.S. and S.A.M. are listed as inventors on a patent application related to the work. The remaining authors declare no competing interests. EDAT- 2022/11/18 06:00 MHDA- 2022/11/22 06:00 CRDT- 2022/11/17 10:07 PHST- 2021/10/26 00:00 [received] PHST- 2022/10/21 00:00 [accepted] PHST- 2022/11/17 10:07 [entrez] PHST- 2022/11/18 06:00 [pubmed] PHST- 2022/11/22 06:00 [medline] AID - 10.1038/s41467-022-34334-1 [pii] AID - 34334 [pii] AID - 10.1038/s41467-022-34334-1 [doi] PST - epublish SO - Nat Commun. 2022 Nov 16;13(1):6993. doi: 10.1038/s41467-022-34334-1. PMID- 36205477 OWN - NLM STAT- MEDLINE DCOM- 20221011 LR - 20221104 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 11 DP - 2022 Oct 7 TI - A single-cell atlas of the cycling murine ovary. LID - 10.7554/eLife.77239 [doi] LID - e77239 AB - The estrous cycle is regulated by rhythmic endocrine interactions of the nervous and reproductive systems, which coordinate the hormonal and ovulatory functions of the ovary. Folliculogenesis and follicle progression require the orchestrated response of a variety of cell types to allow the maturation of the follicle and its sequela, ovulation, corpus luteum formation, and ovulatory wound repair. Little is known about the cell state dynamics of the ovary during the estrous cycle and the paracrine factors that help coordinate this process. Herein, we used single-cell RNA sequencing to evaluate the transcriptome of >34,000 cells of the adult mouse ovary and describe the transcriptional changes that occur across the normal estrous cycle and other reproductive states to build a comprehensive dynamic atlas of murine ovarian cell types and states. CI - © 2022, Morris, Meinsohn et al. FAU - Morris, Mary E AU - Morris ME AD - Department of Gynecology and Reproductive Biology, Massachusetts General Hospital, Boston, United States. FAU - Meinsohn, Marie-Charlotte AU - Meinsohn MC AUID- ORCID: 0000-0002-1378-4655 AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States. AD - Department of Surgery, Harvard Medical School, Boston, United States. FAU - Chauvin, Maeva AU - Chauvin M AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States. AD - Department of Surgery, Harvard Medical School, Boston, United States. FAU - Saatcioglu, Hatice D AU - Saatcioglu HD AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States. AD - Department of Surgery, Harvard Medical School, Boston, United States. FAU - Kashiwagi, Aki AU - Kashiwagi A AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States. AD - Department of Surgery, Harvard Medical School, Boston, United States. FAU - Sicher, Natalie A AU - Sicher NA AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States. AD - Department of Surgery, Harvard Medical School, Boston, United States. FAU - Nguyen, Ngoc AU - Nguyen N AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States. AD - Department of Surgery, Harvard Medical School, Boston, United States. FAU - Yuan, Selena AU - Yuan S AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States. AD - Department of Surgery, Harvard Medical School, Boston, United States. FAU - Stavely, Rhian AU - Stavely R AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States. AD - Department of Surgery, Harvard Medical School, Boston, United States. FAU - Hyun, Minsuk AU - Hyun M AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Donahoe, Patricia K AU - Donahoe PK AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States. AD - Department of Surgery, Harvard Medical School, Boston, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Pépin, David AU - Pépin D AUID- ORCID: 0000-0003-2046-6708 AD - Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States. AD - Department of Surgery, Harvard Medical School, Boston, United States. LA - eng GR - R01 HD102014/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20221007 PL - England TA - Elife JT - eLife JID - 101579614 SB - IM MH - Animals MH - Estrous Cycle/physiology MH - Female MH - Mice MH - Ovarian Follicle/physiology MH - *Ovary MH - *Ovulation/physiology MH - Pelvis PMC - PMC9545525 OTO - NOTNLM OT - developmental biology OT - estrous cycle OT - mouse OT - ovary OT - single-cell RNA sequencing COIS- MM, MM, MC, HS, AK, NS, NN, SY, RS, MH, PD, BS, DP No competing interests declared EDAT- 2022/10/08 06:00 MHDA- 2022/10/12 06:00 CRDT- 2022/10/07 08:52 PHST- 2022/01/20 00:00 [received] PHST- 2022/09/12 00:00 [accepted] PHST- 2022/10/07 08:52 [entrez] PHST- 2022/10/08 06:00 [pubmed] PHST- 2022/10/12 06:00 [medline] AID - 77239 [pii] AID - 10.7554/eLife.77239 [doi] PST - epublish SO - Elife. 2022 Oct 7;11:e77239. doi: 10.7554/eLife.77239. PMID- 36137999 OWN - NLM STAT- MEDLINE DCOM- 20220926 LR - 20230524 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 13 IP - 1 DP - 2022 Sep 22 TI - Wireless multi-lateral optofluidic microsystems for real-time programmable optogenetics and photopharmacology. PG - 5571 LID - 10.1038/s41467-022-32947-0 [doi] LID - 5571 AB - In vivo optogenetics and photopharmacology are two techniques for controlling neuronal activity that have immense potential in neuroscience research. Their applications in tether-free groups of animals have been limited in part due to tools availability. Here, we present a wireless, battery-free, programable multilateral optofluidic platform with user-selected modalities for optogenetics, pharmacology and photopharmacology. This system features mechanically compliant microfluidic and electronic interconnects, capabilities for dynamic control over the rates of drug delivery and real-time programmability, simultaneously for up to 256 separate devices in a single cage environment. Our behavioral experiments demonstrate control of motor behaviors in grouped mice through in vivo optogenetics with co-located gene delivery and controlled photolysis of caged glutamate. These optofluidic systems may expand the scope of wireless techniques to study neural processing in animal models. CI - © 2022. The Author(s). FAU - Wu, Yixin AU - Wu Y AUID- ORCID: 0000-0002-6315-4694 AD - Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA. AD - Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA. AD - Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL, USA. FAU - Wu, Mingzheng AU - Wu M AUID- ORCID: 0000-0003-4415-6296 AD - Department of Neurobiology, Northwestern University, Evanston, IL, USA. FAU - Vázquez-Guardado, Abraham AU - Vázquez-Guardado A AUID- ORCID: 0000-0002-0648-5921 AD - Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA. AD - Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL, USA. FAU - Kim, Joohee AU - Kim J AD - Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA. AD - Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL, USA. AD - Center for Bionics of Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea. FAU - Zhang, Xin AU - Zhang X AD - Department of Neurobiology, Northwestern University, Evanston, IL, USA. FAU - Avila, Raudel AU - Avila R AD - Department of Mechanical Engineering, Northwestern University, Evanston, IL, USA. FAU - Kim, Jin-Tae AU - Kim JT AUID- ORCID: 0000-0001-9933-1931 AD - Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA. AD - Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL, USA. FAU - Deng, Yujun AU - Deng Y AD - Department of Mechanical Engineering, Northwestern University, Evanston, IL, USA. AD - State Key Laboratory of Mechanical System and Vibration, Shanghai Jiao Tong University, Shanghai, China. FAU - Yu, Yongjoon AU - Yu Y AD - Neurolux Inc, Northfield, IL, USA. FAU - Melzer, Sarah AU - Melzer S AUID- ORCID: 0000-0001-6028-9764 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Ave, Boston, MA, 02115, USA. FAU - Bai, Yun AU - Bai Y AD - Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA. AD - Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA. AD - Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL, USA. FAU - Yoon, Hyoseo AU - Yoon H AUID- ORCID: 0000-0001-9263-4948 AD - Department of Neurobiology, Northwestern University, Evanston, IL, USA. FAU - Meng, Lingzi AU - Meng L AD - Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA. AD - Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA. AD - Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL, USA. FAU - Zhang, Yi AU - Zhang Y AD - Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT, 06269, US. AD - Department of Biomedical Engineering, University of Connecticut, Storrs, CT, 06269, US. FAU - Guo, Hexia AU - Guo H AUID- ORCID: 0000-0002-7904-9135 AD - Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA. AD - Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA. AD - Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL, USA. FAU - Hong, Liu AU - Hong L AD - Mechanical Science and Engineering Department, University of Illinois, Urbana, IL, USA. FAU - Kanatzidis, Evangelos E AU - Kanatzidis EE AUID- ORCID: 0000-0001-7803-9958 AD - Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA. AD - Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL, USA. AD - Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA. FAU - Haney, Chad R AU - Haney CR AUID- ORCID: 0000-0001-5981-2925 AD - Center for Advanced Molecular Imaging, Radiology, and Biomedical Engineering, Northwestern University, Evanston, IL, 60208, USA. FAU - Waters, Emily A AU - Waters EA AUID- ORCID: 0000-0003-3479-6054 AD - Center for Advanced Molecular Imaging, Radiology, and Biomedical Engineering, Northwestern University, Evanston, IL, 60208, USA. FAU - Banks, Anthony R AU - Banks AR AD - Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA. AD - Neurolux Inc, Northfield, IL, USA. FAU - Hu, Ziying AU - Hu Z AD - Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA. AD - Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL, USA. FAU - Lie, Ferrona AU - Lie F AD - Neurolux Inc, Northfield, IL, USA. FAU - Chamorro, Leonardo P AU - Chamorro LP AUID- ORCID: 0000-0002-5199-424X AD - Mechanical Science and Engineering Department, University of Illinois, Urbana, IL, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Ave, Boston, MA, 02115, USA. FAU - Huang, Yonggang AU - Huang Y AUID- ORCID: 0000-0002-0483-8359 AD - Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA. y-huang@northwestern.edu. AD - Department of Mechanical Engineering, Northwestern University, Evanston, IL, USA. y-huang@northwestern.edu. AD - Department of Civil and Environmental Engineering, Northwestern University, Evanston, IL, USA. y-huang@northwestern.edu. FAU - Kozorovitskiy, Yevgenia AU - Kozorovitskiy Y AUID- ORCID: 0000-0002-3710-1484 AD - Department of Neurobiology, Northwestern University, Evanston, IL, USA. yevgenia.kozorovitskiy@northwestern.edu. AD - Chemistry of Life Processes Institutes, Northwestern University, Evanston, IL, USA. yevgenia.kozorovitskiy@northwestern.edu. FAU - Rogers, John A AU - Rogers JA AUID- ORCID: 0000-0002-2980-3961 AD - Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA. jrogers@northwestern.edu. AD - Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA. jrogers@northwestern.edu. AD - Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL, USA. jrogers@northwestern.edu. AD - Neurolux Inc, Northfield, IL, USA. jrogers@northwestern.edu. AD - Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA. jrogers@northwestern.edu. AD - Simpson Querrey Institute & Feinberg Medical School, Northwestern University, Evanston, IL, USA. jrogers@northwestern.edu. AD - Department of Chemistry, Northwestern University, Evanston, IL, USA. jrogers@northwestern.edu. AD - Department of Neurological Surgery, Northwestern University, Evanston, IL, USA. jrogers@northwestern.edu. AD - Department of Electrical and Computer Engineering, Northwestern University, Evanston, IL, USA. jrogers@northwestern.edu. AD - Department of Computer Science, Northwestern University, Evanston, IL, USA. jrogers@northwestern.edu. LA - eng GR - RF1 NS118287/NS/NINDS NIH HHS/United States GR - U01 NS113295/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - R01 MH117111/MH/NIMH NIH HHS/United States GR - R42 MH116525/MH/NIMH NIH HHS/United States GR - P30 CA060553/CA/NCI NIH HHS/United States GR - R01 NS107539/NS/NINDS NIH HHS/United States GR - R61 DA051489/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20220922 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (Glutamates) SB - IM MH - Animals MH - Brain/physiology MH - Glutamates MH - Mice MH - *Neurosciences MH - *Optogenetics/methods MH - Wireless Technology PMC - PMC9500026 COIS- J.A.R. and A.R.B. are founders in a company, Neurolux, Inc., that offers related technology products to the neuroscience community. The remaining authors declare no competing interests. EDAT- 2022/09/23 06:00 MHDA- 2022/09/28 06:00 CRDT- 2022/09/22 23:14 PHST- 2021/11/04 00:00 [received] PHST- 2022/08/24 00:00 [accepted] PHST- 2022/09/22 23:14 [entrez] PHST- 2022/09/23 06:00 [pubmed] PHST- 2022/09/28 06:00 [medline] AID - 10.1038/s41467-022-32947-0 [pii] AID - 32947 [pii] AID - 10.1038/s41467-022-32947-0 [doi] PST - epublish SO - Nat Commun. 2022 Sep 22;13(1):5571. doi: 10.1038/s41467-022-32947-0. PMID- 35945454 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231228 IS - 1546-1726 (Electronic) IS - 1097-6256 (Linking) VI - 25 IP - 9 DP - 2022 Sep TI - Publisher Correction: Viral manipulation of functionally distinct interneurons in mice, non-human primates and humans. PG - 1247 LID - 10.1038/s41593-022-01155-w [doi] FAU - Vormstein-Schneider, Douglas AU - Vormstein-Schneider D AUID- ORCID: 0000-0002-0345-2470 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Lin, Jessica D AU - Lin JD AUID- ORCID: 0000-0002-4093-0005 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Pelkey, Kenneth A AU - Pelkey KA AD - National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. FAU - Chittajallu, Ramesh AU - Chittajallu R AD - National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. FAU - Guo, Baolin AU - Guo B AUID- ORCID: 0000-0001-7309-5774 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Arias-Garcia, Mario A AU - Arias-Garcia MA AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Allaway, Kathryn AU - Allaway K AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. AD - NYU Langone Medical Center, New York University, New York, NY, USA. FAU - Sakopoulos, Sofia AU - Sakopoulos S AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Schneider, Gates AU - Schneider G AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Stevenson, Olivia AU - Stevenson O AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Vergara, Josselyn AU - Vergara J AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Sharma, Jitendra AU - Sharma J AD - McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA. FAU - Zhang, Qiangge AU - Zhang Q AD - McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA. FAU - Franken, Tom P AU - Franken TP AUID- ORCID: 0000-0001-7160-5152 AD - Systems Neurobiology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA, USA. FAU - Smith, Jared AU - Smith J AUID- ORCID: 0000-0002-0273-4898 AD - Systems Neurobiology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA, USA. FAU - Ibrahim, Leena A AU - Ibrahim LA AUID- ORCID: 0000-0001-8255-3423 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Mastro, Kevin J AU - Mastro KJ AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Sabri, Ehsan AU - Sabri E AD - Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA. FAU - Huang, Shuhan AU - Huang S AUID- ORCID: 0000-0002-3139-7296 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Favuzzi, Emilia AU - Favuzzi E AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Burbridge, Timothy AU - Burbridge T AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Xu, Qing AU - Xu Q AD - Center for Genomics & Systems Biology, New York University, Abu Dhabi, UAE. FAU - Guo, Lihua AU - Guo L AD - Center for Genomics & Systems Biology, New York University, Abu Dhabi, UAE. FAU - Vogel, Ian AU - Vogel I AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Sanchez, Vanessa AU - Sanchez V AUID- ORCID: 0000-0001-9380-5358 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Saldi, Giuseppe A AU - Saldi GA AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Gorissen, Bram L AU - Gorissen BL AUID- ORCID: 0000-0001-5992-0432 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Yuan, Xiaoqing AU - Yuan X AD - National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. FAU - Zaghloul, Kareem A AU - Zaghloul KA AUID- ORCID: 0000-0001-8575-3578 AD - National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. FAU - Devinsky, Orrin AU - Devinsky O AUID- ORCID: 0000-0003-0044-4632 AD - Comprehensive Epilepsy Center, New York University School of Medicine, New York, NY, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Batista-Brito, Renata AU - Batista-Brito R AD - Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA. FAU - Reynolds, John AU - Reynolds J AD - Systems Neurobiology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA, USA. FAU - Feng, Guoping AU - Feng G AUID- ORCID: 0000-0002-8021-277X AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA. FAU - Fu, Zhanyan AU - Fu Z AUID- ORCID: 0000-0001-9473-2402 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - McBain, Chris J AU - McBain CJ AUID- ORCID: 0000-0002-5909-0157 AD - National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. FAU - Fishell, Gord AU - Fishell G AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Dimidschstein, Jordane AU - Dimidschstein J AUID- ORCID: 0000-0001-6289-6891 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. jordane@broadinstitute.org. LA - eng GR - R01 MH127085/MH/NIMH NIH HHS/United States PT - Published Erratum PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 SB - IM EFR - Nat Neurosci. 2020 Dec;23(12):1629-1636. PMID: 32807948 EDAT- 2022/08/10 06:00 MHDA- 2022/08/10 06:01 CRDT- 2022/08/09 23:31 PHST- 2022/08/10 06:00 [pubmed] PHST- 2022/08/10 06:01 [medline] PHST- 2022/08/09 23:31 [entrez] AID - 10.1038/s41593-022-01155-w [pii] AID - 10.1038/s41593-022-01155-w [doi] PST - ppublish SO - Nat Neurosci. 2022 Sep;25(9):1247. doi: 10.1038/s41593-022-01155-w. PMID- 35668147 OWN - NLM STAT- MEDLINE DCOM- 20220701 LR - 20221207 IS - 1476-4660 (Electronic) IS - 1476-1122 (Print) IS - 1476-1122 (Linking) VI - 21 IP - 7 DP - 2022 Jul TI - Tapered fibertrodes for optoelectrical neural interfacing in small brain volumes with reduced artefacts. PG - 826-835 LID - 10.1038/s41563-022-01272-8 [doi] AB - Deciphering the neural patterns underlying brain functions is essential to understanding how neurons are organized into networks. This deciphering has been greatly facilitated by optogenetics and its combination with optoelectronic devices to control neural activity with millisecond temporal resolution and cell type specificity. However, targeting small brain volumes causes photoelectric artefacts, in particular when light emission and recording sites are close to each other. We take advantage of the photonic properties of tapered fibres to develop integrated 'fibertrodes' able to optically activate small brain volumes with abated photoelectric noise. Electrodes are positioned very close to light emitting points by non-planar microfabrication, with angled light emission allowing the simultaneous optogenetic manipulation and electrical read-out of one to three neurons, with no photoelectric artefacts, in vivo. The unconventional implementation of two-photon polymerization on the curved taper edge enables the fabrication of recoding sites all around the implant, making fibertrodes a promising complement to planar microimplants. CI - © 2022. The Author(s), under exclusive licence to Springer Nature Limited. FAU - Spagnolo, Barbara AU - Spagnolo B AUID- ORCID: 0000-0001-7377-2819 AD - Istituto Italiano di Tecnologia, CBN, Lecce, Italy. barbara.spagnolo@iit.it. FAU - Balena, Antonio AU - Balena A AUID- ORCID: 0000-0003-4314-4314 AD - Istituto Italiano di Tecnologia, CBN, Lecce, Italy. antonio.balena@iit.it. FAU - Peixoto, Rui T AU - Peixoto RT AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. AD - Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. FAU - Pisanello, Marco AU - Pisanello M AD - Istituto Italiano di Tecnologia, CBN, Lecce, Italy. FAU - Sileo, Leonardo AU - Sileo L AD - Istituto Italiano di Tecnologia, CBN, Lecce, Italy. FAU - Bianco, Marco AU - Bianco M AD - Istituto Italiano di Tecnologia, CBN, Lecce, Italy. AD - Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - Rizzo, Alessandro AU - Rizzo A AD - Istituto Italiano di Tecnologia, CBN, Lecce, Italy. AD - Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - Pisano, Filippo AU - Pisano F AD - Istituto Italiano di Tecnologia, CBN, Lecce, Italy. FAU - Qualtieri, Antonio AU - Qualtieri A AUID- ORCID: 0000-0002-2207-8111 AD - Istituto Italiano di Tecnologia, CBN, Lecce, Italy. FAU - Lofrumento, Dario Domenico AU - Lofrumento DD AUID- ORCID: 0000-0002-0106-3615 AD - DiSTeBA - Department of Biological and Environmental Sciences and Technologies, Università del Salento, Lecce, Italy. FAU - De Nuccio, Francesco AU - De Nuccio F AD - DiSTeBA - Department of Biological and Environmental Sciences and Technologies, Università del Salento, Lecce, Italy. FAU - Assad, John A AU - Assad JA AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. AD - Istituto Italiano di Tecnologia, Genova, Italy. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - De Vittorio, Massimo AU - De Vittorio M AUID- ORCID: 0000-0003-1601-6392 AD - Istituto Italiano di Tecnologia, CBN, Lecce, Italy. massimo.devittorio@iit.it. AD - Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Lecce, Italy. massimo.devittorio@iit.it. FAU - Pisanello, Ferruccio AU - Pisanello F AUID- ORCID: 0000-0002-1489-7758 AD - Istituto Italiano di Tecnologia, CBN, Lecce, Italy. ferruccio.pisanello@iit.it. LA - eng GR - 677683/ERC_/European Research Council/International GR - 966674/ERC_/European Research Council/International GR - 692943/ERC_/European Research Council/International GR - U01 NS094190/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - UF1 NS108177/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220606 PL - England TA - Nat Mater JT - Nature materials JID - 101155473 SB - IM MH - *Artifacts MH - Brain MH - Electrodes MH - Neurons/physiology MH - *Optogenetics PMC - PMC7612923 MID - EMS144588 COIS- Competing Interests Statement LS, BLS, MDV, and F. Pisanello are founders and hold private equity in Optogenix, a company that develops, produces and sells technologies to deliver light into the brain. Tapered fibers commercially available from Optogenix were used as tools in the research. The remaining authors declare no competing interests. EDAT- 2022/06/07 06:00 MHDA- 2022/07/02 06:00 CRDT- 2022/06/06 23:20 PHST- 2020/05/23 00:00 [received] PHST- 2022/04/27 00:00 [accepted] PHST- 2022/06/07 06:00 [pubmed] PHST- 2022/07/02 06:00 [medline] PHST- 2022/06/06 23:20 [entrez] AID - 10.1038/s41563-022-01272-8 [pii] AID - 10.1038/s41563-022-01272-8 [doi] PST - ppublish SO - Nat Mater. 2022 Jul;21(7):826-835. doi: 10.1038/s41563-022-01272-8. Epub 2022 Jun 6. PMID- 35120627 OWN - NLM STAT- MEDLINE DCOM- 20220425 LR - 20230917 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 110 IP - 8 DP - 2022 Apr 20 TI - Co-packaging of opposing neurotransmitters in individual synaptic vesicles in the central nervous system. PG - 1371-1384.e7 LID - S0896-6273(22)00007-1 [pii] LID - 10.1016/j.neuron.2022.01.007 [doi] AB - Many mammalian neurons release multiple neurotransmitters to activate diverse classes of postsynaptic ionotropic receptors. Entopeduncular nucleus somatostatin (EP Sst+) projection neurons to the lateral habenula (LHb) release both glutamate and GABA, but it is unclear whether these are packaged into the same or segregated pools of synaptic vesicles. Here, we describe a method combining electrophysiology, spatially patterned optogenetics, and computational modeling designed to analyze the mechanism of glutamate/GABA co-release in mouse brain. We find that the properties of postsynaptic currents elicited in LHb neurons by optogenetically activating EP Sst+ terminals are only consistent with co-packaging of glutamate/GABA into individual vesicles. Furthermore, presynaptic neuromodulators that weaken EP Sst+ to LHb synapses maintain the co-packaging of glutamate/GABA while reducing vesicular release probability. Our approach is applicable to the study of multi-transmitter neurons throughout the brain, and our results constrain the mechanisms of neuromodulation and synaptic integration in LHb. CI - Copyright © 2022 Elsevier Inc. All rights reserved. FAU - Kim, SeulAh AU - Kim S AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave, Boston, MA 02115, USA. FAU - Wallace, Michael L AU - Wallace ML AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave, Boston, MA 02115, USA. FAU - El-Rifai, Mahmoud AU - El-Rifai M AD - Department of Neurobiology, Harvard Medical School, 220 Longwood Ave, Boston, MA 01225, USA. FAU - Knudsen, Alexa R AU - Knudsen AR AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave, Boston, MA 02115, USA. Electronic address: bsabatini@hms.harvard.edu. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - K99 NS105883/NS/NINDS NIH HHS/United States GR - R00 NS105883/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - R01 NS103226/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220203 PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Neurotransmitter Agents) RN - 3KX376GY7L (Glutamic Acid) RN - 56-12-2 (gamma-Aminobutyric Acid) SB - IM CIN - Neuron. 2022 Apr 20;110(8):1280-1283. PMID: 35447097 MH - Animals MH - Glutamic Acid MH - *Habenula MH - Mammals MH - Mice MH - Neurotransmitter Agents MH - *Synaptic Vesicles MH - gamma-Aminobutyric Acid PMC - PMC9056948 MID - NIHMS1778555 OTO - NOTNLM OT - GABA OT - basal ganglia OT - computational modeling OT - digital micromirror device OT - entopeduncular nucleus OT - glutamate OT - lateral habenula OT - neurotransmitter co-release COIS- Declaration of interests B.L.S. is a member of the Neuron advisory board. EDAT- 2022/02/06 06:00 MHDA- 2022/04/26 06:00 CRDT- 2022/02/05 05:33 PHST- 2021/03/25 00:00 [received] PHST- 2021/11/16 00:00 [revised] PHST- 2022/01/06 00:00 [accepted] PHST- 2022/02/06 06:00 [pubmed] PHST- 2022/04/26 06:00 [medline] PHST- 2022/02/05 05:33 [entrez] AID - S0896-6273(22)00007-1 [pii] AID - 10.1016/j.neuron.2022.01.007 [doi] PST - ppublish SO - Neuron. 2022 Apr 20;110(8):1371-1384.e7. doi: 10.1016/j.neuron.2022.01.007. Epub 2022 Feb 3. PMID- 35385355 OWN - NLM STAT- MEDLINE DCOM- 20220415 LR - 20221012 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 119 IP - 15 DP - 2022 Apr 12 TI - Mice exhibit stochastic and efficient action switching during probabilistic decision making. PG - e2113961119 LID - 10.1073/pnas.2113961119 [doi] LID - e2113961119 AB - In probabilistic and nonstationary environments, individuals must use internal and external cues to flexibly make decisions that lead to desirable outcomes. To gain insight into the process by which animals choose between actions, we trained mice in a task with time-varying reward probabilities. In our implementation of such a two-armed bandit task, thirsty mice use information about recent action and action–outcome histories to choose between two ports that deliver water probabilistically. Here we comprehensively modeled choice behavior in this task, including the trial-to-trial changes in port selection, i.e., action switching behavior. We find that mouse behavior is, at times, deterministic and, at others, apparently stochastic. The behavior deviates from that of a theoretically optimal agent performing Bayesian inference in a hidden Markov model (HMM). We formulate a set of models based on logistic regression, reinforcement learning, and sticky Bayesian inference that we demonstrate are mathematically equivalent and that accurately describe mouse behavior. The switching behavior of mice in the task is captured in each model by a stochastic action policy, a history-dependent representation of action value, and a tendency to repeat actions despite incoming evidence. The models parsimoniously capture behavior across different environmental conditionals by varying the stickiness parameter, and like the mice, they achieve nearly maximal reward rates. These results indicate that mouse behavior reaches near-maximal performance with reduced action switching and can be described by a set of equivalent models with a small number of relatively fixed parameters. FAU - Beron, Celia C AU - Beron CC AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115. AD - HHMI, Harvard Medical School, Boston, MA 02115. FAU - Neufeld, Shay Q AU - Neufeld SQ AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115. AD - HHMI, Harvard Medical School, Boston, MA 02115. FAU - Linderman, Scott W AU - Linderman SW AD - Department of Statistics, Stanford University, Stanford, CA 94305. AD - Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115. AD - HHMI, Harvard Medical School, Boston, MA 02115. LA - eng GR - P30 EY026877/EY/NEI NIH HHS/United States GR - U19 NS113201/NS/NINDS NIH HHS/United States GR - CIHR/Canada GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - U19NS113201/HHS | National Institutes of Health (NIH)/ GR - R37 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20220406 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 SB - IM MH - Animals MH - *Choice Behavior MH - *Decision Making MH - *Mice/psychology MH - Reward MH - Uncertainty PMC - PMC9169659 OTO - NOTNLM OT - Bayesian inference OT - decision making OT - explore–exploit OT - perseveration OT - stochastic choice COIS- The authors declare no competing interest. EDAT- 2022/04/07 06:00 MHDA- 2022/04/16 06:00 CRDT- 2022/04/06 17:11 PHST- 2022/04/06 17:11 [entrez] PHST- 2022/04/07 06:00 [pubmed] PHST- 2022/04/16 06:00 [medline] AID - 202113961 [pii] AID - 10.1073/pnas.2113961119 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2022 Apr 12;119(15):e2113961119. doi: 10.1073/pnas.2113961119. Epub 2022 Apr 6. PMID- 35319464 OWN - NLM STAT- MEDLINE DCOM- 20220406 LR - 20220914 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 11 DP - 2022 Mar 23 TI - Dendritic branch structure compartmentalizes voltage-dependent calcium influx in cortical layer 2/3 pyramidal cells. LID - 10.7554/eLife.76993 [doi] LID - e76993 AB - Back-propagating action potentials (bAPs) regulate synaptic plasticity by evoking voltage-dependent calcium influx throughout dendrites. Attenuation of bAP amplitude in distal dendritic compartments alters plasticity in a location-specific manner by reducing bAP-dependent calcium influx. However, it is not known if neurons exhibit branch-specific variability in bAP-dependent calcium signals, independent of distance-dependent attenuation. Here, we reveal that bAPs fail to evoke calcium influx through voltage-gated calcium channels (VGCCs) in a specific population of dendritic branches in mouse cortical layer 2/3 pyramidal cells, despite evoking substantial VGCC-mediated calcium influx in sister branches. These branches contain VGCCs and successfully propagate bAPs in the absence of synaptic input; nevertheless, they fail to exhibit bAP-evoked calcium influx due to a branch-specific reduction in bAP amplitude. We demonstrate that these branches have more elaborate branch structure compared to sister branches, which causes a local reduction in electrotonic impedance and bAP amplitude. Finally, we show that bAPs still amplify synaptically-mediated calcium influx in these branches because of differences in the voltage-dependence and kinetics of VGCCs and NMDA-type glutamate receptors. Branch-specific compartmentalization of bAP-dependent calcium signals may provide a mechanism for neurons to diversify synaptic tuning across the dendritic tree. CI - © 2022, Landau et al. FAU - Landau, Andrew T AU - Landau AT AUID- ORCID: 0000-0001-9105-1636 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Park, Pojeong AU - Park P AD - Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States. FAU - Wong-Campos, J David AU - Wong-Campos JD AD - Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States. FAU - Tian, He AU - Tian H AUID- ORCID: 0000-0003-3282-7275 AD - Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States. FAU - Cohen, Adam E AU - Cohen AE AUID- ORCID: 0000-0002-8699-2404 AD - Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States. AD - Department of Physics, Harvard University, Cambridge, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, United States. LA - eng GR - F31 NS113353/NS/NINDS NIH HHS/United States GR - RF1 MH117042/MH/NIMH NIH HHS/United States GR - R37 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20220323 PL - England TA - Elife JT - eLife JID - 101579614 RN - 0 (Calcium Channels) RN - SY7Q814VUP (Calcium) SB - IM MH - Action Potentials/physiology MH - Animals MH - *Calcium/metabolism MH - Calcium Channels/physiology MH - *Dendrites/physiology MH - Mice MH - Pyramidal Cells/physiology PMC - PMC8979587 OTO - NOTNLM OT - action potentials OT - biophysics OT - calcium OT - dendrites OT - impedance OT - mouse OT - neuroscience COIS- AL, PP, JW, BS No competing interests declared, HT has filed a patent on QuasAr6a (Application #: 63247704), AC has filed a patent for QuasAr6a (Application #: 63247704) EDAT- 2022/03/24 06:00 MHDA- 2022/04/07 06:00 CRDT- 2022/03/23 12:14 PHST- 2022/01/11 00:00 [received] PHST- 2022/03/22 00:00 [accepted] PHST- 2022/03/24 06:00 [pubmed] PHST- 2022/04/07 06:00 [medline] PHST- 2022/03/23 12:14 [entrez] AID - 76993 [pii] AID - 10.7554/eLife.76993 [doi] PST - epublish SO - Elife. 2022 Mar 23;11:e76993. doi: 10.7554/eLife.76993. PMID- 35196485 OWN - NLM STAT- MEDLINE DCOM- 20220316 LR - 20220330 IS - 2211-1247 (Electronic) VI - 38 IP - 8 DP - 2022 Feb 22 TI - Astrocyte-neuron crosstalk through Hedgehog signaling mediates cortical synapse development. PG - 110416 LID - S2211-1247(22)00140-1 [pii] LID - 10.1016/j.celrep.2022.110416 [doi] AB - Neuron-glia interactions play a critical role in the regulation of synapse formation and circuit assembly. Here we demonstrate that canonical Sonic hedgehog (Shh) pathway signaling in cortical astrocytes acts to coordinate layer-specific synaptic connectivity. We show that the Shh receptor Ptch1 is expressed by cortical astrocytes during development and that Shh signaling is necessary and sufficient to promote the expression of genes involved in regulating synaptic development and layer-enriched astrocyte molecular identity. Loss of Shh in layer V neurons reduces astrocyte complexity and coverage by astrocytic processes in tripartite synapses; conversely, cell-autonomous activation of Shh signaling in astrocytes promotes cortical excitatory synapse formation. Furthermore, Shh-dependent genes Lrig1 and Sparc distinctively contribute to astrocyte morphology and synapse formation. Together, these results suggest that Shh secreted from deep-layer cortical neurons acts to specialize the molecular and functional features of astrocytes during development to shape circuit assembly and function. CI - Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Xie, Yajun AU - Xie Y AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Kuan, Aaron T AU - Kuan AT AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Wang, Wengang AU - Wang W AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Herbert, Zachary T AU - Herbert ZT AD - Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA 02215, USA. FAU - Mosto, Olivia AU - Mosto O AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Olukoya, Olubusola AU - Olukoya O AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Adam, Manal AU - Adam M AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Vu, Steve AU - Vu S AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Kim, Minsu AU - Kim M AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Tran, Diana AU - Tran D AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Gómez, Nicolás AU - Gómez N AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Charpentier, Claire AU - Charpentier C AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Sorour, Ingie AU - Sorour I AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Lacey, Tiara E AU - Lacey TE AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Tolstorukov, Michael Y AU - Tolstorukov MY AD - Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Lee, Wei-Chung Allen AU - Lee WA AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA. FAU - Harwell, Corey C AU - Harwell CC AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: corey.harwell@ucsf.edu. LA - eng GR - R01 MH119156/MH/NIMH NIH HHS/United States GR - R01 NS102228/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 0 (Hedgehog Proteins) SB - IM MH - *Astrocytes/metabolism MH - *Hedgehog Proteins/metabolism MH - Neurogenesis/physiology MH - Neurons/metabolism MH - Synapses/metabolism PMC - PMC8962654 MID - NIHMS1783317 OTO - NOTNLM OT - Lrig1 OT - Sonic hedgehog OT - Sparc OT - astrocytes OT - cortical circuits OT - neuron-glia interaction OT - synapse formation COIS- Declaration of interests The authors declare no competing interests. EDAT- 2022/02/24 06:00 MHDA- 2022/03/17 06:00 CRDT- 2022/02/23 20:08 PHST- 2021/05/12 00:00 [received] PHST- 2021/11/04 00:00 [revised] PHST- 2022/01/28 00:00 [accepted] PHST- 2022/02/23 20:08 [entrez] PHST- 2022/02/24 06:00 [pubmed] PHST- 2022/03/17 06:00 [medline] AID - S2211-1247(22)00140-1 [pii] AID - 10.1016/j.celrep.2022.110416 [doi] PST - ppublish SO - Cell Rep. 2022 Feb 22;38(8):110416. doi: 10.1016/j.celrep.2022.110416. PMID- 35224188 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220301 IS - 2378-0967 (Electronic) IS - 2378-0967 (Linking) VI - 7 IP - 2 DP - 2022 Feb 1 TI - Orthogonalization of far-field detection in tapered optical fibers for depth-selective fiber photometry in brain tissue. PG - 026106 LID - 10.1063/5.0073594 [doi] LID - 026106 AB - The field of implantable optical neural interfaces has recently enabled the interrogation of neural circuitry with both cell-type specificity and spatial resolution in sub-cortical structures of the mouse brain. This generated the need to integrate multiple optical channels within the same implantable device, motivating the requirement of multiplexing and demultiplexing techniques. In this article, we present an orthogonalization method of the far-field space to introduce mode-division demultiplexing for collecting fluorescence from the implantable tapered optical fibers. This is achieved by exploiting the correlation between the transversal wavevector k (t) of the guided light and the position of the fluorescent sources along the implant, an intrinsic property of the taper waveguide. On these bases, we define a basis of orthogonal vectors in the Fourier space, each of which is associated with a depth along the taper, to simultaneously detect and demultiplex the collected signal when the probe is implanted in fixed mouse brain tissue. Our approach complements the existing multiplexing techniques used in silicon-based photonics probes with the advantage of a significant simplification of the probe itself. CI - © 2022 Author(s). FAU - Bianco, Marco AU - Bianco M AUID- ORCID: 0000-0001-9693-1106 FAU - Pisanello, Marco AU - Pisanello M AUID- ORCID: 0000-0003-2179-7883 AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti 14, Arnesano, 73010 Lecce, Italy. FAU - Balena, Antonio AU - Balena A AUID- ORCID: 0000-0003-4314-4314 AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti 14, Arnesano, 73010 Lecce, Italy. FAU - Montinaro, Cinzia AU - Montinaro C AUID- ORCID: 0000-0002-7184-0854 FAU - Pisano, Filippo AU - Pisano F AUID- ORCID: 0000-0002-5499-160X AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti 14, Arnesano, 73010 Lecce, Italy. FAU - Spagnolo, Barbara AU - Spagnolo B AUID- ORCID: 0000-0001-7377-2819 AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti 14, Arnesano, 73010 Lecce, Italy. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Dipartimento di Scienze e Tecnologie Biologiche e Ambientali, Università del Salento, Via per Monteroni, 73100 Lecce, Italy. FAU - De Vittorio, Massimo AU - De Vittorio M AUID- ORCID: 0000-0003-1601-6392 FAU - Pisanello, Ferruccio AU - Pisanello F AUID- ORCID: 0000-0002-1489-7758 AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti 14, Arnesano, 73010 Lecce, Italy. LA - eng PT - Journal Article DEP - 20220214 PL - United States TA - APL Photonics JT - APL photonics JID - 101719533 PMC - PMC8865573 EDAT- 2022/03/01 06:00 MHDA- 2022/03/01 06:01 CRDT- 2022/02/28 05:41 PHST- 2021/10/01 00:00 [received] PHST- 2022/01/20 00:00 [accepted] PHST- 2022/02/28 05:41 [entrez] PHST- 2022/03/01 06:00 [pubmed] PHST- 2022/03/01 06:01 [medline] AID - 5.0073594 [pii] AID - 10.1063/5.0073594 [doi] PST - ppublish SO - APL Photonics. 2022 Feb 1;7(2):026106. doi: 10.1063/5.0073594. Epub 2022 Feb 14. PMID- 35493335 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231117 IS - 2329-423X (Print) IS - 2329-4248 (Electronic) IS - 2329-423X (Linking) VI - 9 IP - Suppl 1 DP - 2022 Jan TI - Neurophotonic tools for microscopic measurements and manipulation: status report. PG - 013001 LID - 10.1117/1.NPh.9.S1.013001 [doi] LID - 013001 AB - Neurophotonics was launched in 2014 coinciding with the launch of the BRAIN Initiative focused on development of technologies for advancement of neuroscience. For the last seven years, Neurophotonics' agenda has been well aligned with this focus on neurotechnologies featuring new optical methods and tools applicable to brain studies. While the BRAIN Initiative 2.0 is pivoting towards applications of these novel tools in the quest to understand the brain, this status report reviews an extensive and diverse toolkit of novel methods to explore brain function that have emerged from the BRAIN Initiative and related large-scale efforts for measurement and manipulation of brain structure and function. Here, we focus on neurophotonic tools mostly applicable to animal studies. A companion report, scheduled to appear later this year, will cover diffuse optical imaging methods applicable to noninvasive human studies. For each domain, we outline the current state-of-the-art of the respective technologies, identify the areas where innovation is needed, and provide an outlook for the future directions. CI - © 2022 The Authors. FAU - Abdelfattah, Ahmed S AU - Abdelfattah AS AD - Brown University, Department of Neuroscience, Providence, Rhode Island, United States. FAU - Ahuja, Sapna AU - Ahuja S AD - University of Pennsylvania, Perelman School of Medicine, Department of Biochemistry and Biophysics, Philadelphia, Pennsylvania, United States. AD - University of Pennsylvania, School of Arts and Sciences, Department of Chemistry, Philadelphia, Pennsylvania, United States. FAU - Akkin, Taner AU - Akkin T AD - University of Minnesota, Department of Biomedical Engineering, Minneapolis, Minnesota, United States. FAU - Allu, Srinivasa Rao AU - Allu SR AD - University of Pennsylvania, Perelman School of Medicine, Department of Biochemistry and Biophysics, Philadelphia, Pennsylvania, United States. AD - University of Pennsylvania, School of Arts and Sciences, Department of Chemistry, Philadelphia, Pennsylvania, United States. FAU - Brake, Joshua AU - Brake J AD - Harvey Mudd College, Department of Engineering, Claremont, California, United States. FAU - Boas, David A AU - Boas DA AD - Boston University, Department of Biomedical Engineering, Boston, Massachusetts, United States. FAU - Buckley, Erin M AU - Buckley EM AD - Georgia Institute of Technology and Emory University, Wallace H. Coulter Department of Biomedical Engineering, Atlanta, Georgia, United States. AD - Emory University, Department of Pediatrics, Atlanta, Georgia, United States. FAU - Campbell, Robert E AU - Campbell RE AD - University of Tokyo, Department of Chemistry, Tokyo, Japan. AD - University of Alberta, Department of Chemistry, Edmonton, Alberta, Canada. FAU - Chen, Anderson I AU - Chen AI AD - Boston University, Department of Biomedical Engineering, Boston, Massachusetts, United States. FAU - Cheng, Xiaojun AU - Cheng X AD - Boston University, Department of Biomedical Engineering, Boston, Massachusetts, United States. FAU - Čižmár, Tomáš AU - Čižmár T AD - Institute of Scientific Instruments of the Czech Academy of Sciences, Brno, Czech Republic. FAU - Costantini, Irene AU - Costantini I AD - University of Florence, European Laboratory for Non-Linear Spectroscopy, Department of Biology, Florence, Italy. AD - National Institute of Optics, National Research Council, Rome, Italy. FAU - De Vittorio, Massimo AU - De Vittorio M AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, Italy. FAU - Devor, Anna AU - Devor A AD - Boston University, Department of Biomedical Engineering, Boston, Massachusetts, United States. AD - Massachusetts General Hospital, Harvard Medical School, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts, United States. FAU - Doran, Patrick R AU - Doran PR AD - Boston University, Department of Biomedical Engineering, Boston, Massachusetts, United States. FAU - El Khatib, Mirna AU - El Khatib M AD - University of Pennsylvania, Perelman School of Medicine, Department of Biochemistry and Biophysics, Philadelphia, Pennsylvania, United States. AD - University of Pennsylvania, School of Arts and Sciences, Department of Chemistry, Philadelphia, Pennsylvania, United States. FAU - Emiliani, Valentina AU - Emiliani V AD - Sorbonne University, INSERM, CNRS, Institut de la Vision, Paris, France. FAU - Fomin-Thunemann, Natalie AU - Fomin-Thunemann N AD - Boston University, Department of Biomedical Engineering, Boston, Massachusetts, United States. FAU - Fainman, Yeshaiahu AU - Fainman Y AD - University of California San Diego, Department of Electrical and Computer Engineering, La Jolla, California, United States. FAU - Fernandez-Alfonso, Tomas AU - Fernandez-Alfonso T AD - University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom. FAU - Ferri, Christopher G L AU - Ferri CGL AD - University of California San Diego, Departments of Neurosciences, La Jolla, California, United States. FAU - Gilad, Ariel AU - Gilad A AD - The Hebrew University of Jerusalem, Institute for Medical Research Israel-Canada, Department of Medical Neurobiology, Faculty of Medicine, Jerusalem, Israel. FAU - Han, Xue AU - Han X AD - Boston University, Department of Biomedical Engineering, Boston, Massachusetts, United States. FAU - Harris, Andrew AU - Harris A AD - Weizmann Institute of Science, Department of Brain Sciences, Rehovot, Israel. FAU - Hillman, Elizabeth M C AU - Hillman EMC AD - Columbia University, Zuckerman Mind Brain Behavior Institute, New York, United States. FAU - Hochgeschwender, Ute AU - Hochgeschwender U AD - Central Michigan University, Department of Neuroscience, Mount Pleasant, Michigan, United States. FAU - Holt, Matthew G AU - Holt MG AD - University of Porto, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal. FAU - Ji, Na AU - Ji N AD - University of California Berkeley, Department of Physics, Berkeley, California, United States. FAU - Kılıç, Kıvılcım AU - Kılıç K AD - Boston University, Department of Biomedical Engineering, Boston, Massachusetts, United States. FAU - Lake, Evelyn M R AU - Lake EMR AD - Yale School of Medicine, Department of Radiology and Biomedical Imaging, New Haven, Connecticut, United States. FAU - Li, Lei AU - Li L AD - California Institute of Technology, Andrew and Peggy Cherng Department of Medical Engineering, Department of Electrical Engineering, Pasadena, California, United States. FAU - Li, Tianqi AU - Li T AD - University of Minnesota, Department of Biomedical Engineering, Minneapolis, Minnesota, United States. FAU - Mächler, Philipp AU - Mächler P AD - Boston University, Department of Biomedical Engineering, Boston, Massachusetts, United States. FAU - Miller, Evan W AU - Miller EW AD - University of California Berkeley, Departments of Chemistry and Molecular & Cell Biology and Helen Wills Neuroscience Institute, Berkeley, California, United States. FAU - Mesquita, Rickson C AU - Mesquita RC AD - University of Campinas, Institute of Physics, Campinas, São Paulo, Brazil. FAU - Nadella, K M Naga Srinivas AU - Nadella KMNS AD - University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom. FAU - Nägerl, U Valentin AU - Nägerl UV AD - Interdisciplinary Institute for Neuroscience University of Bordeaux & CNRS, Bordeaux, France. FAU - Nasu, Yusuke AU - Nasu Y AD - University of Tokyo, Department of Chemistry, Tokyo, Japan. FAU - Nimmerjahn, Axel AU - Nimmerjahn A AD - Salk Institute for Biological Studies, Waitt Advanced Biophotonics Center, La Jolla, California, United States. FAU - Ondráčková, Petra AU - Ondráčková P AD - Institute of Scientific Instruments of the Czech Academy of Sciences, Brno, Czech Republic. FAU - Pavone, Francesco S AU - Pavone FS AD - National Institute of Optics, National Research Council, Rome, Italy. AD - University of Florence, European Laboratory for Non-Linear Spectroscopy, Department of Physics, Florence, Italy. FAU - Perez Campos, Citlali AU - Perez Campos C AD - Columbia University, Zuckerman Mind Brain Behavior Institute, New York, United States. FAU - Peterka, Darcy S AU - Peterka DS AD - Columbia University, Zuckerman Mind Brain Behavior Institute, New York, United States. FAU - Pisano, Filippo AU - Pisano F AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, Italy. FAU - Pisanello, Ferruccio AU - Pisanello F AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, Italy. FAU - Puppo, Francesca AU - Puppo F AD - University of California San Diego, Departments of Neurosciences, La Jolla, California, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Harvard Medical School, Howard Hughes Medical Institute, Department of Neurobiology, Boston, Massachusetts, United States. FAU - Sadegh, Sanaz AU - Sadegh S AD - University of California San Diego, Departments of Neurosciences, La Jolla, California, United States. FAU - Sakadzic, Sava AU - Sakadzic S AD - Massachusetts General Hospital, Harvard Medical School, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts, United States. FAU - Shoham, Shy AU - Shoham S AD - New York University Grossman School of Medicine, Tech4Health and Neuroscience Institutes, New York, New York, United States. FAU - Shroff, Sanaya N AU - Shroff SN AD - Boston University, Department of Biomedical Engineering, Boston, Massachusetts, United States. FAU - Silver, R Angus AU - Silver RA AD - University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom. FAU - Sims, Ruth R AU - Sims RR AD - Sorbonne University, INSERM, CNRS, Institut de la Vision, Paris, France. FAU - Smith, Spencer L AU - Smith SL AD - University of California Santa Barbara, Department of Electrical and Computer Engineering, Santa Barbara, California, United States. FAU - Srinivasan, Vivek J AU - Srinivasan VJ AD - New York University Langone Health, Departments of Ophthalmology and Radiology, New York, New York, United States. FAU - Thunemann, Martin AU - Thunemann M AD - Boston University, Department of Biomedical Engineering, Boston, Massachusetts, United States. FAU - Tian, Lei AU - Tian L AD - Boston University, Departments of Electrical Engineering and Biomedical Engineering, Boston, Massachusetts, United States. FAU - Tian, Lin AU - Tian L AD - University of California Davis, Department of Biochemistry and Molecular Medicine, Davis, California, United States. FAU - Troxler, Thomas AU - Troxler T AD - University of Pennsylvania, Perelman School of Medicine, Department of Biochemistry and Biophysics, Philadelphia, Pennsylvania, United States. AD - University of Pennsylvania, School of Arts and Sciences, Department of Chemistry, Philadelphia, Pennsylvania, United States. FAU - Valera, Antoine AU - Valera A AD - University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom. FAU - Vaziri, Alipasha AU - Vaziri A AD - Rockefeller University, Laboratory of Neurotechnology and Biophysics, New York, New York, United States. AD - The Rockefeller University, The Kavli Neural Systems Institute, New York, New York, United States. FAU - Vinogradov, Sergei A AU - Vinogradov SA AD - University of Pennsylvania, Perelman School of Medicine, Department of Biochemistry and Biophysics, Philadelphia, Pennsylvania, United States. AD - University of Pennsylvania, School of Arts and Sciences, Department of Chemistry, Philadelphia, Pennsylvania, United States. FAU - Vitale, Flavia AU - Vitale F AD - Center for Neuroengineering and Therapeutics, Departments of Neurology, Bioengineering, Physical Medicine and Rehabilitation, Philadelphia, Pennsylvania, United States. FAU - Wang, Lihong V AU - Wang LV AD - California Institute of Technology, Andrew and Peggy Cherng Department of Medical Engineering, Department of Electrical Engineering, Pasadena, California, United States. FAU - Uhlířová, Hana AU - Uhlířová H AD - Institute of Scientific Instruments of the Czech Academy of Sciences, Brno, Czech Republic. FAU - Xu, Chris AU - Xu C AD - Cornell University, School of Applied and Engineering Physics, Ithaca, New York, United States. FAU - Yang, Changhuei AU - Yang C AD - California Institute of Technology, Departments of Electrical Engineering, Bioengineering and Medical Engineering, Pasadena, California, United States. FAU - Yang, Mu-Han AU - Yang MH AD - University of California San Diego, Department of Electrical and Computer Engineering, La Jolla, California, United States. FAU - Yellen, Gary AU - Yellen G AD - Harvard Medical School, Department of Neurobiology, Boston, Massachusetts, United States. FAU - Yizhar, Ofer AU - Yizhar O AD - Weizmann Institute of Science, Department of Brain Sciences, Rehovot, Israel. FAU - Zhao, Yongxin AU - Zhao Y AD - Carnegie Mellon University, Department of Biological Sciences, Pittsburgh, Pennsylvania, United States. LA - eng GR - U01 NS103488/NS/NINDS NIH HHS/United States GR - U01 NS099717/NS/NINDS NIH HHS/United States GR - R01 GM124038/GM/NIGMS NIH HHS/United States GR - R01 NS108472/NS/NINDS NIH HHS/United States GR - R01 NS094681/NS/NINDS NIH HHS/United States GR - R01 NS108034/NS/NINDS NIH HHS/United States GR - U01 CA236554/CA/NCI NIH HHS/United States GR - R01 NS109885/NS/NINDS NIH HHS/United States GR - R01 NS115401/NS/NINDS NIH HHS/United States GR - R01 NS098088/NS/NINDS NIH HHS/United States GR - U19 NS107613/NS/NINDS NIH HHS/United States GR - R21 EY030016/EY/NEI NIH HHS/United States GR - U19 NS123719/NS/NINDS NIH HHS/United States GR - R01 NS102586/NS/NINDS NIH HHS/United States GR - R01 NS117756/NS/NINDS NIH HHS/United States GR - UF1 NS108213/NS/NINDS NIH HHS/United States GR - U01 NS113273/NS/NINDS NIH HHS/United States GR - DP2 MH129956/MH/NIMH NIH HHS/United States GR - R44 MH117430/MH/NIMH NIH HHS/United States GR - U19 NS123717/NS/NINDS NIH HHS/United States GR - UF1 NS108177/NS/NINDS NIH HHS/United States GR - U24 EB028941/EB/NIBIB NIH HHS/United States GR - RF1 NS121095/NS/NINDS NIH HHS/United States GR - U01 NS118300/NS/NINDS NIH HHS/United States GR - F31 NS118949/NS/NINDS NIH HHS/United States GR - U01 NS094296/NS/NINDS NIH HHS/United States GR - R01 NS091230/NS/NINDS NIH HHS/United States GR - K25 HL145092/HL/NHLBI NIH HHS/United States GR - R01 NS120832/NS/NINDS NIH HHS/United States GR - R01 NS121219/NS/NINDS NIH HHS/United States GR - R01 EY031469/EY/NEI NIH HHS/United States GR - F31 NS115421/NS/NINDS NIH HHS/United States GR - R01 EB029747/EB/NIBIB NIH HHS/United States GR - RF1 NS110501/NS/NINDS NIH HHS/United States GR - RF1 NS113251/NS/NINDS NIH HHS/United States GR - R01 DA050159/DA/NIDA NIH HHS/United States GR - U19 NS112959/NS/NINDS NIH HHS/United States GR - U01 EB029823/EB/NIBIB NIH HHS/United States PT - Journal Article DEP - 20220427 PL - United States TA - Neurophotonics JT - Neurophotonics JID - 101632875 PMC - PMC9047450 OTO - NOTNLM OT - blood flow OT - fluorescence OT - label free OT - molecular sensors OT - multimodal OT - optical imaging OT - optogenetics EDAT- 2022/05/03 06:00 MHDA- 2022/05/03 06:01 CRDT- 2022/05/02 06:18 PHST- 2022/05/02 06:18 [entrez] PHST- 2022/05/03 06:00 [pubmed] PHST- 2022/05/03 06:01 [medline] AID - 22-0308 [pii] AID - 10.1117/1.NPh.9.S1.013001 [doi] PST - ppublish SO - Neurophotonics. 2022 Jan;9(Suppl 1):013001. doi: 10.1117/1.NPh.9.S1.013001. Epub 2022 Apr 27. PMID- 35167089 OWN - NLM STAT- MEDLINE DCOM- 20220217 LR - 20230929 IS - 1940-6029 (Electronic) IS - 1064-3745 (Linking) VI - 2448 DP - 2022 TI - Analysis of Thermogenesis Experiments with CalR. PG - 43-72 LID - 10.1007/978-1-0716-2087-8_3 [doi] AB - Modern indirect calorimetry systems allow for high-frequency time series measurements of the factors affected by thermogenesis: energy intake and energy expenditure. These indirect calorimetry systems generate a flood of raw data recording oxygen consumption, carbon dioxide production, physical activity, and food intake among other factors. Analysis of these data requires time-consuming manual manipulation for formatting, data cleaning, quality control, and visualization. Beyond data handling, analyses of indirect calorimetry experiments require specialized statistical treatment to account for differential contributions of fat mass and lean mass to metabolic rates.Here we describe how to use the software package CalR version 1.2, to analyze indirect calorimetry data from three examples of thermogenesis, cold exposure, adrenergic agonism, and hyperthyroidism in mice, by providing standardized methods for reproducible research. CalR is a free online tool with an easy-to-use graphical user interface to import data files from the Columbus Instruments' CLAMS, Sable Systems' Promethion, and TSE Systems' PhenoMaster. Once loaded, CalR can quickly visualize experimental results and perform basic statistical analyses. We present a framework that standardizes the data structures and analyses of indirect calorimetry experiments to provide reusable and reproducible methods for the physiological data affecting body weight. CI - © 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Cortopassi, Marissa D AU - Cortopassi MD AD - Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. FAU - Ramachandran, Deepti AU - Ramachandran D AD - Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. FAU - Rubio, William B AU - Rubio WB AD - Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. FAU - Hochbaum, Daniel AU - Hochbaum D AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. FAU - Banks, Alexander S AU - Banks AS AD - Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. asbanks@bidmc.harvard.edu. LA - eng GR - S10 OD028635/OD/NIH HHS/United States PT - Journal Article PL - United States TA - Methods Mol Biol JT - Methods in molecular biology (Clifton, N.J.) JID - 9214969 SB - IM MH - Animals MH - Body Weight MH - Calorimetry, Indirect MH - Energy Metabolism MH - Mice MH - *Obesity MH - *Thermogenesis OTO - NOTNLM OT - Adrenergic agonist OT - Body weight OT - Cold exposure OT - Energy expenditure OT - Hyperthyroid OT - Indirect calorimetry OT - Metabolic rate OT - Thermogenesis OT - Weight gain OT - Weight loss EDAT- 2022/02/16 06:00 MHDA- 2022/02/19 06:00 CRDT- 2022/02/15 12:20 PHST- 2022/02/15 12:20 [entrez] PHST- 2022/02/16 06:00 [pubmed] PHST- 2022/02/19 06:00 [medline] AID - 10.1007/978-1-0716-2087-8_3 [doi] PST - ppublish SO - Methods Mol Biol. 2022;2448:43-72. doi: 10.1007/978-1-0716-2087-8_3. PMID- 34732888 OWN - NLM STAT- MEDLINE DCOM- 20220304 LR - 20230711 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 599 IP - 7886 DP - 2021 Nov TI - Striatal indirect pathway mediates exploration via collicular competition. PG - 645-649 LID - 10.1038/s41586-021-04055-4 [doi] AB - The ability to suppress actions that lead to a negative outcome and explore alternative actions is necessary for optimal decision making. Although the basal ganglia have been implicated in these processes(1-5), the circuit mechanisms underlying action selection and exploration remain unclear. Here, using a simple lateralized licking task, we show that indirect striatal projection neurons (iSPN) in the basal ganglia contribute to these processes through modulation of the superior colliculus (SC). Optogenetic activation of iSPNs suppresses contraversive licking and promotes ipsiversive licking. Activity in lateral superior colliculus (lSC), a region downstream of the basal ganglia, is necessary for task performance and predicts lick direction. Furthermore, iSPN activation suppresses ipsilateral lSC, but surprisingly excites contralateral lSC, explaining the emergence of ipsiversive licking. Optogenetic inactivation reveals inter-collicular competition whereby each hemisphere of the superior colliculus inhibits the other, thus allowing the indirect pathway to disinhibit the contralateral lSC and trigger licking. Finally, inactivating iSPNs impairs suppression of devalued but previously rewarded licking and reduces exploratory licking. Our results reveal that iSPNs engage the competitive interaction between lSC hemispheres to trigger a motor action and suggest a general circuit mechanism for exploration during action selection. CI - © 2021. The Author(s), under exclusive licence to Springer Nature Limited. FAU - Lee, Jaeeon AU - Lee J AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. bsabatini@hms.harvard.edu. LA - eng GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - R01 NS103226/NS/NINDS NIH HHS/United States GR - U19 NS113201/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20211103 PL - England TA - Nature JT - Nature JID - 0410462 SB - IM MH - Animals MH - Basal Ganglia/*cytology/*physiology MH - Behavior, Animal/physiology MH - Corpus Striatum/cytology/*physiology MH - Decision Making MH - Exploratory Behavior/*physiology MH - Female MH - Male MH - Mice MH - Neural Inhibition/*physiology MH - Neural Pathways/*physiology MH - Neurons/physiology MH - Optogenetics MH - Reward MH - Superior Colliculi/cytology/*physiology PMC - PMC10281058 MID - NIHMS1903494 COIS- Declaration of Interests Dr. Sabatini is a founder and holds private equity in Optogenix. Tapered fibers that are commercially available from Optogenix were used as tools in the research. Competing interests. B.L.S. is a founder of and holds private equity in Optogenix. Tapered fibers commercially available from Optogenix were used as tools in the research. EDAT- 2021/11/05 06:00 MHDA- 2022/03/05 06:00 CRDT- 2021/11/04 06:18 PHST- 2020/10/05 00:00 [received] PHST- 2021/09/27 00:00 [accepted] PHST- 2021/11/05 06:00 [pubmed] PHST- 2022/03/05 06:00 [medline] PHST- 2021/11/04 06:18 [entrez] AID - 10.1038/s41586-021-04055-4 [pii] AID - 10.1038/s41586-021-04055-4 [doi] PST - ppublish SO - Nature. 2021 Nov;599(7886):645-649. doi: 10.1038/s41586-021-04055-4. Epub 2021 Nov 3. PMID- 34610277 OWN - NLM STAT- MEDLINE DCOM- 20220106 LR - 20221029 IS - 1097-4172 (Electronic) IS - 0092-8674 (Print) IS - 0092-8674 (Linking) VI - 184 IP - 22 DP - 2021 Oct 28 TI - Bombesin-like peptide recruits disinhibitory cortical circuits and enhances fear memories. PG - 5622-5634.e25 LID - S0092-8674(21)01060-6 [pii] LID - 10.1016/j.cell.2021.09.013 [doi] AB - Disinhibitory neurons throughout the mammalian cortex are powerful enhancers of circuit excitability and plasticity. The differential expression of neuropeptide receptors in disinhibitory, inhibitory, and excitatory neurons suggests that each circuit motif may be controlled by distinct neuropeptidergic systems. Here, we reveal that a bombesin-like neuropeptide, gastrin-releasing peptide (GRP), recruits disinhibitory cortical microcircuits through selective targeting and activation of vasoactive intestinal peptide (VIP)-expressing cells. Using a genetically encoded GRP sensor, optogenetic anterograde stimulation, and trans-synaptic tracing, we reveal that GRP regulates VIP cells most likely via extrasynaptic diffusion from several local and long-range sources. In vivo photometry and CRISPR-Cas9-mediated knockout of the GRP receptor (GRPR) in auditory cortex indicate that VIP cells are strongly recruited by novel sounds and aversive shocks, and GRP-GRPR signaling enhances auditory fear memories. Our data establish peptidergic recruitment of selective disinhibitory cortical microcircuits as a mechanism to regulate fear memories. CI - Copyright © 2021 Elsevier Inc. All rights reserved. FAU - Melzer, Sarah AU - Melzer S AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Newmark, Elena R AU - Newmark ER AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Mizuno, Grace Or AU - Mizuno GO AD - Departments of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA, USA. FAU - Hyun, Minsuk AU - Hyun M AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Philson, Adrienne C AU - Philson AC AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Quiroli, Eleonora AU - Quiroli E AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Righetti, Beatrice AU - Righetti B AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Gregory, Malika R AU - Gregory MR AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Huang, Kee Wui AU - Huang KW AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Levasseur, James AU - Levasseur J AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Tian, Lin AU - Tian L AD - Departments of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. Electronic address: bsabatini@hms.harvard.edu. LA - eng GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - R37 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20211004 PL - United States TA - Cell JT - Cell JID - 0413066 RN - 0 (Receptors, Bombesin) RN - 37221-79-7 (Vasoactive Intestinal Peptide) RN - 80043-53-4 (Gastrin-Releasing Peptide) RN - PX9AZU7QPK (Bombesin) RN - SY7Q814VUP (Calcium) SB - IM CIN - Nat Rev Neurosci. 2021 Dec;22(12):719. PMID: 34707260 CIN - Cell. 2021 Oct 28;184(22):5501-5503. PMID: 34715019 MH - Amino Acid Sequence MH - Animals MH - Auditory Cortex/*metabolism MH - Bombesin/*metabolism MH - Calcium/metabolism MH - Calcium Signaling MH - Conditioning, Classical MH - Fear/*physiology MH - Gastrin-Releasing Peptide/chemistry/metabolism MH - Gene Expression Regulation MH - Genes, Immediate-Early MH - HEK293 Cells MH - Humans MH - Intracellular Space/metabolism MH - Male MH - Memory/*physiology MH - Mice, Inbred C57BL MH - Nerve Net/*metabolism MH - Receptors, Bombesin/metabolism MH - Sound MH - Vasoactive Intestinal Peptide/metabolism PMC - PMC8556345 MID - NIHMS1744663 OTO - NOTNLM OT - CRISPR-Cas9 OT - VIP cells OT - cortex OT - disinhibition OT - fear memory OT - gastrin-releasing peptide OT - neuropeptide COIS- Declaration of interests L.T. and G.O.M. are co-founders of Seven Biosciences. EDAT- 2021/10/06 06:00 MHDA- 2022/01/07 06:00 CRDT- 2021/10/05 20:08 PHST- 2020/10/23 00:00 [received] PHST- 2021/07/12 00:00 [revised] PHST- 2021/09/08 00:00 [accepted] PHST- 2021/10/06 06:00 [pubmed] PHST- 2022/01/07 06:00 [medline] PHST- 2021/10/05 20:08 [entrez] AID - S0092-8674(21)01060-6 [pii] AID - 10.1016/j.cell.2021.09.013 [doi] PST - ppublish SO - Cell. 2021 Oct 28;184(22):5622-5634.e25. doi: 10.1016/j.cell.2021.09.013. Epub 2021 Oct 4. PMID- 34661994 OWN - NLM STAT- MEDLINE DCOM- 20211020 LR - 20221003 IS - 2691-1299 (Electronic) IS - 2691-1299 (Linking) VI - 1 IP - 10 DP - 2021 Oct TI - Real-Time, In Vivo Measurement of Protein Kinase A Activity in Deep Brain Structures Using Fluorescence Lifetime Photometry (FLiP). PG - e265 LID - 10.1002/cpz1.265 [doi] AB - The biochemical state of neurons, and of cells in general, is regulated by extracellular factors, including neurotransmitters, neuromodulators, and growth hormones. Interactions of an animal with its environment trigger neuromodulator release and engage biochemical transduction cascades to modulate synapse and cell function. Although these processes are thought to enact behavioral adaption to changing environments, when and where in the brain they are induced has been mysterious because of the challenge of monitoring biochemical state in real time in defined neurons in behaving animals. Here, we describe a method allowing measurement of activity of protein kinase A (PKA), an important intracellular effector for neuromodulators, in freely moving mice. To monitor PKA activity in vivo, we use a genetically targeted sensor (FLIM-AKAR) and fluorescence lifetime photometry (FLiP). This article describes how to set up a FLiP system and obtain robust recordings of net PKA phosphorylation state in vivo. The methods should be generally useful to monitor other pathways for which fluorescence lifetime reporters exist. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Building a FLiP system Basic Protocol 2: FLIM-AKAR viral injection and fiber implantation for FLiP measurement Basic Protocol 3: Performing measurements using FLiP. CI - © 2021 Wiley Periodicals LLC. FAU - Lodder, Bart AU - Lodder B AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts. AD - Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Boston, Massachusetts. FAU - Lee, Suk Joon AU - Lee SJ AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PL - United States TA - Curr Protoc JT - Current protocols JID - 101773894 RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) SB - IM MH - Animals MH - *Brain/metabolism MH - Cyclic AMP-Dependent Protein Kinases/metabolism MH - Mice MH - Neurons/metabolism MH - Phosphorylation MH - *Photometry PMC - PMC8650723 MID - NIHMS1737670 OTO - NOTNLM OT - FLiP OT - PKA OT - fluorescence OT - lifetime OT - photometry COIS- CONFLICT OF INTEREST STATEMENT: Authors declare no conflict of interest. EDAT- 2021/10/19 06:00 MHDA- 2021/10/21 06:00 CRDT- 2021/10/18 12:49 PHST- 2021/10/18 12:49 [entrez] PHST- 2021/10/19 06:00 [pubmed] PHST- 2021/10/21 06:00 [medline] AID - 10.1002/cpz1.265 [doi] PST - ppublish SO - Curr Protoc. 2021 Oct;1(10):e265. doi: 10.1002/cpz1.265. PMID- 33680555 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210924 IS - 2156-7085 (Print) IS - 2156-7085 (Electronic) IS - 2156-7085 (Linking) VI - 12 IP - 2 DP - 2021 Feb 1 TI - Comparative study of autofluorescence in flat and tapered optical fibers towards application in depth-resolved fluorescence lifetime photometry in brain tissue. PG - 993-1010 LID - 10.1364/BOE.410244 [doi] AB - As the scientific community seeks efficient optical neural interfaces with sub-cortical structures of the mouse brain, a wide set of technologies and methods is being developed to monitor cellular events through fluorescence signals generated by genetically encoded molecules. Among these technologies, tapered optical fibers (TFs) take advantage of the modal properties of narrowing waveguides to enable both depth-resolved and wide-volume light collection from scattering tissue, with minimized invasiveness with respect to standard flat fiber stubs (FFs). However, light guided in patch cords as well as in FFs and TFs can result in autofluorescence (AF) signal, which can act as a source of time-variable noise and limit their application to probe fluorescence lifetime in vivo. In this work, we compare the AF signal of FFs and TFs, highlighting the influence of the cladding composition on AF generation. We show that the autofluorescence signal generated in TFs has a peculiar coupling pattern with guided modes, and that far-field detection can be exploited to separate functional fluorescence from AF. On these bases, we provide evidence that TFs can be employed to implement depth-resolved fluorescence lifetime photometry, potentially enabling the extraction of a new set of information from deep brain regions, as time-correlating single photon counting starts to be applied in freely-moving animals to monitor the intracellular biochemical state of neurons. CI - © 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement. FAU - Bianco, Marco AU - Bianco M AUID- ORCID: 0000-0001-9693-1106 AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti 14, 73010 Arnesano (Lecce), Italy. AD - Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Via per Monteroni, 73100 Lecce, Italy. FAU - Balena, Antonio AU - Balena A AUID- ORCID: 0000-0003-4314-4314 AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti 14, 73010 Arnesano (Lecce), Italy. AD - Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Via per Monteroni, 73100 Lecce, Italy. FAU - Pisanello, Marco AU - Pisanello M AUID- ORCID: 0000-0003-2179-7883 AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti 14, 73010 Arnesano (Lecce), Italy. FAU - Pisano, Filippo AU - Pisano F AUID- ORCID: 0000-0002-5499-160X AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti 14, 73010 Arnesano (Lecce), Italy. FAU - Sileo, Leonardo AU - Sileo L AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti 14, 73010 Arnesano (Lecce), Italy. FAU - Spagnolo, Barbara AU - Spagnolo B AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti 14, 73010 Arnesano (Lecce), Italy. FAU - Montinaro, Cinzia AU - Montinaro C AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti 14, 73010 Arnesano (Lecce), Italy. AD - Dipartimento di Scienze e Tecnologie Biologiche e Ambientali, Università del Salento, Via per Monteroni, 73100 Lecce, Italy. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Vittorio, Massimo De AU - Vittorio M AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti 14, 73010 Arnesano (Lecce), Italy. AD - Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Via per Monteroni, 73100 Lecce, Italy. AD - massimo.devittorio@iit.it. FAU - Pisanello, Ferruccio AU - Pisanello F AUID- ORCID: 0000-0002-1489-7758 AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti 14, 73010 Arnesano (Lecce), Italy. AD - ferruccio.pisanello@iit.it. LA - eng GR - 677683/ERC_/European Research Council/International GR - 692943/ERC_/European Research Council/International GR - U01 NS094190/NS/NINDS NIH HHS/United States GR - UF1 NS108177/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20210126 PL - United States TA - Biomed Opt Express JT - Biomedical optics express JID - 101540630 PMC - PMC7901336 COIS- L.S., M.D.V., B.L.S. and F. Pisanello are founders and hold private equity in Optogenix, a company that develops, produces and sells technologies to deliver light into the brain. Tapered fibers commercially available from Optogenix were used as tools in the research. EDAT- 2021/03/09 06:00 MHDA- 2021/03/09 06:01 CRDT- 2021/03/08 05:53 PHST- 2020/09/16 00:00 [received] PHST- 2020/12/21 00:00 [revised] PHST- 2020/12/29 00:00 [accepted] PHST- 2021/03/08 05:53 [entrez] PHST- 2021/03/09 06:00 [pubmed] PHST- 2021/03/09 06:01 [medline] AID - 410244 [pii] AID - 10.1364/BOE.410244 [doi] PST - epublish SO - Biomed Opt Express. 2021 Jan 26;12(2):993-1010. doi: 10.1364/BOE.410244. eCollection 2021 Feb 1. PMID- 33361810 OWN - NLM STAT- MEDLINE DCOM- 20210312 LR - 20220808 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 590 IP - 7846 DP - 2021 Feb TI - Cell-type-specific asynchronous modulation of PKA by dopamine in learning. PG - 451-456 LID - 10.1038/s41586-020-03050-5 [doi] AB - Reinforcement learning models postulate that neurons that release dopamine encode information about action and action outcome, and provide a teaching signal to striatal spiny projection neurons in the form of dopamine release(1). Dopamine is thought to guide learning via dynamic and differential modulation of protein kinase A (PKA) in each class of spiny projection neuron(2). However, the real-time relationship between dopamine and PKA in spiny projection neurons remains untested in behaving animals. Here we monitor the activity of dopamine-releasing neurons, extracellular levels of dopamine and net PKA activity in spiny projection neurons in the nucleus accumbens of mice during learning. We find positive and negative modulation of dopamine that evolves across training and is both necessary and sufficient to explain concurrent fluctuations in the PKA activity of spiny projection neurons. Modulations of PKA in spiny projection neurons that express type-1 and type-2 dopamine receptors are dichotomous, such that these neurons are selectively sensitive to increases and decreases, respectively, in dopamine that occur at different phases of learning. Thus, PKA-dependent pathways in each class of spiny projection neuron are asynchronously engaged by positive or negative dopamine signals during learning. FAU - Lee, Suk Joon AU - Lee SJ AUID- ORCID: 0000-0002-4719-5824 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Lodder, Bart AU - Lodder B AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Chen, Yao AU - Chen Y AUID- ORCID: 0000-0003-1509-6634 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. AD - Department of Neuroscience, Washington University School of Medicine, St Louis, MO, USA. FAU - Patriarchi, Tommaso AU - Patriarchi T AUID- ORCID: 0000-0001-9351-3734 AD - Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA. AD - Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland. FAU - Tian, Lin AU - Tian L AUID- ORCID: 0000-0001-7012-6926 AD - Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. bsabatini@hms.harvard.edu. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - U19 NS113201/NS/NINDS NIH HHS/United States GR - F32 DA035543/DA/NIDA NIH HHS/United States GR - R35NS105107/NH/NIH HHS/United States GR - U01NS013522/NH/NIH HHS/United States GR - U01 NS090604/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20201223 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Receptors, Dopamine) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) RN - VTD58H1Z2X (Dopamine) SB - IM MH - Animals MH - Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors/*metabolism MH - Dopamine/*metabolism MH - Dopaminergic Neurons/drug effects/enzymology/metabolism MH - Female MH - Fluorescence MH - GABAergic Neurons/drug effects/enzymology/metabolism MH - *Learning/drug effects MH - Male MH - Mice MH - Neuronal Plasticity/drug effects MH - Nucleus Accumbens/cytology MH - Photometry MH - Receptors, Dopamine/classification/metabolism PMC - PMC7889726 MID - NIHMS1642870 EDAT- 2020/12/29 06:00 MHDA- 2021/03/13 06:00 CRDT- 2020/12/28 11:51 PHST- 2019/11/11 00:00 [received] PHST- 2020/10/30 00:00 [accepted] PHST- 2020/12/29 06:00 [pubmed] PHST- 2021/03/13 06:00 [medline] PHST- 2020/12/28 11:51 [entrez] AID - 10.1038/s41586-020-03050-5 [pii] AID - 10.1038/s41586-020-03050-5 [doi] PST - ppublish SO - Nature. 2021 Feb;590(7846):451-456. doi: 10.1038/s41586-020-03050-5. Epub 2020 Dec 23. PMID- 33584320 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220107 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 12 DP - 2021 TI - The Kinase Specificity of Protein Kinase Inhibitor Peptide. PG - 632815 LID - 10.3389/fphar.2021.632815 [doi] LID - 632815 AB - G-protein-coupled-receptor (GPCR) signaling is exquisitely controlled to achieve spatial and temporal specificity. The endogenous protein kinase inhibitor peptide (PKI) confines the spatial and temporal spread of the activity of protein kinase A (PKA), which integrates inputs from three major types of GPCRs. Despite its wide usage as a pharmaceutical inhibitor of PKA, it was unclear whether PKI only inhibits PKA activity. Here, the effects of PKI on 55 mouse kinases were tested in in vitro assays. We found that in addition to inhibiting PKA activity, both PKI (6-22) amide and full-length PKIα facilitated the activation of multiple isoforms of protein kinase C (PKC), albeit at much higher concentrations than necessary to inhibit PKA. Thus, our results call for appropriate interpretation of experimental results using PKI as a pharmaceutical agent. Furthermore, our study lays the foundation to explore the potential functions of PKI in regulating PKC activity and in coordinating PKC and PKA activities. CI - Copyright © 2021 Chen and Sabatini. FAU - Chen, Yao AU - Chen Y AD - Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States. AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, United States. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20210129 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC7878667 OTO - NOTNLM OT - endogenous OT - facilitation OT - inhibition OT - kinase screen OT - protein kinase A OT - protein kinase C OT - protein kinase inhibitor peptide OT - specificity COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/02/16 06:00 MHDA- 2021/02/16 06:01 CRDT- 2021/02/15 06:07 PHST- 2020/11/24 00:00 [received] PHST- 2021/01/04 00:00 [accepted] PHST- 2021/02/15 06:07 [entrez] PHST- 2021/02/16 06:00 [pubmed] PHST- 2021/02/16 06:01 [medline] AID - 632815 [pii] AID - 10.3389/fphar.2021.632815 [doi] PST - epublish SO - Front Pharmacol. 2021 Jan 29;12:632815. doi: 10.3389/fphar.2021.632815. eCollection 2021. PMID- 33443190 OWN - NLM STAT- MEDLINE DCOM- 20210514 LR - 20210622 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 118 IP - 1 DP - 2021 Jan 5 TI - Social isolation uncovers a circuit underlying context-dependent territory-covering micturition. LID - 10.1073/pnas.2018078118 [doi] LID - e2018078118 AB - The release of urine, or micturition, serves a fundamental physiological function and, in many species, is critical for social communication. In mice, the pattern of urine release is modulated by external and internal factors and transmitted to the spinal cord via the pontine micturition center (PMC). Here, we exploited a behavioral paradigm in which mice, depending on strain, social experience, and sensory context, either vigorously cover an arena with small urine spots or deposit urine in a few isolated large spots. We refer to these micturition modes as, respectively, high and low territory-covering micturition (TCM) and find that the presence of a urine stimulus robustly induces high TCM in socially isolated mice. Comparison of the brain networks activated by social isolation and by urine stimuli to those upstream of the PMC identified the lateral hypothalamic area as a potential modulator of micturition modes. Indeed, chemogenetic manipulations of the lateral hypothalamus can switch micturition behavior between high and low TCM, overriding the influence of social experience and sensory context. Our results suggest that both inhibitory and excitatory signals arising from a network upstream of the PMC are integrated to determine context- and social-experience-dependent micturition patterns. FAU - Hyun, Minsuk AU - Hyun M AD - Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115. AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115. FAU - Taranda, Julian AU - Taranda J AUID- ORCID: 0000-0002-2948-2133 AD - Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. FAU - Radeljic, Gianna AU - Radeljic G AD - Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115. AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115. FAU - Miner, Lauren AU - Miner L AUID- ORCID: 0000-0003-3756-3248 AD - Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115. AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115. FAU - Wang, Wengang AU - Wang W AD - Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115. AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115. FAU - Ochandarena, Nicole AU - Ochandarena N AD - Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115. AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115. FAU - Huang, Kee Wui AU - Huang KW AUID- ORCID: 0000-0003-2265-4550 AD - Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115. AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115. FAU - Osten, Pavel AU - Osten P AD - Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; bsabatini@hms.harvard.edu. AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115. LA - eng GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - R01 DK114834/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 SB - IM MH - Animals MH - Brain/physiology MH - Communication MH - Hypothalamus/*physiology MH - Male MH - Mice MH - Mice, 129 Strain MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Pons/physiology MH - Reflex/physiology MH - Social Isolation/*psychology MH - Spinal Cord/physiology MH - Urinary Bladder/physiology MH - Urination/genetics/*physiology PMC - PMC7817200 OTO - NOTNLM OT - hypothamaus OT - micturition OT - pons OT - social hierarchy COIS- The authors declare no competing interest. EDAT- 2021/01/15 06:00 MHDA- 2021/05/15 06:00 CRDT- 2021/01/14 08:50 PHST- 2021/01/14 08:50 [entrez] PHST- 2021/01/15 06:00 [pubmed] PHST- 2021/05/15 06:00 [medline] AID - 2018078118 [pii] AID - 202018078 [pii] AID - 10.1073/pnas.2018078118 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2021 Jan 5;118(1):e2018078118. doi: 10.1073/pnas.2018078118. PMID- 32807948 OWN - NLM STAT- MEDLINE DCOM- 20210208 LR - 20220809 IS - 1546-1726 (Electronic) IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 23 IP - 12 DP - 2020 Dec TI - Viral manipulation of functionally distinct interneurons in mice, non-human primates and humans. PG - 1629-1636 LID - 10.1038/s41593-020-0692-9 [doi] AB - Recent success in identifying gene-regulatory elements in the context of recombinant adeno-associated virus vectors has enabled cell-type-restricted gene expression. However, within the cerebral cortex these tools are largely limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple new enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we discovered enhancers selective for parvalbumin (PV) and vasoactive intestinal peptide-expressing interneurons. Demonstrating the functional utility of these elements, we show that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across vertebrate species, including humans. Finally, we demonstrate that our selection method is generalizable and characterizes additional PV-specific enhancers with exquisite specificity within distinct brain regions. Altogether, these viral tools can be used for cell-type-specific circuit manipulation and hold considerable promise for use in therapeutic interventions. FAU - Vormstein-Schneider, Douglas AU - Vormstein-Schneider D AUID- ORCID: 0000-0002-0345-2470 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Lin, Jessica D AU - Lin JD AUID- ORCID: 0000-0002-4093-0005 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Pelkey, Kenneth A AU - Pelkey KA AD - National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. FAU - Chittajallu, Ramesh AU - Chittajallu R AD - National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. FAU - Guo, Baolin AU - Guo B AUID- ORCID: 0000-0001-7309-5774 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Arias-Garcia, Mario A AU - Arias-Garcia MA AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Allaway, Kathryn AU - Allaway K AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. AD - NYU Langone Medical Center, New York University, New York, NY, USA. FAU - Sakopoulos, Sofia AU - Sakopoulos S AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Schneider, Gates AU - Schneider G AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Stevenson, Olivia AU - Stevenson O AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Vergara, Josselyn AU - Vergara J AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Sharma, Jitendra AU - Sharma J AD - McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA. FAU - Zhang, Qiangge AU - Zhang Q AD - McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA. FAU - Franken, Tom P AU - Franken TP AUID- ORCID: 0000-0001-7160-5152 AD - Systems Neurobiology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA, USA. FAU - Smith, Jared AU - Smith J AUID- ORCID: 0000-0002-0273-4898 AD - Systems Neurobiology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA, USA. FAU - Ibrahim, Leena A AU - Ibrahim LA AUID- ORCID: 0000-0001-8255-3423 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Mastro, Kevin J AU - Mastro KJ AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Sabri, Ehsan AU - Sabri E AD - Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA. FAU - Huang, Shuhan AU - Huang S AUID- ORCID: 0000-0002-3139-7296 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Favuzzi, Emilia AU - Favuzzi E AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Burbridge, Timothy AU - Burbridge T AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Xu, Qing AU - Xu Q AD - Center for Genomics & Systems Biology, New York University, Abu Dhabi, UAE. FAU - Guo, Lihua AU - Guo L AD - Center for Genomics & Systems Biology, New York University, Abu Dhabi, UAE. FAU - Vogel, Ian AU - Vogel I AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Sanchez, Vanessa AU - Sanchez V AUID- ORCID: 0000-0001-9380-5358 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Saldi, Giuseppe A AU - Saldi GA AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Gorissen, Bram L AU - Gorissen BL AUID- ORCID: 0000-0001-5992-0432 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Yuan, Xiaoqing AU - Yuan X AD - National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. FAU - Zaghloul, Kareem A AU - Zaghloul KA AUID- ORCID: 0000-0001-8575-3578 AD - National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. FAU - Devinsky, Orrin AU - Devinsky O AUID- ORCID: 0000-0003-0044-4632 AD - Comprehensive Epilepsy Center, New York University School of Medicine, New York, NY, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Batista-Brito, Renata AU - Batista-Brito R AD - Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA. FAU - Reynolds, John AU - Reynolds J AD - Systems Neurobiology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA, USA. FAU - Feng, Guoping AU - Feng G AUID- ORCID: 0000-0002-8021-277X AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA. FAU - Fu, Zhanyan AU - Fu Z AUID- ORCID: 0000-0001-9473-2402 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - McBain, Chris J AU - McBain CJ AUID- ORCID: 0000-0002-5909-0157 AD - National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. FAU - Fishell, Gord AU - Fishell G AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Dimidschstein, Jordane AU - Dimidschstein J AUID- ORCID: 0000-0001-6289-6891 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. jordane@broadinstitute.org. LA - eng GR - P01 NS074972/NS/NINDS NIH HHS/United States GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - P50 MH094271/MH/NIMH NIH HHS/United States GR - R01 MH071679/MH/NIMH NIH HHS/United States GR - UG3 MH120096/MH/NIMH NIH HHS/United States GR - R37 MH071679/MH/NIMH NIH HHS/United States GR - R01 NS081297/NS/NINDS NIH HHS/United States GR - K99 NS106528/NS/NINDS NIH HHS/United States GR - R01 MH111529/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20200817 PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 0 (NAV1.1 Voltage-Gated Sodium Channel) RN - 0 (Parvalbumins) RN - 0 (Scn1a protein, mouse) RN - 37221-79-7 (Vasoactive Intestinal Peptide) SB - IM CIN - Epilepsy Curr. 2021 Jan 7;:1535759720985841. PMID: 33412946 EIN - Nat Neurosci. 2022 Sep;25(9):1247. PMID: 35945454 MH - Animals MH - Callithrix MH - Cerebral Cortex/cytology MH - Dependovirus/*genetics MH - Female MH - Genetic Vectors/*genetics MH - Humans MH - Interneurons/*physiology MH - Macaca mulatta MH - Mice MH - Mice, Inbred C57BL MH - NAV1.1 Voltage-Gated Sodium Channel/genetics MH - Neurons MH - Parvalbumins/physiology MH - Rats MH - Rats, Sprague-Dawley MH - Species Specificity MH - Vasoactive Intestinal Peptide/physiology PMC - PMC8015416 MID - NIHMS1682740 COIS- COMPETING INTEREST STATEMENT The authors declare competing financial interests: The Broad Institute of MIT and Harvard has filed patent applications related to this work with Gord Fishell and Jordane Dimidschstein listed as inventors. EDAT- 2020/08/19 06:00 MHDA- 2021/02/09 06:00 CRDT- 2020/08/19 06:00 PHST- 2019/12/20 00:00 [received] PHST- 2020/07/10 00:00 [accepted] PHST- 2020/08/19 06:00 [pubmed] PHST- 2021/02/09 06:00 [medline] PHST- 2020/08/19 06:00 [entrez] AID - 10.1038/s41593-020-0692-9 [pii] AID - 10.1038/s41593-020-0692-9 [doi] PST - ppublish SO - Nat Neurosci. 2020 Dec;23(12):1629-1636. doi: 10.1038/s41593-020-0692-9. Epub 2020 Aug 17. PMID- 32989293 OWN - NLM STAT- MEDLINE DCOM- 20210115 LR - 20210907 IS - 1546-1726 (Electronic) IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 23 IP - 11 DP - 2020 Nov TI - Anatomically segregated basal ganglia pathways allow parallel behavioral modulation. PG - 1388-1398 LID - 10.1038/s41593-020-00712-5 [doi] AB - In the basal ganglia (BG), anatomically segregated and topographically organized feedforward circuits are thought to modulate multiple behaviors in parallel. Although topographically arranged BG circuits have been described, the extent to which these relationships are maintained across the BG output nuclei and in downstream targets is unclear. Here, using focal trans-synaptic anterograde tracing, we show that the motor-action-related topographical organization of the striatum is preserved in all BG output nuclei. The topography is also maintained downstream of the BG and in multiple parallel closed loops that provide striatal input. Furthermore, focal activation of two distinct striatal regions induces either licking or turning, consistent with their respective anatomical targets of projection outside of the BG. Our results confirm the parallel model of BG function and suggest that the integration and competition of information relating to different behavior occur largely outside of the BG. FAU - Lee, Jaeeon AU - Lee J AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Wang, Wengang AU - Wang W AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. bsabatini@hms.harvard.edu. LA - eng GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - U19 NS113201/NS/NINDS NIH HHS/United States GR - R01 NS103226/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200928 PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 SB - IM MH - Animals MH - Basal Ganglia/*cytology/*physiology MH - Behavior, Animal/*physiology MH - Cerebral Cortex/physiology MH - Female MH - Intralaminar Thalamic Nuclei/cytology/physiology MH - Male MH - Mice, Inbred C57BL MH - Neural Pathways/cytology/physiology MH - Neuroanatomical Tract-Tracing Techniques MH - Neurons/*physiology MH - Pars Reticulata/cytology/physiology MH - Superior Colliculi/cytology/physiology MH - Ventral Thalamic Nuclei/cytology/physiology PMC - PMC7606600 MID - NIHMS1622624 EDAT- 2020/09/30 06:00 MHDA- 2021/01/16 06:00 CRDT- 2020/09/29 05:35 PHST- 2020/01/29 00:00 [received] PHST- 2020/08/21 00:00 [accepted] PHST- 2020/09/30 06:00 [pubmed] PHST- 2021/01/16 06:00 [medline] PHST- 2020/09/29 05:35 [entrez] AID - 10.1038/s41593-020-00712-5 [pii] AID - 10.1038/s41593-020-00712-5 [doi] PST - ppublish SO - Nat Neurosci. 2020 Nov;23(11):1388-1398. doi: 10.1038/s41593-020-00712-5. Epub 2020 Sep 28. PMID- 33058762 OWN - NLM STAT- MEDLINE DCOM- 20201130 LR - 20221020 IS - 1097-4199 (Electronic) IS - 0896-6273 (Linking) VI - 108 IP - 1 DP - 2020 Oct 14 TI - Imaging Neurotransmitter and Neuromodulator Dynamics In Vivo with Genetically Encoded Indicators. PG - 17-32 LID - S0896-6273(20)30760-1 [pii] LID - 10.1016/j.neuron.2020.09.036 [doi] AB - The actions of neuromodulation are thought to mediate the ability of the mammalian brain to dynamically adjust its functional state in response to changes in the environment. Altered neurotransmitter (NT) and neuromodulator (NM) signaling is central to the pathogenesis or treatment of many human neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, depression, and addiction. To reveal the precise mechanisms by which these neurochemicals regulate healthy and diseased neural circuitry, one needs to measure their spatiotemporal dynamics in the living brain with great precision. Here, we discuss recent development, optimization, and applications of optical approaches to measure the spatial and temporal profiles of NT and NM release in the brain using genetically encoded sensors for in vivo studies. CI - Copyright © 2020 Elsevier Inc. All rights reserved. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. Electronic address: bernardo_sabatini@hms.harvard.edu. FAU - Tian, Lin AU - Tian L AD - Departments of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA, USA. Electronic address: lintian@ucdavis.edu. LA - eng GR - DP2 MH107056/MH/NIMH NIH HHS/United States GR - U01 NS103571/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - U01 NS090604/NS/NINDS NIH HHS/United States GR - R21 NS095325/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Neurotransmitter Agents) RN - 0 (Periplasmic Binding Proteins) RN - 0 (Receptors, G-Protein-Coupled) SB - IM MH - Animals MH - *Biosensing Techniques MH - Brain/diagnostic imaging/*metabolism MH - Humans MH - Neurons/*metabolism MH - Neurotransmitter Agents/*metabolism MH - *Optical Imaging MH - *Optogenetics MH - Periplasmic Binding Proteins/genetics MH - Protein Engineering MH - Receptors, G-Protein-Coupled/genetics COIS- Declaration of Interests L.T. is a co-founder of Seven Biosciences. EDAT- 2020/10/16 06:00 MHDA- 2020/12/01 06:00 CRDT- 2020/10/15 20:09 PHST- 2020/07/20 00:00 [received] PHST- 2020/08/10 00:00 [revised] PHST- 2020/09/25 00:00 [accepted] PHST- 2020/10/15 20:09 [entrez] PHST- 2020/10/16 06:00 [pubmed] PHST- 2020/12/01 06:00 [medline] AID - S0896-6273(20)30760-1 [pii] AID - 10.1016/j.neuron.2020.09.036 [doi] PST - ppublish SO - Neuron. 2020 Oct 14;108(1):17-32. doi: 10.1016/j.neuron.2020.09.036. PMID- 33043885 OWN - NLM STAT- MEDLINE DCOM- 20210224 LR - 20210224 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 9 DP - 2020 Oct 12 TI - Rapid purification and metabolomic profiling of synaptic vesicles from mammalian brain. LID - 10.7554/eLife.59699 [doi] LID - e59699 AB - Neurons communicate by the activity-dependent release of small-molecule neurotransmitters packaged into synaptic vesicles (SVs). Although many molecules have been identified as neurotransmitters, technical limitations have precluded a full metabolomic analysis of SV content. Here, we present a workflow to rapidly isolate SVs and to interrogate their metabolic contents at high-resolution using mass spectrometry. We validated the enrichment of glutamate in SVs of primary cortical neurons using targeted polar metabolomics. Unbiased and extensive global profiling of SVs isolated from these neurons revealed that the only detectable polar metabolites they contain are the established neurotransmitters glutamate and GABA. In addition, we adapted the approach to enable quick capture of SVs directly from brain tissue and determined the neurotransmitter profiles of diverse brain regions in a cell-type-specific manner. The speed, robustness, and precision of this method to interrogate SV contents will facilitate novel insights into the chemical basis of neurotransmission. CI - © 2020, Chantranupong et al. FAU - Chantranupong, Lynne AU - Chantranupong L AUID- ORCID: 0000-0001-9814-5264 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Saulnier, Jessica L AU - Saulnier JL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Wang, Wengang AU - Wang W AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Jones, Drew R AU - Jones DR AD - New York University School of Medicine, Metabolomics Core Resource Laboratory at NYU Langone Health, New York, United States. FAU - Pacold, Michael E AU - Pacold ME AUID- ORCID: 0000-0003-3688-2378 AD - Department of Radiation Oncology, New York University Langone Medical Center, New York, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - HHS-NIH-NIAD-BAA2018/GF/NIH HHS/United States GR - 017-032/Mary Kay Foundation/International GR - RFA 2018-PACT001/FNIH/International GR - R01 NS108151/NS/NINDS NIH HHS/United States GR - V2017-004/Hearst Foundations/International GR - K22 CA212059/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20201012 PL - England TA - Elife JT - eLife JID - 101579614 RN - 3KX376GY7L (Glutamic Acid) SB - IM MH - Animals MH - Brain/*metabolism MH - Female MH - Glutamic Acid/metabolism MH - Male MH - Mass Spectrometry/*methods MH - *Metabolome MH - Metabolomics/*methods MH - Mice MH - Synaptic Vesicles/*metabolism PMC - PMC7575323 OTO - NOTNLM OT - metabolomics OT - mouse OT - neuroscience OT - neurotransmitters OT - synaptic vesicle COIS- LC, JS, WW, DJ, MP, BS No competing interests declared EDAT- 2020/10/13 06:00 MHDA- 2021/02/25 06:00 CRDT- 2020/10/12 08:48 PHST- 2020/06/05 00:00 [received] PHST- 2020/10/11 00:00 [accepted] PHST- 2020/10/13 06:00 [pubmed] PHST- 2021/02/25 06:00 [medline] PHST- 2020/10/12 08:48 [entrez] AID - 59699 [pii] AID - 10.7554/eLife.59699 [doi] PST - epublish SO - Elife. 2020 Oct 12;9:e59699. doi: 10.7554/eLife.59699. PMID- 32752416 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210708 IS - 1094-4087 (Electronic) IS - 1094-4087 (Linking) VI - 28 IP - 15 DP - 2020 Jul 20 TI - Two-photon fluorescence-assisted laser ablation of non-planar metal surfaces: fabrication of optical apertures on tapered fibers for optical neural interfaces. PG - 21368-21381 LID - 10.1364/OE.395187 [doi] AB - We propose a feedback-assisted direct laser writing method to perform laser ablation of fiber optic devices in which their light-collection signal is used to optimize their properties. A femtosecond-pulsed laser beam is used to ablate a metal coating deposited around a tapered optical fiber, employed to show the suitability of the approach to pattern devices with a small radius of curvature. During processing, the same pulses generate two-photon fluorescence in the surrounding environment and the signal is monitored to identify different patterning regimes over time through spectral analysis. The employed fs beam mostly interacts with the metal coating, leaving almost intact the underlying silica and enabling fluorescence to couple with a specific subset of guided modes, as verified by far-field analysis. Although the method is described here for tapered optical fibers used to obtain efficient light collection in the field of optical neural interfaces, it can be easily extended to other waveguide-based devices and represents a general approach to support the implementation of a closed-loop laser ablation system of fiber optics. FAU - Balena, Antonio AU - Balena A FAU - Bianco, Marco AU - Bianco M FAU - Pisano, Filippo AU - Pisano F FAU - Pisanello, Marco AU - Pisanello M FAU - Sileo, Leonardo AU - Sileo L FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Vittorio, Massimo De AU - Vittorio M FAU - Pisanello, Ferruccio AU - Pisanello F LA - eng GR - U01 NS094190/NS/NINDS NIH HHS/United States GR - UF1 NS108177/NS/NINDS NIH HHS/United States PT - Journal Article PL - United States TA - Opt Express JT - Optics express JID - 101137103 SB - IM PMC - PMC7470681 COIS- LS, MDV, BLS and F. Pisanello are founders and hold private equity in Optogenix, a company that develops, produces and sells technologies to deliver light into the brain. Tapered fibers commercially available from Optogenix were used as tools in the research. EDAT- 2020/08/06 06:00 MHDA- 2020/08/06 06:01 CRDT- 2020/08/06 06:00 PHST- 2020/08/06 06:00 [entrez] PHST- 2020/08/06 06:00 [pubmed] PHST- 2020/08/06 06:01 [medline] AID - 433256 [pii] AID - 395187 [pii] AID - 10.1364/OE.395187 [doi] PST - ppublish SO - Opt Express. 2020 Jul 20;28(15):21368-21381. doi: 10.1364/OE.395187. PMID- 32667302 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20200722 LR - 20210924 IS - 1539-4794 (Electronic) IS - 0146-9592 (Linking) VI - 45 IP - 14 DP - 2020 Jul 15 TI - Ray tracing models for estimating light collection properties of microstructured tapered optical fibers for optical neural interfaces. PG - 3856-3859 LID - 10.1364/OL.397022 [doi] AB - Tapered optical fibers (TFs) were recently employed for depth-resolved monitoring of functional fluorescence in subcortical brain structures, enabling light collection from groups of a few cells through small optical windows located on the taper edge [Pisano et al., Nat. Methods16, 1185 (2019)1548-709110.1038/s41592-019-0581-x]. Here we present a numerical model to estimate light collection properties of microstructured TFs implanted in scattering brain tissue. Ray tracing coupled with the Henyey-Greenstein scattering model enables the estimation of both light collection and fluorescence excitation fields in three dimensions, whose combination is employed to retrieve the volume of tissue probed by the device. FAU - Maglie, Emanuela AU - Maglie E FAU - Pisanello, Marco AU - Pisanello M FAU - Pisano, Filippo AU - Pisano F FAU - Balena, Antonio AU - Balena A FAU - Bianco, Marco AU - Bianco M FAU - Spagnolo, Barbara AU - Spagnolo B FAU - Sileo, Leonardo AU - Sileo L FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - De Vittorio, Massimo AU - De Vittorio M FAU - Pisanello, Ferruccio AU - Pisanello F LA - eng GR - 677683/ERC_/European Research Council/International GR - 692943/ERC_/European Research Council/International GR - U01 NS094190/NS/NINDS NIH HHS/United States GR - UF1 NS108177/NS/NINDS NIH HHS/United States PT - Journal Article PL - United States TA - Opt Lett JT - Optics letters JID - 7708433 SB - IM EDAT- 2020/07/16 06:00 MHDA- 2020/07/16 06:01 CRDT- 2020/07/16 06:00 PHST- 2020/07/16 06:00 [entrez] PHST- 2020/07/16 06:00 [pubmed] PHST- 2020/07/16 06:01 [medline] AID - 433197 [pii] AID - 10.1364/OL.397022 [doi] PST - ppublish SO - Opt Lett. 2020 Jul 15;45(14):3856-3859. doi: 10.1364/OL.397022. PMID- 32613945 OWN - NLM STAT- MEDLINE DCOM- 20210514 LR - 20210514 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 9 DP - 2020 Jul 2 TI - Cortical ChAT(+) neurons co-transmit acetylcholine and GABA in a target- and brain-region-specific manner. LID - 10.7554/eLife.57749 [doi] LID - e57749 AB - The mouse cerebral cortex contains neurons that express choline acetyltransferase (ChAT) and are a potential local source of acetylcholine. However, the neurotransmitters released by cortical ChAT(+) neurons and their synaptic connectivity are unknown. We show that the nearly all cortical ChAT(+) neurons in mice are specialized VIP(+) interneurons that release GABA strongly onto other inhibitory interneurons and acetylcholine sparsely onto layer 1 interneurons and other VIP(+)/ChAT(+) interneurons. This differential transmission of ACh and GABA based on the postsynaptic target neuron is reflected in VIP(+)/ChAT(+) interneuron pre-synaptic terminals, as quantitative molecular analysis shows that only a subset of these are specialized to release acetylcholine. In addition, we identify a separate, sparse population of non-VIP ChAT(+) neurons in the medial prefrontal cortex with a distinct developmental origin that robustly release acetylcholine in layer 1. These results demonstrate both cortex-region heterogeneity in cortical ChAT(+) interneurons and target-specific co-release of acetylcholine and GABA. CI - © 2020, Granger et al. FAU - Granger, Adam J AU - Granger AJ AUID- ORCID: 0000-0002-3953-6764 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Wang, Wengang AU - Wang W AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Robertson, Keiramarie AU - Robertson K AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - El-Rifai, Mahmoud AU - El-Rifai M AD - Neurobiology Imaging Facility, Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Zanello, Andrea F AU - Zanello AF AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Bistrong, Karina AU - Bistrong K AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Saunders, Arpiar AU - Saunders A AD - Department of Genetics, Harvard Medical School, Boston, United States. FAU - Chow, Brian W AU - Chow BW AD - Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Nuñez, Vicente AU - Nuñez V AD - Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Turrero García, Miguel AU - Turrero García M AUID- ORCID: 0000-0002-7294-169X AD - Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Harwell, Corey C AU - Harwell CC AD - Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Gu, Chenghua AU - Gu C AUID- ORCID: 0000-0002-4212-7232 AD - Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, United States. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - R01 MH119156/MH/NIMH NIH HHS/United States GR - R56 MH119156/MH/NIMH NIH HHS/United States GR - K99 NS102429/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200702 PL - England TA - Elife JT - eLife JID - 101579614 RN - 56-12-2 (gamma-Aminobutyric Acid) RN - EC 2.3.1.6 (Choline O-Acetyltransferase) RN - N9YNS0M02X (Acetylcholine) SB - IM MH - Acetylcholine/*metabolism MH - Animals MH - Brain/*metabolism MH - Cerebral Cortex/metabolism MH - Choline O-Acetyltransferase/*metabolism MH - Heterozygote MH - Interneurons/metabolism MH - Mice MH - Neurons/*metabolism MH - Prefrontal Cortex/metabolism MH - Presynaptic Terminals/metabolism MH - gamma-Aminobutyric Acid/*metabolism PMC - PMC7360370 OTO - NOTNLM OT - Acetylcholine OT - GABA OT - VIP OT - cortical interneurons OT - mouse OT - neuromodulation OT - neuroscience OT - neurotransmitter co-release COIS- AG, WW, KR, ME, AZ, KB, AS, BC, VN, MT, CH, CG, BS No competing interests declared EDAT- 2020/07/03 06:00 MHDA- 2021/05/15 06:00 CRDT- 2020/07/03 06:00 PHST- 2020/04/10 00:00 [received] PHST- 2020/07/01 00:00 [accepted] PHST- 2020/07/03 06:00 [pubmed] PHST- 2021/05/15 06:00 [medline] PHST- 2020/07/03 06:00 [entrez] AID - 57749 [pii] AID - 10.7554/eLife.57749 [doi] PST - epublish SO - Elife. 2020 Jul 2;9:e57749. doi: 10.7554/eLife.57749. PMID- 32265666 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210310 IS - 1662-5102 (Print) IS - 1662-5102 (Electronic) IS - 1662-5102 (Linking) VI - 14 DP - 2020 TI - Single-Cell Analysis of Neuroinflammatory Responses Following Intracranial Injection of G-Deleted Rabies Viruses. PG - 65 LID - 10.3389/fncel.2020.00065 [doi] LID - 65 AB - Viral vectors are essential tools for the study of neural circuits, with glycoprotein-deleted rabies viruses being widely used for monosynaptic retrograde tracing to map connectivity between specific cell types in the nervous system. However, the use of rabies virus is limited by the cytotoxicity and the inflammatory responses these viruses trigger. While components of the rabies virus genome contribute to its cytotoxic effects, the function of other neuronal and non-neuronal cells within the vicinity of the infected host neurons in either effecting or mitigating virally-induced tissue damage are still being elucidated. Here, we analyzed 60,212 single-cell RNA profiles to assess both global and cell-type-specific transcriptional responses in the mouse dorsal raphe nucleus (DRN) following intracranial injection of glycoprotein-deleted rabies viruses and axonal infection of dorsal raphe serotonergic neurons. Gene pathway analyses revealed a down-regulation of genes involved in metabolic processes and neurotransmission following infection. We also identified several transcriptionally diverse leukocyte populations that infiltrate the brain and are distinct from resident immune cells. Cell type-specific patterns of cytokine expression showed that antiviral responses were likely orchestrated by Type I and Type II interferon signaling from microglia and infiltrating CD4(+) T cells, respectively. Additionally, we uncovered transcriptionally distinct states of microglia along an activation trajectory that may serve different functions, which range from surveillance to antigen presentation and cytokine secretion. Intercellular interactions inferred from transcriptional data suggest that CD4(+) T cells facilitate microglial state transitions during the inflammatory response. Our study uncovers the heterogeneity of immune cells mediating neuroinflammatory responses and provides a critical evaluation of the compatibility between rabies-mediated connectivity mapping and single-cell transcriptional profiling. These findings provide additional insights into the distinct contributions of various cell types in mediating different facets of antiviral responses in the brain and will facilitate the design of strategies to circumvent immune responses to improve the efficacy of viral gene delivery. CI - Copyright © 2020 Huang and Sabatini. FAU - Huang, Kee Wui AU - Huang KW AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, United States. LA - eng GR - R01 NS103226/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20200320 PL - Switzerland TA - Front Cell Neurosci JT - Frontiers in cellular neuroscience JID - 101477935 PMC - PMC7098990 OTO - NOTNLM OT - G-deleted rabies virus OT - brain infiltration OT - microglia OT - neuroinflammation OT - scRNA-seq EDAT- 2020/04/09 06:00 MHDA- 2020/04/09 06:01 CRDT- 2020/04/09 06:00 PHST- 2020/01/16 00:00 [received] PHST- 2020/03/04 00:00 [accepted] PHST- 2020/04/09 06:00 [entrez] PHST- 2020/04/09 06:00 [pubmed] PHST- 2020/04/09 06:01 [medline] AID - 10.3389/fncel.2020.00065 [doi] PST - epublish SO - Front Cell Neurosci. 2020 Mar 20;14:65. doi: 10.3389/fncel.2020.00065. eCollection 2020. PMID- 32076269 OWN - NLM STAT- MEDLINE DCOM- 20200413 LR - 20220418 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 579 IP - 7797 DP - 2020 Mar TI - Caveolae in CNS arterioles mediate neurovascular coupling. PG - 106-110 LID - 10.1038/s41586-020-2026-1 [doi] AB - Proper brain function depends on neurovascular coupling: neural activity rapidly increases local blood flow to meet moment-to-moment changes in regional brain energy demand(1). Neurovascular coupling is the basis for functional brain imaging(2), and impaired neurovascular coupling is implicated in neurodegeneration(1). The underlying molecular and cellular mechanisms of neurovascular coupling remain poorly understood. The conventional view is that neurons or astrocytes release vasodilatory factors that act directly on smooth muscle cells (SMCs) to induce arterial dilation and increase local blood flow(1). Here, using two-photon microscopy to image neural activity and vascular dynamics simultaneously in the barrel cortex of awake mice under whisker stimulation, we found that arteriolar endothelial cells (aECs) have an active role in mediating neurovascular coupling. We found that aECs, unlike other vascular segments of endothelial cells in the central nervous system, have abundant caveolae. Acute genetic perturbations that eliminated caveolae in aECs, but not in neighbouring SMCs, impaired neurovascular coupling. Notably, caveolae function in aECs is independent of the endothelial NO synthase (eNOS)-mediated NO pathway. Ablation of both caveolae and eNOS completely abolished neurovascular coupling, whereas the single mutants exhibited partial impairment, revealing that the caveolae-mediated pathway in aECs is a major contributor to neurovascular coupling. Our findings indicate that vasodilation is largely mediated by endothelial cells that actively relay signals from the central nervous system to SMCs via a caveolae-dependent pathway. FAU - Chow, Brian W AU - Chow BW AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Nuñez, Vicente AU - Nuñez V AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Kaplan, Luke AU - Kaplan L AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Granger, Adam J AU - Granger AJ AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Bistrong, Karina AU - Bistrong K AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Zucker, Hannah L AU - Zucker HL AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Kumar, Payal AU - Kumar P AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Gu, Chenghua AU - Gu C AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. chenghua_gu@hms.harvard.edu. LA - eng GR - DP1 NS092473/NS/NINDS NIH HHS/United States GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - K99 NS102429/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200219 PL - England TA - Nature JT - Nature JID - 0410462 RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - EC 1.14.13.39 (Nos3 protein, mouse) SB - IM MH - Animals MH - Arterioles/*cytology/*metabolism MH - Caveolae/*metabolism MH - Central Nervous System/*cytology MH - Cerebral Cortex/cytology MH - Endothelial Cells/metabolism MH - Female MH - Male MH - Mice MH - Microscopy, Fluorescence, Multiphoton MH - *Neurovascular Coupling MH - Nitric Oxide Synthase Type III/deficiency/metabolism MH - Vasodilation MH - Vibrissae/physiology PMC - PMC7060132 MID - NIHMS1548198 COIS- Competing Interests: The authors declare no competing financial interests. EDAT- 2020/02/23 06:00 MHDA- 2020/04/14 06:00 CRDT- 2020/02/21 06:00 PHST- 2019/02/19 00:00 [received] PHST- 2020/01/03 00:00 [accepted] PHST- 2020/02/23 06:00 [pubmed] PHST- 2020/04/14 06:00 [medline] PHST- 2020/02/21 06:00 [entrez] AID - 10.1038/s41586-020-2026-1 [pii] AID - 10.1038/s41586-020-2026-1 [doi] PST - ppublish SO - Nature. 2020 Mar;579(7797):106-110. doi: 10.1038/s41586-020-2026-1. Epub 2020 Feb 19. PMID- 32043968 OWN - NLM STAT- MEDLINE DCOM- 20210402 LR - 20210402 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 9 DP - 2020 Feb 11 TI - Anatomical and single-cell transcriptional profiling of the murine habenular complex. LID - 10.7554/eLife.51271 [doi] LID - e51271 AB - The lateral habenula (LHb) is an epithalamic brain structure critical for processing and adapting to negative action outcomes. However, despite the importance of LHb to behavior and the clear anatomical and molecular diversity of LHb neurons, the neuron types of the habenula remain unknown. Here, we use high-throughput single-cell transcriptional profiling, monosynaptic retrograde tracing, and multiplexed FISH to characterize the cells of the mouse habenula. We find five subtypes of neurons in the medial habenula (MHb) that are organized into anatomical subregions. In the LHb, we describe four neuronal subtypes and show that they differentially target dopaminergic and GABAergic cells in the ventral tegmental area (VTA). These data provide a valuable resource for future study of habenular function and dysfunction and demonstrate neuronal subtype specificity in the LHb-VTA circuit. CI - © 2020, Wallace et al. FAU - Wallace, Michael L AU - Wallace ML AUID- ORCID: 0000-0002-7270-8521 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Huang, Kee Wui AU - Huang KW AUID- ORCID: 0000-0003-2265-4550 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Hochbaum, Daniel AU - Hochbaum D AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Hyun, Minsuk AU - Hyun M AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Radeljic, Gianna AU - Radeljic G AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. LA - eng GR - R01 NS103226/NS/NINDS NIH HHS/United States GR - NS105883/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200211 PL - England TA - Elife JT - eLife JID - 101579614 SB - IM MH - Animals MH - Brain Mapping MH - Dopaminergic Neurons MH - GABAergic Neurons MH - Gene Expression Profiling MH - Habenula/cytology/*metabolism MH - Mice MH - Single-Cell Analysis MH - *Transcriptome MH - Ventral Tegmental Area/cytology PMC - PMC7012610 OTO - NOTNLM OT - VTA OT - dopamine OT - habenula OT - mouse OT - neuroscience OT - serotonin COIS- MW, KH, DH, MH, GR, BS No competing interests declared EDAT- 2020/02/12 06:00 MHDA- 2021/04/07 06:00 CRDT- 2020/02/12 06:00 PHST- 2019/08/22 00:00 [received] PHST- 2020/01/21 00:00 [accepted] PHST- 2020/02/12 06:00 [entrez] PHST- 2020/02/12 06:00 [pubmed] PHST- 2021/04/07 06:00 [medline] AID - 51271 [pii] AID - 10.7554/eLife.51271 [doi] PST - epublish SO - Elife. 2020 Feb 11;9:e51271. doi: 10.7554/eLife.51271. PMID- 31722214 OWN - NLM STAT- MEDLINE DCOM- 20200916 LR - 20210116 IS - 2211-1247 (Electronic) VI - 29 IP - 7 DP - 2019 Nov 12 TI - Abnormal Striatal Development Underlies the Early Onset of Behavioral Deficits in Shank3B(-/-) Mice. PG - 2016-2027.e4 LID - S2211-1247(19)31321-X [pii] LID - 10.1016/j.celrep.2019.10.021 [doi] AB - The neural substrates and pathophysiological mechanisms underlying the onset of cognitive and motor deficits in autism spectrum disorders (ASDs) remain unclear. Mutations in ASD-associated SHANK3 in mice (Shank3B(-/-)) result in the accelerated maturation of corticostriatal circuits during the second and third postnatal weeks. Here, we show that during this period, there is extensive remodeling of the striatal synaptic proteome and a developmental switch in glutamatergic synaptic plasticity induced by cortical hyperactivity in striatal spiny projection neurons (SPNs). Behavioral abnormalities in Shank3B(-/-) mice emerge during this stage and are ameliorated by normalizing excitatory synapse connectivity in medial striatal regions by the downregulation of PKA activity. These results suggest that the abnormal postnatal development of striatal circuits is implicated in the onset of behavioral deficits in Shank3B(-/-) mice and that modulation of postsynaptic PKA activity can be used to regulate corticostriatal drive in developing SPNs of mouse models of ASDs and other neurodevelopmental disorders. CI - Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved. FAU - Peixoto, Rui Tiago AU - Peixoto RT AD - Department of Psychiatry, University of Pittsburgh, 450 Technology Dr, Pittsburgh, PA 15219, USA; Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. Electronic address: rup14@pitt.edu. FAU - Chantranupong, Lynne AU - Chantranupong L AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. FAU - Hakim, Richard AU - Hakim R AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. FAU - Levasseur, James AU - Levasseur J AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. FAU - Wang, Wengang AU - Wang W AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. FAU - Merchant, Tasha AU - Merchant T AD - Department of Psychiatry, University of Pittsburgh, 450 Technology Dr, Pittsburgh, PA 15219, USA; Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. FAU - Gorman, Kelly AU - Gorman K AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. FAU - Budnik, Bogdan AU - Budnik B AD - Mass Spectrometry and Proteomic Laboratory, FAS Division of Science, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA. FAU - Sabatini, Bernardo Luis AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 0 (Microfilament Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (Shank3 protein, mouse) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) SB - IM MH - Animals MH - Autism Spectrum Disorder/*genetics/*metabolism/pathology MH - *Behavior, Animal MH - Corpus Striatum/*metabolism/pathology MH - Cyclic AMP-Dependent Protein Kinases/genetics/metabolism MH - Disease Models, Animal MH - Mice MH - Mice, Knockout MH - Microfilament Proteins/*deficiency/metabolism MH - Nerve Tissue Proteins/*deficiency/metabolism MH - Neurons/*metabolism/pathology PMC - PMC6889826 MID - NIHMS1542972 OTO - NOTNLM OT - ASD OT - Shank3 OT - autism OT - circuit OT - cortical OT - corticostriatal OT - development OT - plasticity OT - striatal OT - synaptic COIS- DECLARATION OF INTERESTS B.B. is a scientific advisor to Merck & Co. All of the other authors declare no competing interests. EDAT- 2019/11/14 06:00 MHDA- 2020/09/17 06:00 CRDT- 2019/11/14 06:00 PHST- 2018/10/30 00:00 [received] PHST- 2019/07/12 00:00 [revised] PHST- 2019/10/04 00:00 [accepted] PHST- 2019/11/14 06:00 [entrez] PHST- 2019/11/14 06:00 [pubmed] PHST- 2020/09/17 06:00 [medline] AID - S2211-1247(19)31321-X [pii] AID - 10.1016/j.celrep.2019.10.021 [doi] PST - ppublish SO - Cell Rep. 2019 Nov 12;29(7):2016-2027.e4. doi: 10.1016/j.celrep.2019.10.021. PMID- 31591577 OWN - NLM STAT- MEDLINE DCOM- 20200203 LR - 20210518 IS - 1548-7105 (Electronic) IS - 1548-7091 (Linking) VI - 16 IP - 11 DP - 2019 Nov TI - Depth-resolved fiber photometry with a single tapered optical fiber implant. PG - 1185-1192 LID - 10.1038/s41592-019-0581-x [doi] AB - Fiber photometry is increasingly utilized to monitor fluorescent sensors of neural activity in the brain. However, most implementations are based on flat-cleaved optical fibers that can only interface with shallow tissue volumes adjacent to the fiber. We exploit modal properties of tapered optical fibers (TFs) to enable light collection over an extent of up to 2 mm of tissue and multisite photometry along the taper. Using a single TF, we simultaneously observed distinct dopamine transients in dorsal and ventral striatum in freely moving mice performing a simple, operant conditioning task. Collection volumes from TFs can also be engineered in both shape and size by microstructuring the nonplanar surface of the taper, to optically target multiple sites not only in the deep brain but, in general, in any biological system or organ in which light collection is beneficial but challenging because of light scattering and absorption. FAU - Pisano, Filippo AU - Pisano F AUID- ORCID: 0000-0002-5499-160X AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, Italy. filippo.pisano@iit.it. FAU - Pisanello, Marco AU - Pisanello M AUID- ORCID: 0000-0003-2179-7883 AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, Italy. FAU - Lee, Suk Joon AU - Lee SJ AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Lee, Jaeeon AU - Lee J AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Maglie, Emanuela AU - Maglie E AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, Italy. AD - Dip. di Ingegneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - Balena, Antonio AU - Balena A AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, Italy. AD - Dip. di Ingegneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - Sileo, Leonardo AU - Sileo L AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, Italy. FAU - Spagnolo, Barbara AU - Spagnolo B AUID- ORCID: 0000-0001-7377-2819 AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, Italy. FAU - Bianco, Marco AU - Bianco M AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, Italy. AD - Dip. di Ingegneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - Hyun, Minsuk AU - Hyun M AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - De Vittorio, Massimo AU - De Vittorio M AUID- ORCID: 0000-0003-1601-6392 AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, Italy. massimo.devittorio@iit.it. AD - Dip. di Ingegneria dell'Innovazione, Università del Salento, Lecce, Italy. massimo.devittorio@iit.it. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. bernardo_sabatini@hms.harvard.edu. FAU - Pisanello, Ferruccio AU - Pisanello F AUID- ORCID: 0000-0002-1489-7758 AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, Italy. ferruccio.pisanello@iit.it. LA - eng GR - U01 NS094190/NS/NINDS NIH HHS/United States GR - UF1 NS108177/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20191007 PL - United States TA - Nat Methods JT - Nature methods JID - 101215604 RN - VTD58H1Z2X (Dopamine) SB - IM MH - Animals MH - Corpus Striatum/metabolism MH - Dopamine/metabolism MH - Fluorescence MH - Male MH - Mice MH - Mice, Inbred C57BL MH - *Optical Fibers MH - Photometry/*methods EDAT- 2019/10/09 06:00 MHDA- 2020/02/06 06:00 CRDT- 2019/10/09 06:00 PHST- 2018/10/15 00:00 [received] PHST- 2019/08/22 00:00 [accepted] PHST- 2019/10/09 06:00 [pubmed] PHST- 2020/02/06 06:00 [medline] PHST- 2019/10/09 06:00 [entrez] AID - 10.1038/s41592-019-0581-x [pii] AID - 10.1038/s41592-019-0581-x [doi] PST - ppublish SO - Nat Methods. 2019 Nov;16(11):1185-1192. doi: 10.1038/s41592-019-0581-x. Epub 2019 Oct 7. PMID- 31597963 OWN - NLM STAT- MEDLINE DCOM- 20200330 LR - 20220417 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 574 IP - 7778 DP - 2019 Oct TI - Population imaging of neural activity in awake behaving mice. PG - 413-417 LID - 10.1038/s41586-019-1641-1 [doi] AB - A longstanding goal in neuroscience has been to image membrane voltage across a population of individual neurons in an awake, behaving mammal. Here we describe a genetically encoded fluorescent voltage indicator, SomArchon, which exhibits millisecond response times and is compatible with optogenetic control, and which increases the sensitivity, signal-to-noise ratio, and number of neurons observable several-fold over previously published fully genetically encoded reagents(1-8). Under conventional one-photon microscopy, SomArchon enables the routine population analysis of around 13 neurons at once, in multiple brain regions (cortex, hippocampus, and striatum) of head-fixed, awake, behaving mice. Using SomArchon, we detected both positive and negative responses of striatal neurons during movement, as previously reported by electrophysiology but not easily detected using modern calcium imaging techniques(9-11), highlighting the power of voltage imaging to reveal bidirectional modulation. We also examined how spikes relate to the subthreshold theta oscillations of individual hippocampal neurons, with SomArchon showing that the spikes of individual neurons are more phase-locked to their own subthreshold theta oscillations than to local field potential theta oscillations. Thus, SomArchon reports both spikes and subthreshold voltage dynamics in awake, behaving mice. FAU - Piatkevich, Kiryl D AU - Piatkevich KD AD - Media Lab, MIT, Cambridge, MA, USA. AD - MIT McGovern Institute for Brain Research, MIT, Cambridge, MA, USA. FAU - Bensussen, Seth AU - Bensussen S AD - Department of Biomedical Engineering, Boston University, Boston, MA, USA. FAU - Tseng, Hua-An AU - Tseng HA AD - Department of Biomedical Engineering, Boston University, Boston, MA, USA. FAU - Shroff, Sanaya N AU - Shroff SN AD - Department of Biomedical Engineering, Boston University, Boston, MA, USA. FAU - Lopez-Huerta, Violeta Gisselle AU - Lopez-Huerta VG AD - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. FAU - Park, Demian AU - Park D AD - Media Lab, MIT, Cambridge, MA, USA. AD - MIT McGovern Institute for Brain Research, MIT, Cambridge, MA, USA. FAU - Jung, Erica E AU - Jung EE AD - Media Lab, MIT, Cambridge, MA, USA. AD - Department of Mechanical and Industrial Engineering, University of Illinois, Chicago, IL, USA. FAU - Shemesh, Or A AU - Shemesh OA AD - Media Lab, MIT, Cambridge, MA, USA. AD - MIT McGovern Institute for Brain Research, MIT, Cambridge, MA, USA. FAU - Straub, Christoph AU - Straub C AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Gritton, Howard J AU - Gritton HJ AD - Department of Biomedical Engineering, Boston University, Boston, MA, USA. FAU - Romano, Michael F AU - Romano MF AD - Department of Biomedical Engineering, Boston University, Boston, MA, USA. FAU - Costa, Emma AU - Costa E AD - Media Lab, MIT, Cambridge, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Fu, Zhanyan AU - Fu Z AD - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. FAU - Boyden, Edward S AU - Boyden ES AD - Media Lab, MIT, Cambridge, MA, USA. esb@media.mit.edu. AD - MIT McGovern Institute for Brain Research, MIT, Cambridge, MA, USA. esb@media.mit.edu. AD - Department of Biological Engineering, MIT, Cambridge, MA, USA. esb@media.mit.edu. AD - MIT Center for Neurobiological Engineering, MIT, Cambridge, MA, USA. esb@media.mit.edu. AD - Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA. esb@media.mit.edu. AD - Koch Institute, MIT, Cambridge, MA, USA. esb@media.mit.edu. FAU - Han, Xue AU - Han X AD - Department of Biomedical Engineering, Boston University, Boston, MA, USA. xuehan@bu.edu. LA - eng GR - T32 GM008764/GM/NIGMS NIH HHS/United States GR - R01 DA045549/DA/NIDA NIH HHS/United States GR - R01 EB024261/EB/NIBIB NIH HHS/United States GR - 1R01NS109794-01/NS/NINDS NIH HHS/United States GR - DP1 NS087724/NS/NINDS NIH HHS/United States GR - R01 NS081716/NS/NINDS NIH HHS/United States GR - R01 DA029639/DA/NIDA NIH HHS/United States GR - R01 MH114031/MH/NIMH NIH HHS/United States GR - R01 NS102727/NS/NINDS NIH HHS/United States GR - T32 MH020016/MH/NIMH NIH HHS/United States GR - R01 NS087950/NS/NINDS NIH HHS/United States GR - R01 GM104948/GM/NIGMS NIH HHS/United States GR - DP2 NS082126/NS/NINDS NIH HHS/United States GR - R43 MH109332/MH/NIMH NIH HHS/United States GR - R01 NS109794/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20191009 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Environmental Biomarkers) SB - IM MH - Action Potentials/physiology MH - Animals MH - *Environmental Biomarkers/genetics MH - Hippocampus/*cytology/diagnostic imaging MH - Mice MH - Neurons/*physiology MH - Optical Imaging/*methods MH - Optogenetics MH - Wakefulness/*physiology PMC - PMC6858559 MID - NIHMS1538640 EDAT- 2019/10/11 06:00 MHDA- 2020/03/31 06:00 CRDT- 2019/10/11 06:00 PHST- 2018/08/23 00:00 [received] PHST- 2019/08/28 00:00 [accepted] PHST- 2019/10/11 06:00 [pubmed] PHST- 2020/03/31 06:00 [medline] PHST- 2019/10/11 06:00 [entrez] AID - 10.1038/s41586-019-1641-1 [pii] AID - 10.1038/s41586-019-1641-1 [doi] PST - ppublish SO - Nature. 2019 Oct;574(7778):413-417. doi: 10.1038/s41586-019-1641-1. Epub 2019 Oct 9. PMID- 31411560 OWN - NLM STAT- MEDLINE DCOM- 20200211 LR - 20210110 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 8 DP - 2019 Aug 14 TI - Molecular and anatomical organization of the dorsal raphe nucleus. LID - 10.7554/eLife.46464 [doi] LID - e46464 AB - The dorsal raphe nucleus (DRN) is an important source of neuromodulators and has been implicated in a wide variety of behavioral and neurological disorders. The DRN is subdivided into distinct anatomical subregions comprised of multiple cell types, and its complex cellular organization has impeded efforts to investigate the distinct circuit and behavioral functions of its subdomains. Here we used single-cell RNA sequencing, in situ hybridization, anatomical tracing, and spatial correlation analysis to map the transcriptional and spatial profiles of cells from the mouse DRN. Our analysis of 39,411 single-cell transcriptomes revealed at least 18 distinct neuron subtypes and 5 serotonergic neuron subtypes with distinct molecular and anatomical properties, including a serotonergic neuron subtype that preferentially innervates the basal ganglia. Our study lays out the molecular organization of distinct serotonergic and non-serotonergic subsystems, and will facilitate the design of strategies for further dissection of the DRN and its diverse functions. CI - © 2019, Huang et al. FAU - Huang, Kee Wui AU - Huang KW AUID- ORCID: 0000-0003-2265-4550 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Ochandarena, Nicole E AU - Ochandarena NE AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Philson, Adrienne C AU - Philson AC AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Hyun, Minsuk AU - Hyun M AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Birnbaum, Jaclyn E AU - Birnbaum JE AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Cicconet, Marcelo AU - Cicconet M AD - Image and Data Analysis Core, Harvard Medical School, Boston, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. LA - eng SI - GEO/GSE134163 GR - Graduate Fellowship/Department of Neurobiology, Harvard Medical School/International GR - Bipolar Disorder Seed Grant/Harvard Brain Initiative/International GR - Stuart HQ and Victoria Quan Fellowship in Neurobiology/Department of Neurobiology, Harvard Medical School/International GR - R01 NS103226/NS/NINDS NIH HHS/United States GR - MH100568/MH/NIMH NIH HHS/United States GR - NS103226/NS/NINDS NIH HHS/United States GR - Samsung Scholarship/Samsung/International GR - Lefler Center for the Study of Neurodegenerative Disorder/Harvard Medical School/International PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190814 PL - England TA - Elife JT - eLife JID - 101579614 SB - IM MH - Animals MH - Dorsal Raphe Nucleus/*anatomy & histology/*cytology MH - Gene Expression Profiling MH - Genotype MH - In Situ Hybridization MH - Mice MH - Neuroanatomical Tract-Tracing Techniques MH - Neurons/*classification MH - Phenotype MH - Sequence Analysis, RNA MH - Spatial Analysis PMC - PMC6726424 OTO - NOTNLM OT - dorsal raphe nucleus OT - mouse OT - neuromodulation OT - neuroscience OT - serotonin OT - single cell RNAseq COIS- KH, NO, AP, MH, JB, MC, BS No competing interests declared EDAT- 2019/08/15 06:00 MHDA- 2020/02/12 06:00 CRDT- 2019/08/15 06:00 PHST- 2019/02/28 00:00 [received] PHST- 2019/08/13 00:00 [accepted] PHST- 2019/08/15 06:00 [pubmed] PHST- 2020/02/12 06:00 [medline] PHST- 2019/08/15 06:00 [entrez] AID - 46464 [pii] AID - 10.7554/eLife.46464 [doi] PST - epublish SO - Elife. 2019 Aug 14;8:e46464. doi: 10.7554/eLife.46464. PMID- 31417343 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231013 IS - 1662-4548 (Print) IS - 1662-453X (Electronic) IS - 1662-453X (Linking) VI - 13 DP - 2019 TI - Monitoring Behaviorally Induced Biochemical Changes Using Fluorescence Lifetime Photometry. PG - 766 LID - 10.3389/fnins.2019.00766 [doi] LID - 766 AB - All cells respond to extracellular signals by altering their intracellular biochemical state. In neurons, such signaling regulates many aspects of cell and synapse biology and induces changes that are thought to be important for nervous system development, its adaptation in the face of a changing environment, and ongoing homeostatic maintenance. Although great advances have been made in developing novel fluorescent reporters of intracellular signaling as well as in methods of fluorescence detection for use in freely moving animals, these approaches have generally not been combined. Thus, we know relatively little about how the intracellular biochemical state of neurons, and other cell classes, is dynamically regulated during animals' behavior. Here we describe a single multi-mode fiber based fluorescence lifetime photometry system (FLiP) designed to monitor the state of fluorescence reporters of biochemical state in freely moving animals. We demonstrate the utility of FLiP by monitoring the lifetime of FLIM-AKAR, a genetically encoded fluorescent reporter of PKA phosphorylation, in populations of direct and indirect pathway striatal projection neurons in mice receiving food rewards. We find that the activity of PKA in each pathway is transiently regulated by reward acquisition, with PKA phosphorylation being enhanced and repressed in direct and indirect pathway neurons, respectively. This study demonstrates the power of FLiP to detect changes in biochemical state induced by naturalistic experiences in behaving animals. FAU - Lee, Suk Joon AU - Lee SJ AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, United States. FAU - Chen, Yao AU - Chen Y AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, United States. AD - Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States. FAU - Lodder, Bart AU - Lodder B AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, United States. AD - Master Program Neuroscience and Cognition, Graduate School of Life Sciences, Utrecht University and Department of Translational Neuroscience, Brain Center, University Medical Center, Utrecht, Netherlands. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, United States. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20190731 PL - Switzerland TA - Front Neurosci JT - Frontiers in neuroscience JID - 101478481 PMC - PMC6685078 OTO - NOTNLM OT - FLIM (fluorescence lifetime imaging microscopy) OT - PKA OT - accumbens OT - dopamine OT - fiber photometry EDAT- 2019/08/17 06:00 MHDA- 2019/08/17 06:01 CRDT- 2019/08/17 06:00 PHST- 2019/06/06 00:00 [received] PHST- 2019/07/09 00:00 [accepted] PHST- 2019/08/17 06:00 [entrez] PHST- 2019/08/17 06:00 [pubmed] PHST- 2019/08/17 06:01 [medline] AID - 10.3389/fnins.2019.00766 [doi] PST - epublish SO - Front Neurosci. 2019 Jul 31;13:766. doi: 10.3389/fnins.2019.00766. eCollection 2019. PMID- 31175277 OWN - NLM STAT- MEDLINE DCOM- 20190617 LR - 20220107 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 10 IP - 1 DP - 2019 Jun 7 TI - In vivo nuclear capture and molecular profiling identifies Gmeb1 as a transcriptional regulator essential for dopamine neuron function. PG - 2508 LID - 10.1038/s41467-019-10267-0 [doi] LID - 2508 AB - Midbrain dopamine (mDA) neurons play a central role in reward signaling and are widely implicated in psychiatric and neurodegenerative disorders. To understand how mDA neurons perform these functions, it is important to understand how mDA-specific genes are regulated. However, cellular heterogeneity in the mammalian brain presents a major challenge to obtaining this understanding. To this end, we developed a virus-based approach to label and capture mDA nuclei for transcriptome (RNA-Seq), and low-input chromatin accessibility (liDNase-Seq) profiling, followed by predictive modeling to identify putative transcriptional regulators of mDA neurons. Using this method, we identified Gmeb1, a transcription factor predicted to regulate expression of Th and Dat, genes critical for dopamine synthesis and reuptake, respectively. Gmeb1 knockdown in mDA neurons resulted in downregulation of Th and Dat, as well as in severe motor deficits. This study thus identifies Gmeb1 as a master regulator of mDA gene expression and function, and provides a general method for identifying cell type-specific transcriptional regulators. FAU - Tuesta, Luis M AU - Tuesta LM AD - Howard Hughes Medical Institute, Boston, MA, 02115, USA. AD - Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, 02115, USA. AD - Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. FAU - Djekidel, Mohamed N AU - Djekidel MN AD - Howard Hughes Medical Institute, Boston, MA, 02115, USA. AD - Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, 02115, USA. AD - Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. FAU - Chen, Renchao AU - Chen R AD - Howard Hughes Medical Institute, Boston, MA, 02115, USA. AD - Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, 02115, USA. AD - Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. FAU - Lu, Falong AU - Lu F AUID- ORCID: 0000-0002-8321-4818 AD - Howard Hughes Medical Institute, Boston, MA, 02115, USA. AD - Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, 02115, USA. AD - Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. FAU - Wang, Wengang AU - Wang W AD - Howard Hughes Medical Institute, Boston, MA, 02115, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Howard Hughes Medical Institute, Boston, MA, 02115, USA. AD - Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA. FAU - Zhang, Yi AU - Zhang Y AUID- ORCID: 0000-0002-2789-0811 AD - Howard Hughes Medical Institute, Boston, MA, 02115, USA. yzhang@genetics.med.harvard.edu. AD - Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, 02115, USA. yzhang@genetics.med.harvard.edu. AD - Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. yzhang@genetics.med.harvard.edu. AD - Division of Hematology/Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, MA, 02115, USA. yzhang@genetics.med.harvard.edu. AD - Harvard Stem Cell Institute, WAB-149G, 200 Longwood Avenue, Boston, MA, 02115, USA. yzhang@genetics.med.harvard.edu. LA - eng GR - DA045294/U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)/International GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - R01DA042283/U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)/International GR - R01 DA042283/DA/NIDA NIH HHS/United States GR - K01 DA045294/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190607 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (Dopamine Plasma Membrane Transport Proteins) RN - 0 (Gmeb1 protein, mouse) RN - 0 (Transcription Factors) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) SB - IM MH - Animals MH - Dopamine Plasma Membrane Transport Proteins/*genetics MH - Dopaminergic Neurons/*metabolism MH - Gene Expression Profiling MH - Gene Expression Regulation MH - Gene Knockdown Techniques MH - Mesencephalon/cytology MH - Mice MH - Pars Compacta/*metabolism MH - Transcription Factors/*genetics MH - Tyrosine 3-Monooxygenase/*genetics PMC - PMC6555850 COIS- The authors declare no competing interests. EDAT- 2019/06/09 06:00 MHDA- 2019/06/18 06:00 CRDT- 2019/06/09 06:00 PHST- 2018/04/24 00:00 [received] PHST- 2019/04/26 00:00 [accepted] PHST- 2019/06/09 06:00 [entrez] PHST- 2019/06/09 06:00 [pubmed] PHST- 2019/06/18 06:00 [medline] AID - 10.1038/s41467-019-10267-0 [pii] AID - 10267 [pii] AID - 10.1038/s41467-019-10267-0 [doi] PST - epublish SO - Nat Commun. 2019 Jun 7;10(1):2508. doi: 10.1038/s41467-019-10267-0. PMID- 31198228 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220127 IS - 0167-9317 (Print) IS - 1873-5568 (Electronic) IS - 0167-9317 (Linking) VI - 195 DP - 2019 May 29 TI - Focused ion beam nanomachining of tapered optical fibers for patterned light delivery. PG - 41-49 LID - 10.1016/j.mee.2018.03.023 [doi] AB - With the advent of optogenetic techniques, a major need for precise and versatile light-delivery techniques has arisen from the neuroscience community. Driven by this demand, research on innovative illuminating devices has opened previously inaccessible experimental paths. However, tailoring light delivery to functionally and anatomically diverse brain structures still remains a challenging task. We progressed in this endeavor by micro-structuring metal-coated tapered optical fibers and exploiting the resulting mode-division multiplexing/demultiplexing properties. To do this, a non-conventional Focused Ion Beam (FIB) milling method was developed in order to pattern the non-planar surface of the taper around the full 360°, by equipping the FIB chamber with a micromanipulation system. This led us to develop three novel typologies of micro-structured illuminating tools: (a) a tapered fiber that emits light from a narrow slot of adjustable length; (b) a tapered fiber that emits light from four independently addressable optical windows; (c) a tapered fiber that emits light from an annular aperture with 360° symmetry. The result is a versatile technology enabling reconfigurable light-delivery that can be tailored to specific experimental needs. FAU - Pisano, Filippo AU - Pisano F AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, 73010, Arnesano, Lecce, Italy. FAU - Pisanello, Marco AU - Pisanello M AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, 73010, Arnesano, Lecce, Italy. FAU - Sileo, Leonardo AU - Sileo L AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, 73010, Arnesano, Lecce, Italy. FAU - Qualtieri, Antonio AU - Qualtieri A AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, 73010, Arnesano, Lecce, Italy. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Dipartimento di Ingegneria dell'Innovazione, Università del Salento, 73100 Lecce, Italy. FAU - De Vittorio, Massimo AU - De Vittorio M AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, 73010, Arnesano, Lecce, Italy. AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 02115, MA, Boston, USA. FAU - Pisanello, Ferruccio AU - Pisanello F AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, 73010, Arnesano, Lecce, Italy. LA - eng GR - 677683/ERC_/European Research Council/International GR - 692943/ERC_/European Research Council/International GR - UF1 NS108177/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20180328 PL - Netherlands TA - Microelectron Eng JT - Microelectronic engineering JID - 101552621 PMC - PMC6565430 MID - EMS83121 OTO - NOTNLM OT - Focused ion beam OT - Milling OT - Nanomachining OT - Optical fibers OT - Optogenetics EDAT- 2019/06/15 06:00 MHDA- 2019/06/15 06:01 CRDT- 2019/06/15 06:00 PHST- 2019/06/15 06:00 [entrez] PHST- 2019/06/15 06:00 [pubmed] PHST- 2019/06/15 06:01 [medline] AID - 10.1016/j.mee.2018.03.023 [doi] PST - ppublish SO - Microelectron Eng. 2019 May 29;195:41-49. doi: 10.1016/j.mee.2018.03.023. Epub 2018 Mar 28. PMID- 30905392 OWN - NLM STAT- MEDLINE DCOM- 20191112 LR - 20200421 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 102 IP - 3 DP - 2019 May 8 TI - Distinct Cortical-Thalamic-Striatal Circuits through the Parafascicular Nucleus. PG - 636-652.e7 LID - S0896-6273(19)30170-9 [pii] LID - 10.1016/j.neuron.2019.02.035 [doi] AB - The thalamic parafascicular nucleus (PF), an excitatory input to the basal ganglia, is targeted with deep-brain stimulation to alleviate a range of neuropsychiatric symptoms. Furthermore, PF lesions disrupt the execution of correct motor actions in uncertain environments. Nevertheless, the circuitry of the PF and its contribution to action selection are poorly understood. We find that, in mice, PF has the highest density of striatum-projecting neurons among all sub-cortical structures. This projection arises from transcriptionally and physiologically distinct classes of PF neurons that are also reciprocally connected with functionally distinct cortical regions, differentially innervate striatal neurons, and are not synaptically connected in PF. Thus, mouse PF contains heterogeneous neurons that are organized into parallel and independent associative, limbic, and somatosensory circuits. Furthermore, these subcircuits share motifs of cortical-PF-cortical and cortical-PF-striatum organization that allow each PF subregion, via its precise connectivity with cortex, to coordinate diverse inputs to striatum. CI - Copyright © 2019 Elsevier Inc. All rights reserved. FAU - Mandelbaum, Gil AU - Mandelbaum G AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Taranda, Julian AU - Taranda J AD - Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. FAU - Haynes, Trevor M AU - Haynes TM AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Hochbaum, Daniel R AU - Hochbaum DR AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Society of Fellows, Harvard University, Cambridge, MA 02138, USA. FAU - Huang, Kee Wui AU - Huang KW AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Hyun, Minsuk AU - Hyun M AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Umadevi Venkataraju, Kannan AU - Umadevi Venkataraju K AD - Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. FAU - Straub, Christoph AU - Straub C AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Wang, Wengang AU - Wang W AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Robertson, Keiramarie AU - Robertson K AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Osten, Pavel AU - Osten P AD - Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bsabatini@hms.harvard.edu. LA - eng GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - R01 NS103226/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Video-Audio Media DEP - 20190321 PL - United States TA - Neuron JT - Neuron JID - 8809320 SB - IM MH - Animals MH - Cerebral Cortex/*cytology/physiology MH - Corpus Striatum/*cytology/physiology MH - Gene Expression Profiling MH - Intralaminar Thalamic Nuclei/*cytology/physiology MH - Mice MH - Neural Pathways MH - Neuroanatomical Tract-Tracing Techniques MH - Neurons/*cytology/metabolism/physiology MH - Patch-Clamp Techniques MH - Single-Cell Analysis MH - Thalamus/cytology/physiology PMC - PMC7164542 MID - NIHMS1054840 OTO - NOTNLM OT - STPT OT - action selection OT - basal ganglia OT - corticothalamic loops OT - electrophysiology OT - parafascicular nucleus OT - single-cell transcriptional analysis OT - thalamus EDAT- 2019/03/25 06:00 MHDA- 2019/11/13 06:00 CRDT- 2019/03/26 06:00 PHST- 2018/07/02 00:00 [received] PHST- 2019/01/03 00:00 [revised] PHST- 2019/02/20 00:00 [accepted] PHST- 2019/03/25 06:00 [pubmed] PHST- 2019/11/13 06:00 [medline] PHST- 2019/03/26 06:00 [entrez] AID - S0896-6273(19)30170-9 [pii] AID - 10.1016/j.neuron.2019.02.035 [doi] PST - ppublish SO - Neuron. 2019 May 8;102(3):636-652.e7. doi: 10.1016/j.neuron.2019.02.035. Epub 2019 Mar 21. PMID- 30863275 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231006 IS - 1662-4548 (Print) IS - 1662-453X (Electronic) IS - 1662-453X (Linking) VI - 13 DP - 2019 TI - The Three-Dimensional Signal Collection Field for Fiber Photometry in Brain Tissue. PG - 82 LID - 10.3389/fnins.2019.00082 [doi] LID - 82 AB - Fiber photometry is used to monitor signals from fluorescent indicators in genetically-defined neural populations in behaving animals. Recently, fiber photometry has rapidly expanded and it now provides researchers with increasingly powerful means to record neural dynamics and neuromodulatory action. However, it is not clear how to select the optimal fiber optic given the constraints and goals of a particular experiment. Here, using combined confocal/2-photon microscope, we quantitatively characterize the fluorescence collection properties of various optical fibers in brain tissue. We show that the fiber size plays a major role in defining the volume of the optically sampled brain region, whereas numerical aperture impacts the total amount of collected signal and, marginally, the shape and size of the collection volume. We show that ~80% of the effective signal arises from 10(5) to 10(6) μm(3) volume extending ~200 μm from the fiber facet for 200 μm core optical fibers. Together with analytical and ray tracing collection maps, our results reveal the light collection properties of different optical fibers in brain tissue, allowing for an accurate selection of the fibers for photometry and helping for a more precise interpretation of measurements in terms of sampled volume. FAU - Pisanello, Marco AU - Pisanello M AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Lecce, Italy. FAU - Pisano, Filippo AU - Pisano F AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Lecce, Italy. FAU - Hyun, Minsuk AU - Hyun M AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, United States. FAU - Maglie, Emanuela AU - Maglie E AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Lecce, Italy. AD - Dipartimento di Ingeneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - Balena, Antonio AU - Balena A AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Lecce, Italy. AD - Dipartimento di Ingeneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - De Vittorio, Massimo AU - De Vittorio M AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Lecce, Italy. AD - Dipartimento di Ingeneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, United States. FAU - Pisanello, Ferruccio AU - Pisanello F AD - Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Lecce, Italy. LA - eng GR - U01 NS094190/NS/NINDS NIH HHS/United States GR - UF1 NS108177/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20190226 PL - Switzerland TA - Front Neurosci JT - Frontiers in neuroscience JID - 101478481 PMC - PMC6399578 OTO - NOTNLM OT - collection fields OT - collection volumes OT - fiber photometry OT - optical fibers OT - optogenetics EDAT- 2019/03/14 06:00 MHDA- 2019/03/14 06:01 CRDT- 2019/03/14 06:00 PHST- 2018/08/12 00:00 [received] PHST- 2019/01/25 00:00 [accepted] PHST- 2019/03/14 06:00 [entrez] PHST- 2019/03/14 06:00 [pubmed] PHST- 2019/03/14 06:01 [medline] AID - 10.3389/fnins.2019.00082 [doi] PST - epublish SO - Front Neurosci. 2019 Feb 26;13:82. doi: 10.3389/fnins.2019.00082. eCollection 2019. PMID- 30100184 OWN - NLM STAT- MEDLINE DCOM- 20190522 LR - 20220131 IS - 1097-4172 (Electronic) IS - 0092-8674 (Print) IS - 0092-8674 (Linking) VI - 174 IP - 6 DP - 2018 Sep 6 TI - Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships. PG - 1450-1464.e23 LID - S0092-8674(18)30858-4 [pii] LID - 10.1016/j.cell.2018.07.002 [doi] AB - Synapses are fundamental units of communication in the brain. The prototypical synapse-organizing complex neurexin-neuroligin mediates synapse development and function and is central to a shared genetic risk pathway in autism and schizophrenia. Neurexin's role in synapse development is thought to be mediated purely by its protein domains, but we reveal a requirement for a rare glycan modification. Mice lacking heparan sulfate (HS) on neurexin-1 show reduced survival, as well as structural and functional deficits at central synapses. HS directly binds postsynaptic partners neuroligins and LRRTMs, revealing a dual binding mode involving intrinsic glycan and protein domains for canonical synapse-organizing complexes. Neurexin HS chains also bind novel ligands, potentially expanding the neurexin interactome to hundreds of HS-binding proteins. Because HS structure is heterogeneous, our findings indicate an additional dimension to neurexin diversity, provide a molecular basis for fine-tuning synaptic function, and open therapeutic directions targeting glycan-binding motifs critical for brain development. CI - Copyright © 2018 Elsevier Inc. All rights reserved. FAU - Zhang, Peng AU - Zhang P AD - Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada. Electronic address: peng.pengzhang@gmail.com. FAU - Lu, Hong AU - Lu H AD - Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada. FAU - Peixoto, Rui T AU - Peixoto RT AD - Howard Hughes Medical Institute, Harvard Medical School, Department of Neurobiology, Boston, MA 02115, USA; Istituto Italiano di Tecnologia, Genova 16163, Italy. FAU - Pines, Mary K AU - Pines MK AD - Department of Zoology and Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. FAU - Ge, Yuan AU - Ge Y AD - Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada. FAU - Oku, Shinichiro AU - Oku S AD - Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada. FAU - Siddiqui, Tabrez J AU - Siddiqui TJ AD - Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada. FAU - Xie, Yicheng AU - Xie Y AD - Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada. FAU - Wu, Wenlan AU - Wu W AD - Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Medical School, Henan University of Science and Technology, Luoyang 471023, China. FAU - Archer-Hartmann, Stephanie AU - Archer-Hartmann S AD - Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA. FAU - Yoshida, Keitaro AU - Yoshida K AD - Department of Neuropsychiatry, Keio University School of Medicine, Tokyo 160-8582, Japan. FAU - Tanaka, Kenji F AU - Tanaka KF AD - Department of Neuropsychiatry, Keio University School of Medicine, Tokyo 160-8582, Japan. FAU - Aricescu, A Radu AU - Aricescu AR AD - MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. FAU - Azadi, Parastoo AU - Azadi P AD - Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA. FAU - Gordon, Michael D AU - Gordon MD AD - Department of Zoology and Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Harvard Medical School, Department of Neurobiology, Boston, MA 02115, USA. FAU - Wong, Rachel O L AU - Wong ROL AD - Department of Biological Structure, University of Washington, Seattle, WA 98195, USA. FAU - Craig, Ann Marie AU - Craig AM AD - Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada. Electronic address: acraig@mail.ubc.ca. LA - eng GR - MC_EX_MR/L009609/2/MRC_/Medical Research Council/United Kingdom GR - HHMI/Howard Hughes Medical Institute/United States GR - MOP-11934/CIHR/Canada GR - P41 GM103390/GM/NIGMS NIH HHS/United States GR - FDN-143206/CIHR/Canada GR - R01 MH070860/MH/NIMH NIH HHS/United States GR - S10 OD018530/OD/NIH HHS/United States GR - MC_UP_1201/15/Medical Research Council/United Kingdom GR - G0700232/MRC_/Medical Research Council/United Kingdom GR - MR/L009609/1/MRC_/Medical Research Council/United Kingdom GR - R37 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180809 PL - United States TA - Cell JT - Cell JID - 0413066 RN - 0 (Calcium-Binding Proteins) RN - 0 (Cell Adhesion Molecules, Neuronal) RN - 0 (Drosophila Proteins) RN - 0 (Glycopeptides) RN - 0 (LRRTM2 protein, mouse) RN - 0 (Membrane Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (Neural Cell Adhesion Molecules) RN - 0 (Nrxn1 protein, mouse) RN - 0 (RNA, Small Interfering) RN - 0 (neuroligin 1) RN - 9050-30-0 (Heparitin Sulfate) SB - IM CIN - Cell. 2018 Sep 6;174(6):1337-1338. PMID: 30193105 MH - Amino Acid Sequence MH - Animals MH - Calcium-Binding Proteins MH - Cell Adhesion Molecules, Neuronal/antagonists & inhibitors/genetics/metabolism MH - Drosophila MH - Drosophila Proteins/antagonists & inhibitors/genetics/metabolism MH - Female MH - Glycopeptides/analysis MH - Heparitin Sulfate/chemistry/*metabolism MH - Humans MH - Membrane Proteins MH - Mice MH - Mice, Inbred C57BL MH - Nerve Tissue Proteins MH - Neural Cell Adhesion Molecules/antagonists & inhibitors/genetics/*metabolism MH - Neurons/cytology/metabolism MH - Protein Binding MH - RNA Interference MH - RNA, Small Interfering/metabolism MH - Rats MH - Sequence Alignment MH - Synapses/*metabolism PMC - PMC6173057 OTO - NOTNLM OT - LRRTM OT - heparan sulphate OT - mossy fiber OT - neurexin OT - neuroligin OT - proteoglycan OT - synaptic adhesion protein OT - synaptic transmission OT - synaptogenesis OT - thorny excrescence EDAT- 2018/08/14 06:00 MHDA- 2019/05/23 06:00 CRDT- 2018/08/14 06:00 PHST- 2017/09/12 00:00 [received] PHST- 2018/06/23 00:00 [revised] PHST- 2018/06/29 00:00 [accepted] PHST- 2018/08/14 06:00 [pubmed] PHST- 2019/05/23 06:00 [medline] PHST- 2018/08/14 06:00 [entrez] AID - S0092-8674(18)30858-4 [pii] AID - 10.1016/j.cell.2018.07.002 [doi] PST - ppublish SO - Cell. 2018 Sep 6;174(6):1450-1464.e23. doi: 10.1016/j.cell.2018.07.002. Epub 2018 Aug 9. PMID- 29520042 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20191120 IS - 1552-4469 (Electronic) IS - 1552-4450 (Linking) VI - 14 IP - 9 DP - 2018 Sep TI - Publisher Correction: A robotic multidimensional directed evolution approach applied to fluorescent voltage reporters. PG - 901 LID - 10.1038/s41589-018-0023-6 [doi] AB - In the version of this article originally published, the bottom of Figure 4f,g was partially truncated in the PDF. The error has been corrected in the PDF version of this article. FAU - Piatkevich, Kiryl D AU - Piatkevich KD AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. FAU - Jung, Erica E AU - Jung EE AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. FAU - Straub, Christoph AU - Straub C AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Linghu, Changyang AU - Linghu C AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. AD - Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA, USA. FAU - Park, Demian AU - Park D AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. FAU - Suk, Ho-Jun AU - Suk HJ AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. AD - Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA, USA. FAU - Hochbaum, Daniel R AU - Hochbaum DR AUID- ORCID: 0000-0001-6220-6651 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Goodwin, Daniel AU - Goodwin D AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. FAU - Pnevmatikakis, Eftychios AU - Pnevmatikakis E AUID- ORCID: 0000-0003-1509-6394 AD - Simons Center Data Analysis, Simons Foundation, New York, NY, USA. FAU - Pak, Nikita AU - Pak N AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. AD - Department of Mechanical Engineering, MIT, Cambridge, MA, USA. FAU - Kawashima, Takashi AU - Kawashima T AD - Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, USA. FAU - Yang, Chao-Tsung AU - Yang CT AD - Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, USA. FAU - Rhoades, Jeffrey L AU - Rhoades JL AUID- ORCID: 0000-0001-5077-2533 AD - Picower Institute for Learning & Memory and Department of Brain & Cognitive Sciences, MIT, Cambridge, MA, USA. FAU - Shemesh, Or AU - Shemesh O AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. FAU - Asano, Shoh AU - Asano S AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. FAU - Yoon, Young-Gyu AU - Yoon YG AUID- ORCID: 0000-0002-5660-049X AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. AD - Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA, USA. FAU - Freifeld, Limor AU - Freifeld L AUID- ORCID: 0000-0002-0739-6947 AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. FAU - Saulnier, Jessica L AU - Saulnier JL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Riegler, Clemens AU - Riegler C AD - Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, USA. AD - Department of Neurobiology, Faculty of Life Sciences, University of Vienna, Wien, Austria. FAU - Engert, Florian AU - Engert F AD - Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, USA. FAU - Hughes, Thom AU - Hughes T AUID- ORCID: 0000-0002-8430-070X AD - Department of Cell Biology and Neuroscience, Montana State University, Bozeman, Montana, USA. FAU - Drobizhev, Mikhail AU - Drobizhev M AD - Department of Cell Biology and Neuroscience, Montana State University, Bozeman, Montana, USA. FAU - Szabo, Balint AU - Szabo B AD - Department of Biological Physics, Eotvos University, Budapest, Hungary. FAU - Ahrens, Misha B AU - Ahrens MB AD - Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, USA. FAU - Flavell, Steven W AU - Flavell SW AD - Picower Institute for Learning & Memory and Department of Brain & Cognitive Sciences, MIT, Cambridge, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Boyden, Edward S AU - Boyden ES AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. esb@media.mit.edu. AD - Department of Biological Engineering, MIT, Cambridge, MA, USA. esb@media.mit.edu. AD - MIT Center for Neurobiological Engineering, MIT, Cambridge, MA, USA. esb@media.mit.edu. AD - Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA. esb@media.mit.edu. AD - MIT McGovern Institute for Brain Research, MIT, Cambridge, MA, USA. esb@media.mit.edu. LA - eng PT - Published Erratum PL - United States TA - Nat Chem Biol JT - Nature chemical biology JID - 101231976 EFR - Nat Chem Biol. 2018 Apr;14(4):352-360. PMID: 29483642 EDAT- 2018/03/10 06:00 MHDA- 2018/03/10 06:01 CRDT- 2018/03/10 06:00 PHST- 2018/03/10 06:00 [pubmed] PHST- 2018/03/10 06:01 [medline] PHST- 2018/03/10 06:00 [entrez] AID - 10.1038/s41589-018-0023-6 [pii] AID - 10.1038/s41589-018-0023-6 [doi] PST - ppublish SO - Nat Chem Biol. 2018 Sep;14(9):901. doi: 10.1038/s41589-018-0023-6. PMID- 29752482 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20191120 IS - 1546-1726 (Electronic) IS - 1097-6256 (Linking) VI - 21 IP - 7 DP - 2018 Jul TI - Publisher Correction: Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex. PG - 1017 LID - 10.1038/s41593-018-0112-6 [doi] AB - In the version of this article initially published, the x-axis labels in Fig. 3c read Vglut, Gad1/2, Aldh1l1 and Pecam1; they should have read Vglut(+), Gad1/2(+), Aldh1l1(+) and Pecam1(+). In Fig. 4, the range values were missing from the color scales; they are, from left to right, 4-15, 0-15, 4-15 and 0-15 in Fig. 4a and 4-15, 4-15 and 4-8 in Fig. 4h. In the third paragraph of the main text, the phrase reading "Previous approaches have analyzed a limited number of inhibitory cell types, thus masking the full diversity of excitatory populations" should have read "Previous approaches have analyzed a limited number of inhibitory cell types and masked the full diversity of excitatory populations." In the second paragraph of Results section "Diversity of experience-regulated ERGs," the phrase reading "thus suggesting considerable divergence within the gene expression program responding to early stimuli" should have read "thus suggesting considerable divergence within the early stimulus-responsive gene expression program." In the fourth paragraph of Results section "Excitatory neuronal LRGs," the sentence reading "The anatomical organization of these cell types into sublayers, coupled with divergent transcriptional responses to a sensory stimulus, suggested previously unappreciated functional subdivisions located within the laminae of the mouse visual cortex and resembling the cytoarchitecture in higher mammals" should have read "The anatomical organization of these cell types into sublayers, coupled with divergent transcriptional responses to a sensory stimulus, suggests previously unappreciated functional subdivisions located within the laminae of the mouse visual cortex, resembling the cytoarchitecture in higher mammals." In the last sentence of the Results, "sensory-responsive genes" should have read "sensory-stimulus-responsive genes." The errors have been corrected in the HTML and PDF versions of the article. FAU - Hrvatin, Sinisa AU - Hrvatin S AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Hochbaum, Daniel R AU - Hochbaum DR AUID- ORCID: 0000-0001-6220-6651 AD - Society of Fellows, Harvard University, Cambridge, MA, USA. AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. FAU - Nagy, M Aurel AU - Nagy MA AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Cicconet, Marcelo AU - Cicconet M AD - Image and Data Analysis Core, Harvard Medical School, Boston, MA, USA. FAU - Robertson, Keiramarie AU - Robertson K AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. FAU - Cheadle, Lucas AU - Cheadle L AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Zilionis, Rapolas AU - Zilionis R AD - Department of Systems Biology, Harvard Medical School, Boston, MA, USA. AD - Vilnius University Institute of Biotechnology, Vilnius, Lithuania. FAU - Ratner, Alex AU - Ratner A AD - ICCB-L Single Cell Core, Harvard Medical School, Boston, MA, USA. FAU - Borges-Monroy, Rebeca AU - Borges-Monroy R AD - Program for Bioinformatics and Integrative Genomics, Graduate School of Arts and Science, Division of Medical Sciences, Harvard University, Cambridge, MA, USA. FAU - Klein, Allon M AU - Klein AM AD - Department of Systems Biology, Harvard Medical School, Boston, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. bernardo_sabatini@hms.harvard.edu. FAU - Greenberg, Michael E AU - Greenberg ME AUID- ORCID: 0000-0003-1380-2160 AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. michael_greenberg@hms.harvard.edu. LA - eng PT - Published Erratum PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 EFR - Nat Neurosci. 2018 Jan;21(1):120-129. PMID: 29230054 EDAT- 2018/05/13 06:00 MHDA- 2018/05/13 06:01 CRDT- 2018/05/13 06:00 PHST- 2018/05/13 06:00 [pubmed] PHST- 2018/05/13 06:01 [medline] PHST- 2018/05/13 06:00 [entrez] AID - 10.1038/s41593-018-0112-6 [pii] AID - 10.1038/s41593-018-0112-6 [doi] PST - ppublish SO - Nat Neurosci. 2018 Jul;21(7):1017. doi: 10.1038/s41593-018-0112-6. PMID- 29779950 OWN - NLM STAT- MEDLINE DCOM- 20190321 LR - 20230926 IS - 1097-4172 (Electronic) IS - 0092-8674 (Print) IS - 0092-8674 (Linking) VI - 174 IP - 1 DP - 2018 Jun 28 TI - The Striatum Organizes 3D Behavior via Moment-to-Moment Action Selection. PG - 44-58.e17 LID - S0092-8674(18)30512-9 [pii] LID - 10.1016/j.cell.2018.04.019 [doi] AB - Many naturalistic behaviors are built from modular components that are expressed sequentially. Although striatal circuits have been implicated in action selection and implementation, the neural mechanisms that compose behavior in unrestrained animals are not well understood. Here, we record bulk and cellular neural activity in the direct and indirect pathways of dorsolateral striatum (DLS) as mice spontaneously express action sequences. These experiments reveal that DLS neurons systematically encode information about the identity and ordering of sub-second 3D behavioral motifs; this encoding is facilitated by fast-timescale decorrelations between the direct and indirect pathways. Furthermore, lesioning the DLS prevents appropriate sequence assembly during exploratory or odor-evoked behaviors. By characterizing naturalistic behavior at neural timescales, these experiments identify a code for elemental 3D pose dynamics built from complementary pathway dynamics, support a role for DLS in constructing meaningful behavioral sequences, and suggest models for how actions are sculpted over time. CI - Copyright © 2018 Elsevier Inc. All rights reserved. FAU - Markowitz, Jeffrey E AU - Markowitz JE AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. FAU - Gillis, Winthrop F AU - Gillis WF AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Beron, Celia C AU - Beron CC AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. FAU - Neufeld, Shay Q AU - Neufeld SQ AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. FAU - Robertson, Keiramarie AU - Robertson K AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. FAU - Bhagat, Neha D AU - Bhagat ND AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Peterson, Ralph E AU - Peterson RE AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Peterson, Emalee AU - Peterson E AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Hyun, Minsuk AU - Hyun M AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. FAU - Linderman, Scott W AU - Linderman SW AD - Grossman Center for the Statistics of Mind, Columbia University, New York, NY, USA; Departments of Statistics and Computer Science, Columbia University, New York, NY, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. FAU - Datta, Sandeep Robert AU - Datta SR AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. Electronic address: srdatta@hms.harvard.edu. LA - eng GR - U01 NS094190/NS/NINDS NIH HHS/United States GR - R01 DC016222/DC/NIDCD NIH HHS/United States GR - R01 DC011558/DC/NIDCD NIH HHS/United States GR - P30 HD018655/HD/NICHD NIH HHS/United States GR - P30 EY012196/EY/NEI NIH HHS/United States GR - U01 NS094191/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180517 PL - United States TA - Cell JT - Cell JID - 0413066 RN - 0 (Drd1 protein, mouse) RN - 0 (Receptors, Dopamine D1) RN - 6384-92-5 (N-Methylaspartate) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - *Behavior, Animal/drug effects MH - Calcium/metabolism MH - Corpus Striatum/drug effects/*metabolism MH - Electrodes, Implanted MH - Female MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - N-Methylaspartate/pharmacology MH - Neurons/drug effects/physiology MH - Photometry MH - Receptors, Dopamine D1/deficiency/genetics PMC - PMC6026065 MID - NIHMS967127 OTO - NOTNLM OT - basal ganglia OT - behavior OT - coding OT - direct pathway OT - ethology OT - indirect pathway OT - machine learning OT - mouse OT - photometry OT - striatum EDAT- 2018/05/22 06:00 MHDA- 2019/03/22 06:00 CRDT- 2018/05/22 06:00 PHST- 2017/09/18 00:00 [received] PHST- 2018/01/19 00:00 [revised] PHST- 2018/04/16 00:00 [accepted] PHST- 2018/05/22 06:00 [pubmed] PHST- 2019/03/22 06:00 [medline] PHST- 2018/05/22 06:00 [entrez] AID - S0092-8674(18)30512-9 [pii] AID - 10.1016/j.cell.2018.04.019 [doi] PST - ppublish SO - Cell. 2018 Jun 28;174(1):44-58.e17. doi: 10.1016/j.cell.2018.04.019. Epub 2018 May 17. PMID- 29906444 OWN - NLM STAT- MEDLINE DCOM- 20190304 LR - 20190304 IS - 1097-4172 (Electronic) IS - 0092-8674 (Linking) VI - 173 IP - 7 DP - 2018 Jun 14 TI - Sunlight Brightens Learning and Memory. PG - 1570-1572 LID - S0092-8674(18)30656-1 [pii] LID - 10.1016/j.cell.2018.05.044 [doi] AB - Sunlight can alter mood, behavior, and cognition, but the cellular basis of this phenomenon remains to be fully elucidated. In this issue of Cell, Zhu et al. shed light on a UV-dependent metabolic pathway that leads to increased synaptic release of glutamate and enhanced motor learning and memory in mice. CI - Copyright © 2018 Elsevier Inc. All rights reserved. FAU - Chantranupong, Lynne AU - Chantranupong L AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. Electronic address: bernardo_sabatini@hms.harvard.edu. LA - eng PT - Comment PT - Journal Article PL - United States TA - Cell JT - Cell JID - 0413066 RN - 3KX376GY7L (Glutamic Acid) SB - IM CON - Cell. 2018 Jun 14;173(7):1716-1727.e17. PMID: 29779945 MH - Animals MH - Biosynthetic Pathways MH - Brain MH - *Glutamic Acid MH - Learning MH - *Memory MH - Mice MH - Sunlight EDAT- 2018/06/16 06:00 MHDA- 2019/03/05 06:00 CRDT- 2018/06/16 06:00 PHST- 2018/06/16 06:00 [entrez] PHST- 2018/06/16 06:00 [pubmed] PHST- 2019/03/05 06:00 [medline] AID - S0092-8674(18)30656-1 [pii] AID - 10.1016/j.cell.2018.05.044 [doi] PST - ppublish SO - Cell. 2018 Jun 14;173(7):1570-1572. doi: 10.1016/j.cell.2018.05.044. PMID- 29266926 OWN - NLM STAT- MEDLINE DCOM- 20190521 LR - 20190521 IS - 1948-7193 (Electronic) IS - 1948-7193 (Linking) VI - 9 IP - 4 DP - 2018 Apr 18 TI - A Caged Enkephalin Optimized for Simultaneously Probing Mu and Delta Opioid Receptors. PG - 684-690 LID - 10.1021/acschemneuro.7b00485 [doi] AB - Physiological responses to the opioid neuropeptide enkephalin often involve both mu and delta opioid receptors. To facilitate quantitative studies into opioid signaling, we previously developed a caged [Leu(5)]-enkephalin that responds to ultraviolet irradiation, but its residual activity at delta receptors confounds experiments that involve both receptors. To reduce residual activity, we evaluated side-chain, N-terminus, and backbone caging sites and further incorporated the dimethoxy-nitrobenzyl moiety to improve sensitivity to ultraviolet light-emitting diodes (LEDs). Residual activity was characterized using an in vitro functional assay, and the power dependence and kinetics of the uncaging response to 355 nm laser irradiation were assayed using electrophysiological recordings of mu opioid receptor-mediated potassium currents in brain slices of rat locus coeruleus. These experiments identified N-MNVOC-LE as an optimal compound. Using ultraviolet LED illumination to photoactivate N-MNVOC-LE in the CA1 region of hippocampus, we found that enkephalin engages both mu and delta opioid receptors to suppress inhibitory synaptic transmission. FAU - Banghart, Matthew R AU - Banghart MR AUID- ORCID: 0000-0001-7248-2932 AD - Division of Biological Sciences, Section on Neurobiology , University of California San Diego , La Jolla , California 92093 , United States. AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston , Massachusetts 02115 , United States. FAU - He, Xinyi J AU - He XJ AD - Division of Biological Sciences, Section on Neurobiology , University of California San Diego , La Jolla , California 92093 , United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston , Massachusetts 02115 , United States. LA - eng GR - R01 MH085498/MH/NIMH NIH HHS/United States GR - R00 DA034648/DA/NIDA NIH HHS/United States GR - R01 MH100568/MH/NIMH NIH HHS/United States GR - T32 GM007240/GM/NIGMS NIH HHS/United States GR - K99 DA034648/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20171227 PL - United States TA - ACS Chem Neurosci JT - ACS chemical neuroscience JID - 101525337 RN - 0 (Enkephalins) RN - 0 (Potassium Channels) RN - 0 (Receptors, Opioid, delta) RN - 0 (Receptors, Opioid, mu) RN - 100929-53-1 (Enkephalin, Ala(2)-MePhe(4)-Gly(5)-) SB - IM MH - Animals MH - Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology MH - Enkephalins/*pharmacology MH - Hippocampus/drug effects MH - Neurons/drug effects MH - Potassium Channels/drug effects MH - Rats, Sprague-Dawley MH - Receptors, Opioid, delta/*drug effects MH - Receptors, Opioid, mu/*drug effects MH - Synaptic Transmission/*drug effects PMC - PMC5906201 MID - NIHMS932777 OTO - NOTNLM OT - Caged compounds OT - neuropeptides OT - neurophysiology OT - opioid receptors OT - potassium channels OT - synaptic transmission COIS- The authors declare no competing financial interest. EDAT- 2017/12/22 06:00 MHDA- 2019/05/22 06:00 CRDT- 2017/12/22 06:00 PHST- 2017/12/22 06:00 [pubmed] PHST- 2019/05/22 06:00 [medline] PHST- 2017/12/22 06:00 [entrez] AID - 10.1021/acschemneuro.7b00485 [doi] PST - ppublish SO - ACS Chem Neurosci. 2018 Apr 18;9(4):684-690. doi: 10.1021/acschemneuro.7b00485. Epub 2017 Dec 27. PMID- 29483642 OWN - NLM STAT- MEDLINE DCOM- 20190503 LR - 20190503 IS - 1552-4469 (Electronic) IS - 1552-4450 (Print) IS - 1552-4450 (Linking) VI - 14 IP - 4 DP - 2018 Apr TI - A robotic multidimensional directed evolution approach applied to fluorescent voltage reporters. PG - 352-360 LID - 10.1038/s41589-018-0004-9 [doi] AB - We developed a new way to engineer complex proteins toward multidimensional specifications using a simple, yet scalable, directed evolution strategy. By robotically picking mammalian cells that were identified, under a microscope, as expressing proteins that simultaneously exhibit several specific properties, we can screen hundreds of thousands of proteins in a library in just a few hours, evaluating each along multiple performance axes. To demonstrate the power of this approach, we created a genetically encoded fluorescent voltage indicator, simultaneously optimizing its brightness and membrane localization using our microscopy-guided cell-picking strategy. We produced the high-performance opsin-based fluorescent voltage reporter Archon1 and demonstrated its utility by imaging spiking and millivolt-scale subthreshold and synaptic activity in acute mouse brain slices and in larval zebrafish in vivo. We also measured postsynaptic responses downstream of optogenetically controlled neurons in C. elegans. FAU - Piatkevich, Kiryl D AU - Piatkevich KD AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. FAU - Jung, Erica E AU - Jung EE AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. FAU - Straub, Christoph AU - Straub C AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Linghu, Changyang AU - Linghu C AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. AD - Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA, USA. FAU - Park, Demian AU - Park D AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. FAU - Suk, Ho-Jun AU - Suk HJ AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. AD - Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA, USA. FAU - Hochbaum, Daniel R AU - Hochbaum DR AUID- ORCID: 0000-0001-6220-6651 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Goodwin, Daniel AU - Goodwin D AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. FAU - Pnevmatikakis, Eftychios AU - Pnevmatikakis E AUID- ORCID: 0000-0003-1509-6394 AD - Simons Center Data Analysis, Simons Foundation, New York, NY, USA. FAU - Pak, Nikita AU - Pak N AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. AD - Department of Mechanical Engineering, MIT, Cambridge, MA, USA. FAU - Kawashima, Takashi AU - Kawashima T AD - Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, USA. FAU - Yang, Chao-Tsung AU - Yang CT AD - Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, USA. FAU - Rhoades, Jeffrey L AU - Rhoades JL AUID- ORCID: 0000-0001-5077-2533 AD - Picower Institute for Learning & Memory and Department of Brain & Cognitive Sciences, MIT, Cambridge, MA, USA. FAU - Shemesh, Or AU - Shemesh O AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. FAU - Asano, Shoh AU - Asano S AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. FAU - Yoon, Young-Gyu AU - Yoon YG AUID- ORCID: 0000-0002-5660-049X AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. AD - Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA, USA. FAU - Freifeld, Limor AU - Freifeld L AUID- ORCID: 0000-0002-0739-6947 AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. FAU - Saulnier, Jessica L AU - Saulnier JL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Riegler, Clemens AU - Riegler C AD - Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, USA. AD - Department of Neurobiology, Faculty of Life Sciences, University of Vienna, Wien, Austria. FAU - Engert, Florian AU - Engert F AD - Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, USA. FAU - Hughes, Thom AU - Hughes T AUID- ORCID: 0000-0002-8430-070X AD - Department of Cell Biology and Neuroscience, Montana State University, Bozeman, Montana, USA. FAU - Drobizhev, Mikhail AU - Drobizhev M AD - Department of Cell Biology and Neuroscience, Montana State University, Bozeman, Montana, USA. FAU - Szabo, Balint AU - Szabo B AD - Department of Biological Physics, Eotvos University, Budapest, Hungary. FAU - Ahrens, Misha B AU - Ahrens MB AD - Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, USA. FAU - Flavell, Steven W AU - Flavell SW AD - Picower Institute for Learning & Memory and Department of Brain & Cognitive Sciences, MIT, Cambridge, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Boyden, Edward S AU - Boyden ES AD - Media Lab, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. esb@media.mit.edu. AD - Department of Biological Engineering, MIT, Cambridge, MA, USA. esb@media.mit.edu. AD - MIT Center for Neurobiological Engineering, MIT, Cambridge, MA, USA. esb@media.mit.edu. AD - Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA. esb@media.mit.edu. AD - MIT McGovern Institute for Brain Research, MIT, Cambridge, MA, USA. esb@media.mit.edu. LA - eng GR - U01 NS099691/NS/NINDS NIH HHS/United States GR - R01 DA029639/DA/NIDA NIH HHS/United States GR - R24 MH106075/MH/NIMH NIH HHS/United States GR - R01 MH103910/MH/NIMH NIH HHS/United States GR - R01 EY023173/EY/NEI NIH HHS/United States GR - R01 GM104948/GM/NIGMS NIH HHS/United States GR - R01 NS087950/NS/NINDS NIH HHS/United States GR - DP1 NS087724/NS/NINDS NIH HHS/United States GR - R43 MH109332/MH/NIMH NIH HHS/United States GR - R01 NS104892/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180226 PL - United States TA - Nat Chem Biol JT - Nature chemical biology JID - 101231976 RN - 0 (Luminescent Proteins) SB - IM EIN - Nat Chem Biol. 2018 Mar 8;:. PMID: 29520042 MH - Animals MH - Brain/diagnostic imaging MH - Caenorhabditis elegans MH - Cell Separation MH - Directed Molecular Evolution/*methods MH - Female MH - Flow Cytometry MH - Fluorescence MH - Gene Library MH - Genes, Reporter MH - HEK293 Cells MH - Hippocampus/cytology MH - Humans MH - Luminescent Proteins/*chemistry MH - Male MH - Mice MH - Microscopy, Fluorescence MH - Neurons/cytology MH - Optogenetics MH - Protein Engineering/*methods MH - *Robotics MH - Zebrafish/*embryology PMC - PMC5866759 MID - NIHMS929464 COIS- COMPETING FINANCIAL INTERESTS B.S. is a founder of the CellSorter startup company. K.D.P., E.E.J., and E.S.B. are inventors on patent applications regarding the molecules here reported. B.S., K.D.P., E.E.J., and E.S.B. are inventors on a patent application regarding the screening method here developed. EDAT- 2018/02/28 06:00 MHDA- 2019/05/06 06:00 CRDT- 2018/02/28 06:00 PHST- 2017/04/18 00:00 [received] PHST- 2017/12/19 00:00 [accepted] PHST- 2018/02/28 06:00 [pubmed] PHST- 2019/05/06 06:00 [medline] PHST- 2018/02/28 06:00 [entrez] AID - 10.1038/s41589-018-0004-9 [pii] AID - 10.1038/s41589-018-0004-9 [doi] PST - ppublish SO - Nat Chem Biol. 2018 Apr;14(4):352-360. doi: 10.1038/s41589-018-0004-9. Epub 2018 Feb 26. PMID- 29562189 OWN - NLM STAT- MEDLINE DCOM- 20190916 LR - 20210109 IS - 2211-1247 (Electronic) VI - 22 IP - 12 DP - 2018 Mar 20 TI - Silk Fibroin Films Facilitate Single-Step Targeted Expression of Optogenetic Proteins. PG - 3351-3361 LID - S2211-1247(18)30291-2 [pii] LID - 10.1016/j.celrep.2018.02.081 [doi] AB - Optical methods of interrogating neural circuits have emerged as powerful tools for understanding how the brain drives behaviors. Optogenetic proteins are widely used to control neuronal activity, while genetically encoded fluorescent reporters are used to monitor activity. These proteins are often expressed by injecting viruses, which frequently leads to inconsistent experiments due to misalignment of expression and optical components. Here, we describe how silk fibroin films simplify optogenetic experiments by providing targeted delivery of viruses. Films composed of silk fibroin and virus are applied to the surface of implantable optical components. After surgery, silk releases the virus to transduce nearby cells and provide localized expression around optical fibers and endoscopes. Silk films can also be used to express genetically encoded sensors in large cortical regions by using cranial windows coated with a silk/virus mixture. The ease of use and improved performance provided by silk make this a promising approach for optogenetic studies. CI - Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved. FAU - Jackman, Skyler L AU - Jackman SL AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Chen, Christopher H AU - Chen CH AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Chettih, Selmaan N AU - Chettih SN AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Neufeld, Shay Q AU - Neufeld SQ AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. FAU - Drew, Iain R AU - Drew IR AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Agba, Chimuanya K AU - Agba CK AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Flaquer, Isabella AU - Flaquer I AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Stefano, Alexis N AU - Stefano AN AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Kennedy, Thomas J AU - Kennedy TJ AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Belinsky, Justine E AU - Belinsky JE AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Roberston, Keiramarie AU - Roberston K AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. FAU - Beron, Celia C AU - Beron CC AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. FAU - Harvey, Christopher D AU - Harvey CD AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Regehr, Wade G AU - Regehr WG AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: wade_regher@hms.harvard.edu. LA - eng GR - U01 NS094190/NS/NINDS NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - R01 MH100568/MH/NIMH NIH HHS/United States GR - R35 NS097284/NS/NINDS NIH HHS/United States GR - R21 NS093498/NS/NINDS NIH HHS/United States GR - R01 NS032405/NS/NINDS NIH HHS/United States GR - R01 MH107620/MH/NIMH NIH HHS/United States GR - R01 NS089521/NS/NINDS NIH HHS/United States GR - F32 NS101889/NS/NINDS NIH HHS/United States GR - CIHR/Canada PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 9007-76-5 (Fibroins) SB - IM MH - Fibroins/*metabolism MH - Humans MH - Optogenetics/*methods PMC - PMC5894120 MID - NIHMS955606 OTO - NOTNLM OT - 2-photon calcium imaging OT - biomaterials OT - cranial windows OT - in vivo imaging OT - optical fiber implants OT - optogenetics OT - silk OT - stereotaxic injections OT - tapered optical fibers OT - viral vectors COIS- DECLARATION OF INTERESTS The authors declare no competing interests. EDAT- 2018/03/22 06:00 MHDA- 2019/09/17 06:00 CRDT- 2018/03/22 06:00 PHST- 2017/12/11 00:00 [received] PHST- 2018/02/07 00:00 [revised] PHST- 2018/02/21 00:00 [accepted] PHST- 2018/03/22 06:00 [entrez] PHST- 2018/03/22 06:00 [pubmed] PHST- 2019/09/17 06:00 [medline] AID - S2211-1247(18)30291-2 [pii] AID - 10.1016/j.celrep.2018.02.081 [doi] PST - ppublish SO - Cell Rep. 2018 Mar 20;22(12):3351-3361. doi: 10.1016/j.celrep.2018.02.081. PMID- 29535413 OWN - NLM STAT- MEDLINE DCOM- 20190920 LR - 20220127 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 8 IP - 1 DP - 2018 Mar 13 TI - Tailoring light delivery for optogenetics by modal demultiplexing in tapered optical fibers. PG - 4467 LID - 10.1038/s41598-018-22790-z [doi] LID - 4467 AB - Optogenetic control of neural activity in deep brain regions ideally requires precise and flexible light delivery with non-invasive devices. To this end, Tapered Optical Fibers (TFs) represent a versatile tool that can deliver light over either large brain volumes or spatially confined sub-regions, while being sensibly smaller than flat-cleaved optical fibers. In this work, we report on the possibility of further extending light emission length along the taper in the range 0.4 mm-3.0 mm by increasing the numerical aperture of the TFs to NA = 0.66. We investigated the dependence between the input angle of light (θ(in)) and the output position along the taper, finding that for θ(in) > 10° this relationship is linear. This mode-division demultiplexing property of the taper was confirmed with a ray tracing model and characterized for 473 nm and 561 nm light in quasi-transparent solution and in brain slices, with the two wavelengths used to illuminate simultaneously two different regions of the brain using only one waveguide. The results presented in this manuscript can guide neuroscientists to design their optogenetic experiments on the base of this mode-division demultiplexing approach, providing a tool that potentially allow for dynamic targeting of regions with diverse extension, from the mouse VTA up to the macaque visual cortex. FAU - Pisanello, Marco AU - Pisanello M AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, 73010, Arnesano (LE), Italy. AD - Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - Pisano, Filippo AU - Pisano F AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, 73010, Arnesano (LE), Italy. FAU - Sileo, Leonardo AU - Sileo L AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, 73010, Arnesano (LE), Italy. FAU - Maglie, Emanuela AU - Maglie E AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, 73010, Arnesano (LE), Italy. AD - Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - Bellistri, Elisa AU - Bellistri E AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, 73010, Arnesano (LE), Italy. FAU - Spagnolo, Barbara AU - Spagnolo B AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, 73010, Arnesano (LE), Italy. FAU - Mandelbaum, Gil AU - Mandelbaum G AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, 02115 MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, 02115 MA, USA. FAU - De Vittorio, Massimo AU - De Vittorio M AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, 73010, Arnesano (LE), Italy. AD - Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - Pisanello, Ferruccio AU - Pisanello F AUID- ORCID: 0000-0002-1489-7758 AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, 73010, Arnesano (LE), Italy. ferruccio.pisanello@iit.it. LA - eng GR - U01 NS094190/NS/NINDS NIH HHS/United States GR - UF1 NS108177/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180313 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 SB - IM MH - Animals MH - Humans MH - Male MH - Optical Fibers MH - Optogenetics/*instrumentation MH - Photic Stimulation/*instrumentation MH - Visual Cortex/*physiology PMC - PMC5849750 COIS- M.D.V., F. Pisanello, B.L.S., and L.S. are co-founders of Optogenix LLC, a company based in Italy that produces and markets the tapered fibers described here. EDAT- 2018/03/15 06:00 MHDA- 2019/09/21 06:00 CRDT- 2018/03/15 06:00 PHST- 2017/08/04 00:00 [received] PHST- 2018/03/01 00:00 [accepted] PHST- 2018/03/15 06:00 [entrez] PHST- 2018/03/15 06:00 [pubmed] PHST- 2019/09/21 06:00 [medline] AID - 10.1038/s41598-018-22790-z [pii] AID - 22790 [pii] AID - 10.1038/s41598-018-22790-z [doi] PST - epublish SO - Sci Rep. 2018 Mar 13;8(1):4467. doi: 10.1038/s41598-018-22790-z. PMID- 29469809 OWN - NLM STAT- MEDLINE DCOM- 20190716 LR - 20210109 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 7 DP - 2018 Feb 22 TI - Efficient and accurate extraction of in vivo calcium signals from microendoscopic video data. LID - 10.7554/eLife.28728 [doi] LID - e28728 AB - In vivo calcium imaging through microendoscopic lenses enables imaging of previously inaccessible neuronal populations deep within the brains of freely moving animals. However, it is computationally challenging to extract single-neuronal activity from microendoscopic data, because of the very large background fluctuations and high spatial overlaps intrinsic to this recording modality. Here, we describe a new constrained matrix factorization approach to accurately separate the background and then demix and denoise the neuronal signals of interest. We compared the proposed method against previous independent components analysis and constrained nonnegative matrix factorization approaches. On both simulated and experimental data recorded from mice, our method substantially improved the quality of extracted cellular signals and detected more well-isolated neural signals, especially in noisy data regimes. These advances can in turn significantly enhance the statistical power of downstream analyses, and ultimately improve scientific conclusions derived from microendoscopic data. CI - © 2018, Zhou et al. FAU - Zhou, Pengcheng AU - Zhou P AUID- ORCID: 0000-0003-1237-3931 AD - Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, United States. AD - Department of Statistics, Columbia University, New York, United States. AD - Machine Learning Department, Carnegie Mellon University, Pittsburgh, United States. AD - Grossman Center for the Statistics of Mind, Columbia University, New York, United States. AD - Center for Theoretical Neuroscience, Columbia University, New York, United States. FAU - Resendez, Shanna L AU - Resendez SL AD - Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, United States. FAU - Rodriguez-Romaguera, Jose AU - Rodriguez-Romaguera J AD - Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, United States. FAU - Jimenez, Jessica C AU - Jimenez JC AD - Department of Neuroscience, Columbia University, New York, United States. AD - Division of Integrative Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, New York, United States. AD - Department of Psychiatry & Pharmacology, Columbia University, New York, United States. FAU - Neufeld, Shay Q AU - Neufeld SQ AD - Department of Neurobiology, Harvard Medical School, Howard Hughes Medical Institute, Boston, United States. FAU - Giovannucci, Andrea AU - Giovannucci A AUID- ORCID: 0000-0002-7850-444X AD - Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, United States. FAU - Friedrich, Johannes AU - Friedrich J AUID- ORCID: 0000-0002-1321-5866 AD - Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, United States. FAU - Pnevmatikakis, Eftychios A AU - Pnevmatikakis EA AUID- ORCID: 0000-0003-1509-6394 AD - Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, United States. FAU - Stuber, Garret D AU - Stuber GD AUID- ORCID: 0000-0003-1730-4855 AD - Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, United States. AD - Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States. AD - Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, United States. FAU - Hen, Rene AU - Hen R AD - Department of Neuroscience, Columbia University, New York, United States. AD - Division of Integrative Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, New York, United States. AD - Department of Psychiatry & Pharmacology, Columbia University, New York, United States. FAU - Kheirbek, Mazen A AU - Kheirbek MA AD - Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United States. AD - Neuroscience Graduate Program, University of California, San Francisco, United States. AD - Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, United States. AD - Department of Psychiatry, University of California, San Francisco, San Francisco, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Harvard Medical School, Howard Hughes Medical Institute, Boston, United States. FAU - Kass, Robert E AU - Kass RE AD - Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, United States. AD - Machine Learning Department, Carnegie Mellon University, Pittsburgh, United States. AD - Department of Statistics, Carnegie Mellon University, Pittsburgh, United States. FAU - Paninski, Liam AU - Paninski L AD - Department of Statistics, Columbia University, New York, United States. AD - Grossman Center for the Statistics of Mind, Columbia University, New York, United States. AD - Center for Theoretical Neuroscience, Columbia University, New York, United States. AD - Department of Neuroscience, Columbia University, New York, United States. AD - Kavli Institute for Brain Science, Columbia University, New York, United States. AD - Neurotechnology Center, Columbia University, New York, United States. LA - eng GR - R01 MH108623/MH/NIMH NIH HHS/United States GR - U19 NS104649/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - R01 EB022913/EB/NIBIB NIH HHS/United States GR - CIHR/Canada GR - R01 MH111754/MH/NIMH NIH HHS/United States GR - R01 MH064537/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20180222 PL - England TA - Elife JT - eLife JID - 101579614 SB - IM MH - Animals MH - Brain/*physiology MH - *Calcium Signaling MH - Endoscopy/*methods MH - Image Processing, Computer-Assisted/*methods MH - Mice MH - Neurons/*physiology MH - Video Recording/*methods PMC - PMC5871355 OTO - NOTNLM OT - calcium imaging OT - microendoscope OT - mouse OT - neuroscience OT - source extraction COIS- PZ, SR, JR, JJ, SN, AG, JF, EP, GS, RH, MK, BS, RK, LP No competing interests declared EDAT- 2018/02/23 06:00 MHDA- 2019/07/17 06:00 CRDT- 2018/02/23 06:00 PHST- 2017/05/19 00:00 [received] PHST- 2018/02/20 00:00 [accepted] PHST- 2018/02/23 06:00 [pubmed] PHST- 2019/07/17 06:00 [medline] PHST- 2018/02/23 06:00 [entrez] AID - 28728 [pii] AID - 10.7554/eLife.28728 [doi] PST - epublish SO - Elife. 2018 Feb 22;7:e28728. doi: 10.7554/eLife.28728. PMID- 29230054 OWN - NLM STAT- MEDLINE DCOM- 20190509 LR - 20190509 IS - 1546-1726 (Electronic) IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 21 IP - 1 DP - 2018 Jan TI - Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex. PG - 120-129 LID - 10.1038/s41593-017-0029-5 [doi] AB - Activity-dependent transcriptional responses shape cortical function. However, a comprehensive understanding of the diversity of these responses across the full range of cortical cell types, and how these changes contribute to neuronal plasticity and disease, is lacking. To investigate the breadth of transcriptional changes that occur across cell types in the mouse visual cortex after exposure to light, we applied high-throughput single-cell RNA sequencing. We identified significant and divergent transcriptional responses to stimulation in each of the 30 cell types characterized, thus revealing 611 stimulus-responsive genes. Excitatory pyramidal neurons exhibited inter- and intralaminar heterogeneity in the induction of stimulus-responsive genes. Non-neuronal cells showed clear transcriptional responses that may regulate experience-dependent changes in neurovascular coupling and myelination. Together, these results reveal the dynamic landscape of the stimulus-dependent transcriptional changes occurring across cell types in the visual cortex; these changes are probably critical for cortical function and may be sites of deregulation in developmental brain disorders. FAU - Hrvatin, Sinisa AU - Hrvatin S AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Hochbaum, Daniel R AU - Hochbaum DR AUID- ORCID: 0000-0001-6220-6651 AD - Society of Fellows, Harvard University, Cambridge, MA, USA. AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. FAU - Nagy, M Aurel AU - Nagy MA AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Cicconet, Marcelo AU - Cicconet M AD - Image and Data Analysis Core, Harvard Medical School, Boston, MA, USA. FAU - Robertson, Keiramarie AU - Robertson K AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. FAU - Cheadle, Lucas AU - Cheadle L AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Zilionis, Rapolas AU - Zilionis R AD - Department of Systems Biology, Harvard Medical School, Boston, MA, USA. AD - Vilnius University Institute of Biotechnology, Vilnius, Lithuania. FAU - Ratner, Alex AU - Ratner A AD - ICCB-L Single Cell Core, Harvard Medical School, Boston, MA, USA. FAU - Borges-Monroy, Rebeca AU - Borges-Monroy R AD - Program for Bioinformatics and Integrative Genomics, Graduate School of Arts and Science, Division of Medical Sciences, Harvard University, Cambridge, MA, USA. FAU - Klein, Allon M AU - Klein AM AD - Department of Systems Biology, Harvard Medical School, Boston, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. bernardo_sabatini@hms.harvard.edu. FAU - Greenberg, Michael E AU - Greenberg ME AUID- ORCID: 0000-0003-1380-2160 AD - Department of Neurobiology, Harvard Medical School, Boston, MA, USA. michael_greenberg@hms.harvard.edu. LA - eng GR - R37 NS028829/NS/NINDS NIH HHS/United States GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - T32 AG000222/AG/NIA NIH HHS/United States GR - T32 GM007753/GM/NIGMS NIH HHS/United States GR - R01 NS028829/NS/NINDS NIH HHS/United States GR - U54 HD090255/HD/NICHD NIH HHS/United States GR - R33 CA212697/CA/NCI NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20171211 PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 0 (Basic Helix-Loop-Helix Transcription Factors) RN - 0 (Nerve Tissue Proteins) RN - 0 (Npas4 protein, mouse) RN - 0 (Proto-Oncogene Proteins c-fos) SB - IM EIN - Nat Neurosci. 2018 May 11;:. PMID: 29752482 MH - Animals MH - Basic Helix-Loop-Helix Transcription Factors/metabolism MH - Gene Expression Regulation/physiology MH - Gene Ontology MH - Light MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Nerve Tissue Proteins/genetics/metabolism MH - Neural Inhibition/physiology MH - Neuroglia/*physiology MH - Neurons/cytology/*physiology MH - Neurovascular Coupling/physiology MH - Photic Stimulation MH - Proto-Oncogene Proteins c-fos/metabolism MH - Signal Transduction/physiology MH - Single-Cell Analysis/methods MH - Statistics, Nonparametric MH - Transcription, Genetic/*physiology MH - Transcriptome/*physiology MH - Visual Cortex/*cytology MH - Visual Pathways PMC - PMC5742025 MID - NIHMS917054 COIS- Competing Financial Interests The authors declare no competing financial interests. EDAT- 2017/12/13 06:00 MHDA- 2019/05/10 06:00 CRDT- 2017/12/13 06:00 PHST- 2017/03/09 00:00 [received] PHST- 2017/10/17 00:00 [accepted] PHST- 2017/12/13 06:00 [pubmed] PHST- 2019/05/10 06:00 [medline] PHST- 2017/12/13 06:00 [entrez] AID - 10.1038/s41593-017-0029-5 [pii] AID - 10.1038/s41593-017-0029-5 [doi] PST - ppublish SO - Nat Neurosci. 2018 Jan;21(1):120-129. doi: 10.1038/s41593-017-0029-5. Epub 2017 Dec 11. PMID- 29154125 OWN - NLM STAT- MEDLINE DCOM- 20171220 LR - 20220129 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 96 IP - 5 DP - 2017 Dec 6 TI - Endogenous Gαq-Coupled Neuromodulator Receptors Activate Protein Kinase A. PG - 1070-1083.e5 LID - S0896-6273(17)30991-1 [pii] LID - 10.1016/j.neuron.2017.10.023 [doi] AB - Protein kinase A (PKA) integrates inputs from G-protein-coupled neuromodulator receptors to modulate synaptic and cellular function. Gαs signaling stimulates PKA activity, whereas Gαi inhibits PKA activity. Gαq, on the other hand, signals through phospholipase C, and it remains unclear whether Gαq-coupled receptors signal to PKA in their native context. Here, using two independent optical reporters of PKA activity in acute mouse hippocampus slices, we show that endogenous Gαq-coupled muscarinic acetylcholine receptors activate PKA. Mechanistically, this effect is mediated by parallel signaling via either calcium or protein kinase C. Furthermore, multiple Gαq-coupled receptors modulate phosphorylation by PKA, a classical Gαs/Gαi effector. Thus, these results highlight PKA as a biochemical integrator of three major types of GPCRs and necessitate reconsideration of classic models used to predict neuronal signaling in response to the large family of Gαq-coupled receptors. CI - Copyright © 2017 Elsevier Inc. All rights reserved. FAU - Chen, Yao AU - Chen Y AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Granger, Adam J AU - Granger AJ AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Tran, Trinh AU - Tran T AD - Mind/Brain Institute, John Hopkins University, Baltimore, MD 21218, USA. FAU - Saulnier, Jessica L AU - Saulnier JL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Kirkwood, Alfredo AU - Kirkwood A AD - Mind/Brain Institute, John Hopkins University, Baltimore, MD 21218, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. Electronic address: bernardo_sabatini@hms.harvard.edu. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - F32 DA035543/DA/NIDA NIH HHS/United States GR - R01 EY012124/EY/NEI NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20171116 PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (Receptors, Muscarinic) RN - 0 (Receptors, Neurotransmitter) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) RN - EC 2.7.11.13 (Protein Kinase C) RN - EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gq-G11) SB - IM MH - Animals MH - Calcium Signaling/genetics/physiology MH - Cyclic AMP-Dependent Protein Kinases/*metabolism MH - Enzyme Activation/genetics MH - Female MH - GTP-Binding Protein alpha Subunits, Gq-G11/*genetics MH - HEK293 Cells MH - Hippocampus/cytology/metabolism MH - Humans MH - Mice MH - Mice, Inbred C57BL MH - Phosphorylation MH - Pregnancy MH - Protein Kinase C/metabolism MH - Receptors, G-Protein-Coupled/metabolism MH - Receptors, Muscarinic/genetics/metabolism MH - Receptors, Neurotransmitter/*metabolism MH - Signal Transduction/genetics PMC - PMC5726796 MID - NIHMS914862 OTO - NOTNLM OT - G protein-coupled receptor OT - Gαq signaling OT - acetylcholine OT - designer receptors OT - fluorescence lifetime imaging microscopy OT - hippocampus OT - muscarinic receptors OT - neuromodulation OT - optical reporters OT - protein kinase A EDAT- 2017/11/21 06:00 MHDA- 2017/12/21 06:00 CRDT- 2017/11/21 06:00 PHST- 2016/01/27 00:00 [received] PHST- 2017/09/11 00:00 [revised] PHST- 2017/10/16 00:00 [accepted] PHST- 2017/11/21 06:00 [pubmed] PHST- 2017/12/21 06:00 [medline] PHST- 2017/11/21 06:00 [entrez] AID - S0896-6273(17)30991-1 [pii] AID - 10.1016/j.neuron.2017.10.023 [doi] PST - ppublish SO - Neuron. 2017 Dec 6;96(5):1070-1083.e5. doi: 10.1016/j.neuron.2017.10.023. Epub 2017 Nov 16. PMID- 28628101 OWN - NLM STAT- MEDLINE DCOM- 20170905 LR - 20220129 IS - 1546-1726 (Electronic) IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 20 IP - 8 DP - 2017 Aug TI - Dynamic illumination of spatially restricted or large brain volumes via a single tapered optical fiber. PG - 1180-1188 LID - 10.1038/nn.4591 [doi] AB - Optogenetics promises precise spatiotemporal control of neural processes using light. However, the spatial extent of illumination within the brain is difficult to control and cannot be adjusted using standard fiber optics. We demonstrate that optical fibers with tapered tips can be used to illuminate either spatially restricted or large brain volumes. Remotely adjusting the light input angle to the fiber varies the light-emitting portion of the taper over several millimeters without movement of the implant. We use this mode to activate dorsal versus ventral striatum of individual mice and reveal different effects of each manipulation on motor behavior. Conversely, injecting light over the full numerical aperture of the fiber results in light emission from the entire taper surface, achieving broader and more efficient optogenetic activation of neurons, compared to standard flat-faced fiber stimulation. Thus, tapered fibers permit focal or broad illumination that can be precisely and dynamically matched to experimental needs. FAU - Pisanello, Ferruccio AU - Pisanello F AUID- ORCID: 0000-0002-1489-7758 AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Arnesano, Lecce, Italy. FAU - Mandelbaum, Gil AU - Mandelbaum G AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA. FAU - Pisanello, Marco AU - Pisanello M AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Arnesano, Lecce, Italy. AD - Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - Oldenburg, Ian A AU - Oldenburg IA AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA. FAU - Sileo, Leonardo AU - Sileo L AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Arnesano, Lecce, Italy. FAU - Markowitz, Jeffrey E AU - Markowitz JE AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA. FAU - Peterson, Ralph E AU - Peterson RE AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. FAU - Della Patria, Andrea AU - Della Patria A AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Arnesano, Lecce, Italy. FAU - Haynes, Trevor M AU - Haynes TM AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA. FAU - Emara, Mohamed S AU - Emara MS AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Arnesano, Lecce, Italy. AD - Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - Spagnolo, Barbara AU - Spagnolo B AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Arnesano, Lecce, Italy. AD - Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - Datta, Sandeep Robert AU - Datta SR AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. FAU - De Vittorio, Massimo AU - De Vittorio M AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Arnesano, Lecce, Italy. AD - Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Lecce, Italy. FAU - Sabatini, Bernardo L AU - Sabatini BL AUID- ORCID: 0000-0003-0095-9177 AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA. LA - eng GR - 677683/ERC_/European Research Council/International GR - U01 NS094190/NS/NINDS NIH HHS/United States GR - U01 NS094191/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20170619 PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 9009-81-8 (Rhodopsin) SB - IM MH - Animals MH - Brain/*physiology MH - Female MH - Male MH - Mice, Transgenic MH - Nerve Net/*physiology MH - Neurons/*physiology MH - *Optical Fibers MH - Optogenetics/methods MH - *Photic Stimulation/methods MH - Rhodopsin/genetics PMC - PMC5533215 MID - EMS72925 COIS- Conflict of interest MDV, FP, BS, SD, and LS, authors on this study, are co-founders of Optogenix LLC, a company based in Italy that produces and markets the tapered fibers described here. EDAT- 2017/06/20 06:00 MHDA- 2017/09/07 06:00 CRDT- 2017/06/20 06:00 PHST- 2016/12/22 00:00 [received] PHST- 2017/05/18 00:00 [accepted] PHST- 2017/06/20 06:00 [pubmed] PHST- 2017/09/07 06:00 [medline] PHST- 2017/06/20 06:00 [entrez] AID - nn.4591 [pii] AID - 10.1038/nn.4591 [doi] PST - ppublish SO - Nat Neurosci. 2017 Aug;20(8):1180-1188. doi: 10.1038/nn.4591. Epub 2017 Jun 19. PMID- 28500992 OWN - NLM STAT- MEDLINE DCOM- 20180228 LR - 20210716 IS - 1873-6882 (Electronic) IS - 0959-4388 (Print) IS - 0959-4388 (Linking) VI - 45 DP - 2017 Aug TI - Multi-transmitter neurons in the mammalian central nervous system. PG - 85-91 LID - S0959-4388(17)30016-8 [pii] LID - 10.1016/j.conb.2017.04.007 [doi] AB - It is firmly established that many mammalian neurons release various combinations of amino acids, their derivatives, and other small molecules from presynaptic terminals in order to signal to their postsynaptic targets. Here we discuss recent findings about four types of multi-transmitter neurons-those that release GABA and acetylcholine (Ach); dopamine (DA) and GABA or glutamate; and glutamate and GABA. The mechanisms of co-release in each class differ and highlight the complex and dynamic nature of neurotransmitter release. Furthermore, identifying the neurotransmitter signature of each neuron and the post-synaptic targets of each neurotransmitter remain challenging. The existence of multi-transmitter neurons complicates the interpretation of connectomic wiring diagrams and poses interesting challenges for our understanding of circuit function in the brain. CI - Copyright © 2017 Elsevier Ltd. All rights reserved. FAU - Granger, Adam J AU - Granger AJ AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, United States. FAU - Wallace, Michael L AU - Wallace ML AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, United States. Electronic address: bsabatini@hms.harvard.edu. LA - eng GR - K99 NS102429/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Review DEP - 20170510 PL - England TA - Curr Opin Neurobiol JT - Current opinion in neurobiology JID - 9111376 SB - IM MH - Animals MH - Central Nervous System/*cytology/physiology MH - Mammals MH - Neurons/*physiology MH - Synaptic Transmission/physiology PMC - PMC5609825 MID - NIHMS875759 EDAT- 2017/05/14 06:00 MHDA- 2018/03/01 06:00 CRDT- 2017/05/14 06:00 PHST- 2017/01/18 00:00 [received] PHST- 2017/04/17 00:00 [accepted] PHST- 2017/05/14 06:00 [pubmed] PHST- 2018/03/01 06:00 [medline] PHST- 2017/05/14 06:00 [entrez] AID - S0959-4388(17)30016-8 [pii] AID - 10.1016/j.conb.2017.04.007 [doi] PST - ppublish SO - Curr Opin Neurobiol. 2017 Aug;45:85-91. doi: 10.1016/j.conb.2017.04.007. Epub 2017 May 10. PMID- 28384468 OWN - NLM STAT- MEDLINE DCOM- 20170726 LR - 20220129 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 94 IP - 1 DP - 2017 Apr 5 TI - Genetically Distinct Parallel Pathways in the Entopeduncular Nucleus for Limbic and Sensorimotor Output of the Basal Ganglia. PG - 138-152.e5 LID - S0896-6273(17)30200-3 [pii] LID - 10.1016/j.neuron.2017.03.017 [doi] AB - The basal ganglia (BG) integrate inputs from diverse sensorimotor, limbic, and associative regions to guide action-selection and goal-directed behaviors. The entopeduncular nucleus (EP) is a major BG output nucleus and has been suggested to channel signals from distinct BG nuclei to target regions involved in diverse functions. Here we use single-cell transcriptional and molecular analyses to demonstrate that the EP contains at least three classes of projection neurons-glutamate/GABA co-releasing somatostatin neurons, glutamatergic parvalbumin neurons, and GABAergic parvalbumin neurons. These classes comprise functionally and anatomically distinct output pathways that differentially affect EP target regions, such as the lateral habenula (LHb) and thalamus. Furthermore, LHb- and thalamic-projecting EP neurons are differentially innervated by subclasses of striatal and pallidal neurons. Therefore, we identify previously unknown subdivisions within the EP and reveal the existence of cascading, molecularly distinct projections through striatum and globus pallidus to EP targets within epithalamus and thalamus. CI - Copyright © 2017 Elsevier Inc. All rights reserved. FAU - Wallace, Michael L AU - Wallace ML AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Saunders, Arpiar AU - Saunders A AD - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. FAU - Huang, Kee Wui AU - Huang KW AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Philson, Adrienne C AU - Philson AC AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Goldman, Melissa AU - Goldman M AD - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. FAU - Macosko, Evan Z AU - Macosko EZ AD - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. FAU - McCarroll, Steven A AU - McCarroll SA AD - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bernardo_sabatini@hms.harvard.edu. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - HHMI_/Howard Hughes Medical Institute/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - T32 NS007484/NS/NINDS NIH HHS/United States PT - Journal Article PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Parvalbumins) RN - 3KX376GY7L (Glutamic Acid) RN - 51110-01-1 (Somatostatin) SB - IM CIN - Trends Neurosci. 2017 Jun;40(6):325-327. PMID: 28501393 MH - Animals MH - Basal Ganglia/cytology/*metabolism MH - Entopeduncular Nucleus/cytology/*metabolism MH - GABAergic Neurons/cytology/*metabolism MH - Gene Expression Profiling MH - Globus Pallidus/cytology MH - Glutamic Acid/metabolism MH - Habenula/cytology MH - Humans MH - In Situ Hybridization, Fluorescence MH - Limbic System MH - Mice MH - Neostriatum/cytology MH - Neurons/cytology/metabolism MH - Parvalbumins/metabolism MH - Sensorimotor Cortex MH - Single-Cell Analysis MH - Somatostatin/metabolism MH - Thalamus/cytology PMC - PMC5439268 MID - NIHMS860220 OTO - NOTNLM OT - basal ganglia OT - co-release OT - entopeduncular nucleus OT - lateral habenula OT - single cell sequencing EDAT- 2017/04/07 06:00 MHDA- 2017/07/27 06:00 CRDT- 2017/04/07 06:00 PHST- 2016/06/09 00:00 [received] PHST- 2017/01/31 00:00 [revised] PHST- 2017/03/09 00:00 [accepted] PHST- 2017/04/07 06:00 [entrez] PHST- 2017/04/07 06:00 [pubmed] PHST- 2017/07/27 06:00 [medline] AID - S0896-6273(17)30200-3 [pii] AID - 10.1016/j.neuron.2017.03.017 [doi] PST - ppublish SO - Neuron. 2017 Apr 5;94(1):138-152.e5. doi: 10.1016/j.neuron.2017.03.017. PMID- 27710792 OWN - NLM STAT- MEDLINE DCOM- 20171003 LR - 20220129 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 92 IP - 1 DP - 2016 Oct 5 TI - Principles of Synaptic Organization of GABAergic Interneurons in the Striatum. PG - 84-92 LID - S0896-6273(16)30566-9 [pii] LID - 10.1016/j.neuron.2016.09.007 [doi] AB - The striatum, the entry nucleus of the basal ganglia, lacks laminar or columnar organization of its principal cells; nevertheless, functional data suggest that it is spatially organized. Here we examine whether the connectivity and synaptic organization of striatal GABAergic interneurons contributes to such spatial organization. Focusing on the two main classes of striatal GABAergic interneurons (fast-spiking interneurons [FSIs] and low-threshold-spiking interneurons [LTSIs]), we apply a combination of optogenetics and viral tracing approaches to dissect striatal microcircuits in mice. Our results reveal fundamental differences between the synaptic organizations of both interneuron types. FSIs target exclusively striatal projection neurons (SPNs) within close proximity and form strong synapses on the proximal somatodendritic region. In contrast, LTSIs target both SPNs and cholinergic interneurons, and synaptic connections onto SPNs are made exclusively over long distances and onto distal dendrites. These results suggest fundamentally different functions of FSIs and LTSIs in shaping striatal output. CI - Copyright © 2016 Elsevier Inc. All rights reserved. FAU - Straub, Christoph AU - Straub C AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. FAU - Saulnier, Jessica Lizette AU - Saulnier JL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. FAU - Bègue, Aurelien AU - Bègue A AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. FAU - Feng, Danielle D AU - Feng DD AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. FAU - Huang, Kee Wui AU - Huang KW AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. FAU - Sabatini, Bernardo Luis AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. Electronic address: bernardo_sabatini@hms.harvard.edu. LA - eng GR - HHMI_/Howard Hughes Medical Institute/United States GR - P30 EY012196/EY/NEI NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (DRD2 protein, mouse) RN - 0 (Drd1 protein, mouse) RN - 0 (Receptor, Adenosine A2A) RN - 0 (Receptors, Dopamine D1) RN - 0 (Receptors, Dopamine D2) SB - IM MH - Animals MH - Corpus Striatum/*cytology MH - GABAergic Neurons/*physiology MH - Interneurons/*physiology MH - Mice MH - Mice, Knockout MH - Mice, Transgenic MH - Neural Pathways/cytology/physiology MH - Neuroanatomical Tract-Tracing Techniques MH - Receptor, Adenosine A2A/genetics MH - Receptors, Dopamine D1/genetics MH - Receptors, Dopamine D2/genetics MH - Synapses/*physiology PMC - PMC5074692 MID - NIHMS815966 COIS- The authors declare no competing financial interest. EDAT- 2016/10/07 06:00 MHDA- 2017/10/04 06:00 CRDT- 2016/10/07 06:00 PHST- 2016/04/01 00:00 [received] PHST- 2016/07/11 00:00 [revised] PHST- 2016/08/29 00:00 [accepted] PHST- 2016/10/07 06:00 [entrez] PHST- 2016/10/07 06:00 [pubmed] PHST- 2017/10/04 06:00 [medline] AID - S0896-6273(16)30566-9 [pii] AID - 10.1016/j.neuron.2016.09.007 [doi] PST - ppublish SO - Neuron. 2016 Oct 5;92(1):84-92. doi: 10.1016/j.neuron.2016.09.007. PMID- 27662084 OWN - NLM STAT- MEDLINE DCOM- 20161227 LR - 20181113 IS - 1097-4172 (Electronic) IS - 0092-8674 (Print) IS - 0092-8674 (Linking) VI - 167 IP - 1 DP - 2016 Sep 22 TI - Central Control Circuit for Context-Dependent Micturition. PG - 73-86.e12 LID - S0092-8674(16)31171-0 [pii] LID - 10.1016/j.cell.2016.08.073 [doi] AB - Urine release (micturition) serves an essential physiological function as well as a critical role in social communication in many animals. Here, we show a combined effect of olfaction and social hierarchy on micturition patterns in adult male mice, confirming the existence of a micturition control center that integrates pro- and anti-micturition cues. Furthermore, we demonstrate that a cluster of neurons expressing corticotropin-releasing hormone (Crh) in the pontine micturition center (PMC) is electrophysiologically distinct from their Crh-negative neighbors and sends glutamatergic projections to the spinal cord. The activity of PMC Crh-expressing neurons correlates with and is sufficient to drive bladder contraction, and when silenced impairs micturition behavior. These neurons receive convergent input from widespread higher brain areas that are capable of carrying diverse pro- and anti-micturition signals, and whose activity modulates hierarchy-dependent micturition. Taken together, our results indicate that PMC Crh-expressing neurons are likely the integration center for context-dependent micturition behavior. CI - Copyright © 2016 Elsevier Inc. All rights reserved. FAU - Hou, Xun Helen AU - Hou XH AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Hyun, Minsuk AU - Hyun M AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Taranda, Julian AU - Taranda J AD - Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. FAU - Huang, Kee Wui AU - Huang KW AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Todd, Emmalee AU - Todd E AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Feng, Danielle AU - Feng D AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Atwater, Emily AU - Atwater E AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Croney, Donyell AU - Croney D AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Zeidel, Mark Lawrence AU - Zeidel ML AD - Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. FAU - Osten, Pavel AU - Osten P AD - Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. FAU - Sabatini, Bernardo Luis AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bsabatini@hms.harvard.edu. LA - eng GR - R01 MH096946/MH/NIMH NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - R01 MH115267/MH/NIMH NIH HHS/United States GR - U01 MH105971/MH/NIMH NIH HHS/United States GR - P20 DK103086/DK/NIDDK NIH HHS/United States GR - R01 DK114834/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Cell JT - Cell JID - 0413066 RN - 3KX376GY7L (Glutamic Acid) RN - 9015-71-8 (Corticotropin-Releasing Hormone) SB - IM MH - Animals MH - Corticotropin-Releasing Hormone/*metabolism MH - Female MH - Glutamic Acid/physiology MH - Mice MH - Mice, Inbred C57BL MH - Muscle Contraction/*physiology MH - Neurons/metabolism/*physiology MH - Pons/cytology/*physiology MH - Smell MH - Spinal Cord/cytology/physiology MH - Urinary Bladder/innervation/*physiology MH - Urination/*physiology PMC - PMC6217838 MID - NIHMS984049 OTO - NOTNLM OT - Barrington's nucleus OT - bladder OT - corticotropin-releasing hormone OT - medial pre-optic area OT - micturition OT - pons COIS- COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. EDAT- 2016/09/24 06:00 MHDA- 2016/12/28 06:00 CRDT- 2016/09/24 06:00 PHST- 2016/02/25 00:00 [received] PHST- 2016/06/28 00:00 [revised] PHST- 2016/08/23 00:00 [accepted] PHST- 2016/09/24 06:00 [entrez] PHST- 2016/09/24 06:00 [pubmed] PHST- 2016/12/28 06:00 [medline] AID - S0092-8674(16)31171-0 [pii] AID - 10.1016/j.cell.2016.08.073 [doi] PST - ppublish SO - Cell. 2016 Sep 22;167(1):73-86.e12. doi: 10.1016/j.cell.2016.08.073. PMID- 27271196 OWN - NLM STAT- MEDLINE DCOM- 20170620 LR - 20230731 IS - 1548-7105 (Electronic) IS - 1548-7091 (Print) IS - 1548-7091 (Linking) VI - 13 IP - 8 DP - 2016 Aug TI - An E3-ligase-based method for ablating inhibitory synapses. PG - 673-8 LID - 10.1038/nmeth.3894 [doi] AB - Although neuronal activity can be modulated using a variety of techniques, there are currently few methods for controlling neuronal connectivity. We introduce a tool (GFE3) that mediates the fast, specific and reversible elimination of inhibitory synaptic inputs onto genetically determined neurons. GFE3 is a fusion between an E3 ligase, which mediates the ubiquitination and rapid degradation of proteins, and a recombinant, antibody-like protein (FingR) that binds to gephyrin. Expression of GFE3 leads to a strong and specific reduction of gephyrin in culture or in vivo and to a substantial decrease in phasic inhibition onto cells that express GFE3. By temporarily expressing GFE3 we showed that inhibitory synapses regrow following ablation. Thus, we have created a simple, reversible method for modulating inhibitory synaptic input onto genetically determined cells. FAU - Gross, Garrett G AU - Gross GG AD - Department of Biology, Section of Molecular and Computational Biology, University of Southern California, Los Angeles, Los Angeles, California, USA. FAU - Straub, Christoph AU - Straub C AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. FAU - Perez-Sanchez, Jimena AU - Perez-Sanchez J AD - Centre de recherche, Institut universitaire en santé mentale de Québec, Québec, Québec, Canada. AD - Université Laval, Québec, Québec, Canada. FAU - Dempsey, William P AU - Dempsey WP AD - Department of Biology, Section of Molecular and Computational Biology, University of Southern California, Los Angeles, Los Angeles, California, USA. FAU - Junge, Jason A AU - Junge JA AD - Department of Biology, Section of Molecular and Computational Biology, University of Southern California, Los Angeles, Los Angeles, California, USA. FAU - Roberts, Richard W AU - Roberts RW AD - Department of Chemistry, University of Southern California, Los Angeles, Los Angeles, California, USA. FAU - Trinh, Le A AU - Trinh le A AD - Department of Biology, Section of Molecular and Computational Biology, University of Southern California, Los Angeles, Los Angeles, California, USA. FAU - Fraser, Scott E AU - Fraser SE AD - Department of Biology, Section of Molecular and Computational Biology, University of Southern California, Los Angeles, Los Angeles, California, USA. FAU - De Koninck, Yves AU - De Koninck Y AUID- ORCID: 0000-0002-5779-9330 AD - Centre de recherche, Institut universitaire en santé mentale de Québec, Québec, Québec, Canada. AD - Université Laval, Québec, Québec, Canada. FAU - De Koninck, Paul AU - De Koninck P AD - Centre de recherche, Institut universitaire en santé mentale de Québec, Québec, Québec, Canada. AD - Université Laval, Québec, Québec, Canada. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. FAU - Arnold, Don B AU - Arnold DB AD - Department of Biology, Section of Molecular and Computational Biology, University of Southern California, Los Angeles, Los Angeles, California, USA. LA - eng GR - R01 AI085583/AI/NIAID NIH HHS/United States GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - R01 NS081678/NS/NINDS NIH HHS/United States GR - R01 GM083898/GM/NIGMS NIH HHS/United States GR - R01 NS081687/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160606 PL - United States TA - Nat Methods JT - Nature methods JID - 101215604 RN - 0 (Carrier Proteins) RN - 0 (Membrane Proteins) RN - 0 (gephyrin) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) SB - IM MH - Animals MH - Carrier Proteins/*metabolism MH - Cells, Cultured MH - Embryo, Mammalian/cytology/metabolism MH - Female MH - Hippocampus MH - Male MH - Membrane Proteins/*metabolism MH - Motor Disorders/metabolism/pathology MH - Neurons/cytology/*metabolism MH - Patch-Clamp Techniques/*methods MH - Rats MH - Rats, Sprague-Dawley MH - Spine/cytology/metabolism MH - Synapses/*physiology MH - Synaptic Transmission/*physiology MH - Ubiquitin-Protein Ligases/*metabolism MH - Ubiquitination MH - Zebrafish PMC - PMC5312699 MID - NIHMS836408 EDAT- 2016/06/09 06:00 MHDA- 2017/06/21 06:00 CRDT- 2016/06/09 06:00 PHST- 2015/12/15 00:00 [received] PHST- 2016/05/09 00:00 [accepted] PHST- 2016/06/09 06:00 [entrez] PHST- 2016/06/09 06:00 [pubmed] PHST- 2017/06/21 06:00 [medline] AID - nmeth.3894 [pii] AID - 10.1038/nmeth.3894 [doi] PST - ppublish SO - Nat Methods. 2016 Aug;13(8):673-8. doi: 10.1038/nmeth.3894. Epub 2016 Jun 6. PMID- 27321921 OWN - NLM STAT- MEDLINE DCOM- 20170822 LR - 20220129 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 91 IP - 1 DP - 2016 Jul 6 TI - A Postsynaptic AMPK→p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons. PG - 25-33 LID - S0896-6273(16)30204-5 [pii] LID - 10.1016/j.neuron.2016.05.025 [doi] AB - AMP-activated protein kinase (AMPK) plays an important role in regulating food intake. The downstream AMPK substrates and neurobiological mechanisms responsible for this, however, are ill defined. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus regulate hunger. Their firing increases with fasting, and once engaged they cause feeding. AgRP neuron activity is regulated by state-dependent synaptic plasticity: fasting increases dendritic spines and excitatory synaptic activity; feeding does the opposite. The signaling mechanisms underlying this, however, are also unknown. Using neuron-specific approaches to measure and manipulate kinase activity specifically within AgRP neurons, we establish that fasting increases AMPK activity in AgRP neurons, that increased AMPK activity in AgRP neurons is both necessary and sufficient for fasting-induced spinogenesis and excitatory synaptic activity, and that the AMPK phosphorylation target mediating this plasticity is p21-activated kinase. This provides a signaling and neurobiological basis for both AMPK regulation of energy balance and AgRP neuron state-dependent plasticity. CI - Copyright © 2016 Elsevier Inc. All rights reserved. FAU - Kong, Dong AU - Kong D AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA; Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02215, USA; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02135, USA. Electronic address: dong.kong@tufts.edu. FAU - Dagon, Yossi AU - Dagon Y AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA. FAU - Campbell, John N AU - Campbell JN AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA. FAU - Guo, Yikun AU - Guo Y AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02135, USA. FAU - Yang, Zongfang AU - Yang Z AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA. FAU - Yi, Xinchi AU - Yi X AD - Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02135, USA. FAU - Aryal, Pratik AU - Aryal P AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA. FAU - Wellenstein, Kerry AU - Wellenstein K AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA. FAU - Kahn, Barbara B AU - Kahn BB AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA. Electronic address: bkahn@bidmc.harvard.edu. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bernardo_sabatini@hms.harvard.edu. FAU - Lowell, Bradford B AU - Lowell BB AD - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. Electronic address: blowell@bidmc.harvard.edu. LA - eng GR - K01 DK094943/DK/NIDDK NIH HHS/United States GR - P30 DK046200/DK/NIDDK NIH HHS/United States GR - P30 EY012196/EY/NEI NIH HHS/United States GR - R01 DK108797/DK/NIDDK NIH HHS/United States GR - P30 DK057521/DK/NIDDK NIH HHS/United States GR - R01 DK075632/DK/NIDDK NIH HHS/United States GR - R01 DK098002/DK/NIDDK NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R21 NS097922/NS/NINDS NIH HHS/United States GR - R01 DK089044/DK/NIDDK NIH HHS/United States GR - R01 DK096010/DK/NIDDK NIH HHS/United States GR - R37 DK053477/DK/NIDDK NIH HHS/United States GR - R01 DK071051/DK/NIDDK NIH HHS/United States GR - P30 NS047243/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160616 PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Neuropeptide Y) RN - EC 2.7.11.1 (p21-Activated Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases/*metabolism MH - Animals MH - Dendritic Spines/metabolism MH - Eating/drug effects MH - Energy Metabolism/physiology MH - *Fasting MH - Mice, Transgenic MH - Neuronal Plasticity/*physiology MH - Neurons/*physiology MH - Neuropeptide Y/metabolism MH - *Signal Transduction MH - p21-Activated Kinases/*metabolism PMC - PMC4938763 MID - NIHMS788940 EDAT- 2016/06/21 06:00 MHDA- 2017/08/23 06:00 CRDT- 2016/06/21 06:00 PHST- 2015/04/10 00:00 [received] PHST- 2016/04/03 00:00 [revised] PHST- 2016/05/11 00:00 [accepted] PHST- 2016/06/21 06:00 [entrez] PHST- 2016/06/21 06:00 [pubmed] PHST- 2017/08/23 06:00 [medline] AID - S0896-6273(16)30204-5 [pii] AID - 10.1016/j.neuron.2016.05.025 [doi] PST - ppublish SO - Neuron. 2016 Jul 6;91(1):25-33. doi: 10.1016/j.neuron.2016.05.025. Epub 2016 Jun 16. PMID- 26929152 OWN - NLM STAT- MEDLINE DCOM- 20170328 LR - 20220318 IS - 1439-7633 (Electronic) IS - 1439-4227 (Print) IS - 1439-4227 (Linking) VI - 17 IP - 10 DP - 2016 May 17 TI - Development of Anionically Decorated Caged Neurotransmitters: In Vitro Comparison of 7-Nitroindolinyl- and 2-(p-Phenyl-o-nitrophenyl)propyl-Based Photochemical Probes. PG - 953-61 LID - 10.1002/cbic.201600019 [doi] AB - Neurotransmitter uncaging, especially that of glutamate, has been used to study synaptic function for over 30 years. One limitation of caged glutamate probes is the blockade of γ-aminobutyric acid (GABA)-A receptor function. This problem comes to the fore when the probes are applied at the high concentrations required for effective two-photon photolysis. To mitigate such problems one could improve the photochemical properties of caging chromophores and/or remove receptor blockade. We show that addition of a dicarboxylate unit to the widely used 4-methoxy-7-nitroindolinyl-Glu (MNI-Glu) system reduced the off-target effects by about 50-70 %. When the same strategy was applied to an electron-rich 2-(p-Phenyl-o-nitrophenyl)propyl (PNPP) caging group, the pharmacological improvements were not as significant as in the MNI case. Finally, we used very extensive biological testing of the PNPP-caged Glu (more than 250 uncaging currents at single dendritic spines) to show that nitro-biphenyl caging chromophores have two-photon uncaging efficacies similar to that of MNI-Glu. CI - © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. FAU - Kantevari, Srinivas AU - Kantevari S AD - Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, 10029, USA) graham.davies at mssm.edu. AD - Organic Chemistry Division II (CPC Division), CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India. FAU - Passlick, Stefan AU - Passlick S AD - Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, 10029, USA) graham.davies at mssm.edu. FAU - Kwon, Hyung-Bae AU - Kwon HB AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Cambridge, MA, 02115, USA. AD - Max Planck Florida Institute for Neuroscience, Jupiter, FL, 33458, USA. FAU - Richers, Matthew T AU - Richers MT AD - Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, 10029, USA) graham.davies at mssm.edu. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Cambridge, MA, 02115, USA. FAU - Ellis-Davies, Graham C R AU - Ellis-Davies GC AD - Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, 10029, USA) graham.davies at mssm.edu. LA - eng GR - R01 GM053395/GM/NIGMS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R01 NS069720/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20160409 PL - Germany TA - Chembiochem JT - Chembiochem : a European journal of chemical biology JID - 100937360 RN - 0 (2-amino-5-(5-((methoxycarbonyl)methyl)-7-nitroindol-1-yl)-5-oxopentanoic acid) RN - 0 (Anions) RN - 0 (Biphenyl Compounds) RN - 0 (GABA-A Receptor Antagonists) RN - 0 (Glutamates) RN - 0 (Indoles) RN - 0 (Neurotransmitter Agents) RN - 0 (Receptors, GABA-A) RN - 0 (dcPNPP-Glu) SB - IM MH - Anions MH - Biphenyl Compounds/chemical synthesis/*chemistry/metabolism MH - GABA-A Receptor Antagonists/chemistry/metabolism MH - Glutamates/chemical synthesis/*chemistry/metabolism MH - Indoles/chemical synthesis/*chemistry/metabolism MH - Light MH - Microscopy, Fluorescence MH - Neurotransmitter Agents/*chemistry/metabolism MH - Photolysis/drug effects MH - Receptors, GABA-A/chemistry/metabolism PMC - PMC4870097 MID - NIHMS786271 OTO - NOTNLM OT - GABA receptors OT - caged glutamate OT - neurotransmitters OT - photolysis OT - two-photon photolysis EDAT- 2016/03/02 06:00 MHDA- 2017/03/30 06:00 CRDT- 2016/03/02 06:00 PHST- 2016/01/12 00:00 [received] PHST- 2016/03/02 06:00 [entrez] PHST- 2016/03/02 06:00 [pubmed] PHST- 2017/03/30 06:00 [medline] AID - 10.1002/cbic.201600019 [doi] PST - ppublish SO - Chembiochem. 2016 May 17;17(10):953-61. doi: 10.1002/cbic.201600019. Epub 2016 Apr 9. PMID- 26928064 OWN - NLM STAT- MEDLINE DCOM- 20170829 LR - 20210218 IS - 1546-1726 (Electronic) IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 19 IP - 5 DP - 2016 May TI - Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B(-/-) mice. PG - 716-724 LID - 10.1038/nn.4260 [doi] AB - Some autistic individuals exhibit abnormal development of the caudate nucleus and associative cortical areas, suggesting potential dysfunction of cortico-basal ganglia (BG) circuits. Using optogenetic and electrophysiological approaches in mice, we identified a narrow postnatal period that is characterized by extensive glutamatergic synaptogenesis in striatal spiny projection neurons (SPNs) and a concomitant increase in corticostriatal circuit activity. SPNs during early development have high intrinsic excitability and respond strongly to cortical afferents despite sparse excitatory inputs. As a result, striatum and corticostriatal connectivity are highly sensitive to acute and chronic changes in cortical activity, suggesting that early imbalances in cortical function alter BG development. Indeed, a mouse model of autism with deletions in Shank3 (Shank3B(-/-)) shows early cortical hyperactivity, which triggers increased SPN excitatory synapse and corticostriatal hyperconnectivity. These results indicate that there is a tight functional coupling between cortex and striatum during early postnatal development and suggest a potential common circuit dysfunction that is caused by cortical hyperactivity. FAU - Peixoto, Rui T AU - Peixoto RT AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA. FAU - Wang, Wengang AU - Wang W AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA. FAU - Croney, Donyell M AU - Croney DM AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA. FAU - Kozorovitskiy, Yevgenia AU - Kozorovitskiy Y AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA. LA - eng GR - P30 DK057521/DK/NIDDK NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20160229 PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 0 (Microfilament Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (Shank3 protein, mouse) SB - IM MH - Action Potentials/physiology MH - Animals MH - Autistic Disorder/genetics/physiopathology MH - Cerebral Cortex/*growth & development/*physiology/physiopathology MH - Corpus Striatum/*growth & development/*physiology MH - Disease Models, Animal MH - Female MH - Male MH - Mice MH - Mice, Knockout MH - Mice, Transgenic MH - Microfilament Proteins MH - Nerve Tissue Proteins/genetics/*physiology MH - Neural Pathways/growth & development/physiopathology MH - Neurons/physiology MH - Synapses/physiology PMC - PMC4846490 MID - NIHMS757566 COIS- Competing financial interests: The authors declare no competing financial interests. EDAT- 2016/03/02 06:00 MHDA- 2017/08/30 06:00 CRDT- 2016/03/02 06:00 PHST- 2015/07/20 00:00 [received] PHST- 2016/01/29 00:00 [accepted] PHST- 2016/03/02 06:00 [entrez] PHST- 2016/03/02 06:00 [pubmed] PHST- 2017/08/30 06:00 [medline] AID - nn.4260 [pii] AID - 10.1038/nn.4260 [doi] PST - ppublish SO - Nat Neurosci. 2016 May;19(5):716-724. doi: 10.1038/nn.4260. Epub 2016 Feb 29. PMID- 26865019 OWN - NLM STAT- MEDLINE DCOM- 20160627 LR - 20200128 IS - 1471-0048 (Electronic) IS - 1471-003X (Print) IS - 1471-003X (Linking) VI - 17 IP - 3 DP - 2016 Mar TI - Mechanisms and functions of GABA co-release. PG - 139-45 LID - 10.1038/nrn.2015.21 [doi] AB - The 'one neuron, one neurotransmitter' doctrine states that synaptic communication between two neurons occurs through the release of a single chemical transmitter. However, recent findings suggest that neurons that communicate using more than one classical neurotransmitter are prevalent throughout the adult mammalian CNS. In particular, several populations of neurons previously thought to release only glutamate, acetylcholine, dopamine or histamine also release the major inhibitory neurotransmitter GABA. Here, we review these findings and discuss the implications of GABA co-release for synaptic transmission and plasticity. FAU - Tritsch, Nicolas X AU - Tritsch NX AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. AD - New York University Neuroscience Institute, Department of Neuroscience and Physiology, New York University Langone Medical Center, New York, New York 10016, USA. FAU - Granger, Adam J AU - Granger AJ AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. LA - eng GR - K99 NS087098/NS/NINDS NIH HHS/United States PT - Journal Article PT - Review DEP - 20160211 PL - England TA - Nat Rev Neurosci JT - Nature reviews. Neuroscience JID - 100962781 RN - 0 (Neurotransmitter Agents) RN - 56-12-2 (gamma-Aminobutyric Acid) SB - IM MH - Animals MH - Neurons/*metabolism MH - Neurotransmitter Agents/*metabolism MH - Synapses/*physiology MH - Synaptic Transmission/*physiology MH - gamma-Aminobutyric Acid/*metabolism PMC - PMC6980171 MID - NIHMS841696 COIS- Competing interests statement The authors declare no competing interests. EDAT- 2016/02/13 06:00 MHDA- 2016/06/28 06:00 CRDT- 2016/02/12 06:00 PHST- 2016/02/12 06:00 [entrez] PHST- 2016/02/13 06:00 [pubmed] PHST- 2016/06/28 06:00 [medline] AID - nrn.2015.21 [pii] AID - 10.1038/nrn.2015.21 [doi] PST - ppublish SO - Nat Rev Neurosci. 2016 Mar;17(3):139-45. doi: 10.1038/nrn.2015.21. Epub 2016 Feb 11. PMID- 26941646 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20160305 LR - 20200929 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 7 DP - 2016 TI - Corrigendum: A PKA activity sensor for quantitative analysis of endogenous GPCR signaling via 2-photon FRET-FLIM imaging. PG - 46 LID - 10.3389/fphar.2016.00046 [doi] LID - 46 AB - [This corrects the article on p. 56 in vol. 5, PMID: 24765076.]. FAU - Chen, Yao AU - Chen Y AD - Howard Hughes Medical InstituteBoston, MA, USA; Department of Neurobiology, Harvard Medical SchoolBoston, MA, USA. FAU - Saulnier, Jessica L AU - Saulnier JL AD - Howard Hughes Medical InstituteBoston, MA, USA; Department of Neurobiology, Harvard Medical SchoolBoston, MA, USA. FAU - Yellen, Gary AU - Yellen G AD - Department of Neurobiology, Harvard Medical School Boston, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical InstituteBoston, MA, USA; Department of Neurobiology, Harvard Medical SchoolBoston, MA, USA. LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Published Erratum DEP - 20160225 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 EFR - Front Pharmacol. 2014;5:56. PMID: 24765076 PMC - PMC4766420 OTO - NOTNLM OT - FLIM OT - FLIM-AKAR OT - GPCR OT - PKA OT - cAMP OT - dendritic spine OT - glutamate OT - neuromodulation EDAT- 2016/03/05 06:00 MHDA- 2016/03/05 06:01 CRDT- 2016/03/05 06:00 PHST- 2016/02/17 00:00 [received] PHST- 2016/02/18 00:00 [accepted] PHST- 2016/03/05 06:00 [entrez] PHST- 2016/03/05 06:00 [pubmed] PHST- 2016/03/05 06:01 [medline] AID - 10.3389/fphar.2016.00046 [doi] PST - epublish SO - Front Pharmacol. 2016 Feb 25;7:46. doi: 10.3389/fphar.2016.00046. eCollection 2016. PMID- 26905595 OWN - NLM STAT- MEDLINE DCOM- 20160714 LR - 20201215 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 11 IP - 2 DP - 2016 TI - Globus Pallidus Externus Neurons Expressing parvalbumin Interconnect the Subthalamic Nucleus and Striatal Interneurons. PG - e0149798 LID - 10.1371/journal.pone.0149798 [doi] LID - e0149798 AB - The globus pallidus externus (GP) is a nucleus of the basal ganglia (BG), containing GABAergic projection neurons that arborize widely throughout the BG, thalamus and cortex. Ongoing work seeks to map axonal projection patterns from GP cell types, as defined by their electrophysiological and molecular properties. Here we use transgenic mice and recombinant viruses to characterize parvalbumin expressing (PV+) GP neurons within the BG circuit. We confirm that PV+ neurons 1) make up ~40% of the GP neurons 2) exhibit fast-firing spontaneous activity and 3) provide the major axonal arborization to the STN and substantia nigra reticulata/compacta (SNr/c). PV+ neurons also innervate the striatum. Retrograde labeling identifies ~17% of pallidostriatal neurons as PV+, at least a subset of which also innervate the STN and SNr. Optogenetic experiments in acute brain slices demonstrate that the PV+ pallidostriatal axons make potent inhibitory synapses on low threshold spiking (LTS) and fast-spiking interneurons (FS) in the striatum, but rarely on spiny projection neurons (SPNs). Thus PV+ GP neurons are synaptically positioned to directly coordinate activity between BG input nuclei, the striatum and STN, and thalamic-output from the SNr. FAU - Saunders, Arpiar AU - Saunders A AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Huang, Kee Wui AU - Huang KW AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Sabatini, Bernardo Luis AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. LA - eng GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - P30EY012196/EY/NEI NIH HHS/United States GR - F31 MH093026-01A1/MH/NIMH NIH HHS/United States GR - P30 EY012196/EY/NEI NIH HHS/United States GR - P30NS072030/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - F31 MH093026/MH/NIMH NIH HHS/United States GR - R37 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160223 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Parvalbumins) SB - IM MH - Animals MH - Axons/*metabolism MH - Brain Mapping MH - Globus Pallidus/cytology/*metabolism MH - Mice MH - Mice, Transgenic MH - Parvalbumins/*biosynthesis/genetics MH - Subthalamic Nucleus/*metabolism MH - Synapses/genetics/*metabolism PMC - PMC4764347 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2016/02/26 06:00 MHDA- 2016/07/15 06:00 CRDT- 2016/02/25 06:00 PHST- 2015/04/10 00:00 [received] PHST- 2016/02/04 00:00 [accepted] PHST- 2016/02/25 06:00 [entrez] PHST- 2016/02/26 06:00 [pubmed] PHST- 2016/07/15 06:00 [medline] AID - PONE-D-15-15638 [pii] AID - 10.1371/journal.pone.0149798 [doi] PST - epublish SO - PLoS One. 2016 Feb 23;11(2):e0149798. doi: 10.1371/journal.pone.0149798. eCollection 2016. PMID- 26220313 OWN - NLM STAT- MEDLINE DCOM- 20160706 LR - 20230714 IS - 1873-7064 (Electronic) IS - 0028-3908 (Print) IS - 0028-3908 (Linking) VI - 100 DP - 2016 Jan TI - Cotransmission of acetylcholine and GABA. PG - 40-6 LID - S0028-3908(15)30038-1 [pii] LID - 10.1016/j.neuropharm.2015.07.031 [doi] AB - Neurons that produce acetylcholine (ACh) are positioned to broadly influence the brain, with axonal arborizations that extend throughout the cerebral cortex, striatum, and hippocampus. While the action of these neurons has typically been attributed entirely to ACh, neurons often release more than one primary neurotransmitter. Here, we review evidence for the cotransmission of the inhibitory neurotransmitter GABA from cholinergic neurons throughout the mammalian central nervous system. Functional cotransmission of ACh and GABA has been reported in the retina and cortex, and anatomical studies suggest that GABA cotransmission is a common feature of nearly all forebrain ACh-producing neurons. Further experiments are necessary to confirm the extent of GABA cotransmission from cholinergic neurons, and the contribution of GABA needs to be considered when studying the functional impact of activity in ACh-producing neurons. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'. CI - Copyright © 2015 Elsevier Ltd. All rights reserved. FAU - Granger, Adam J AU - Granger AJ AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Mulder, Nicole AU - Mulder N AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Saunders, Arpiar AU - Saunders A AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. Electronic address: bernardo_sabatini@hms.harvard.edu. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - R01 #NS046579/NS/NINDS NIH HHS/United States GR - #NS072030/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20150726 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 56-12-2 (gamma-Aminobutyric Acid) RN - N9YNS0M02X (Acetylcholine) SB - IM MH - Acetylcholine/*metabolism MH - Animals MH - Brain/*metabolism MH - Cholinergic Neurons/*metabolism MH - Humans MH - Mice MH - Optogenetics MH - *Synaptic Transmission MH - gamma-Aminobutyric Acid/*metabolism PMC - PMC4584188 MID - NIHMS712533 OTO - NOTNLM OT - Acetylcholine OT - Cotransmission OT - GABA OT - Neurotransmitter corelease EDAT- 2015/07/30 06:00 MHDA- 2016/07/07 06:00 CRDT- 2015/07/30 06:00 PHST- 2015/06/03 00:00 [received] PHST- 2015/07/23 00:00 [revised] PHST- 2015/07/24 00:00 [accepted] PHST- 2015/07/30 06:00 [entrez] PHST- 2015/07/30 06:00 [pubmed] PHST- 2016/07/07 06:00 [medline] AID - S0028-3908(15)30038-1 [pii] AID - 10.1016/j.neuropharm.2015.07.031 [doi] PST - ppublish SO - Neuropharmacology. 2016 Jan;100:40-6. doi: 10.1016/j.neuropharm.2015.07.031. Epub 2015 Jul 26. PMID- 26671460 OWN - NLM STAT- MEDLINE DCOM- 20160428 LR - 20181113 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 88 IP - 6 DP - 2015 Dec 16 TI - Enkephalin Disinhibits Mu Opioid Receptor-Rich Striatal Patches via Delta Opioid Receptors. PG - 1227-1239 LID - S0896-6273(15)01016-8 [pii] LID - 10.1016/j.neuron.2015.11.010 [doi] AB - Opioid neuropeptides and their receptors are evolutionarily conserved neuromodulatory systems that profoundly influence behavior. In dorsal striatum, which expresses the endogenous opioid enkephalin, patches (or striosomes) are limbic-associated subcompartments enriched in mu opioid receptors. The functional implications of opioid signaling in dorsal striatum and the circuit elements in patches regulated by enkephalin are unclear. Here, we examined how patch output is modulated by enkephalin and identified the underlying circuit mechanisms. We found that patches are relatively devoid of parvalbumin-expressing interneurons and exist as self-contained inhibitory microcircuits. Enkephalin suppresses inhibition onto striatal projection neurons selectively in patches, thereby disinhibiting their firing in response to cortical input. The majority of this neuromodulation is mediated by delta, not mu-opioid, receptors, acting specifically on intra-striatal collateral axons of striatopallidal neurons. These results suggest that enkephalin gates limbic information flow in dorsal striatum, acting via a patch-specific function for delta opioid receptors. CI - Copyright © 2015 Elsevier Inc. All rights reserved. FAU - Banghart, Matthew Ryan AU - Banghart MR AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave, Boston, MA, 02115, USA. FAU - Neufeld, Shay Quentin AU - Neufeld SQ AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave, Boston, MA, 02115, USA. FAU - Wong, Nicole Christine AU - Wong NC AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave, Boston, MA, 02115, USA. FAU - Sabatini, Bernardo Luis AU - Sabatini BL AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave, Boston, MA, 02115, USA. Electronic address: Bernardo_Sabatini@hms.harvard.edu. LA - eng GR - R01 MH085498/MH/NIMH NIH HHS/United States GR - R01 MH100568/MH/NIMH NIH HHS/United States GR - Howard Hughes Medical Institute/United States GR - K99 DA034648/DA/NIDA NIH HHS/United States GR - R01MH085418/MH/NIMH NIH HHS/United States GR - K99DA034648/DA/NIDA NIH HHS/United States GR - R01MH100568/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151206 PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Enkephalins) RN - 0 (Receptors, Opioid, delta) RN - 0 (Receptors, Opioid, mu) SB - IM CIN - Nat Rev Neurosci. 2016 Feb;17(2):75. PMID: 26697742 MH - Animals MH - Corpus Striatum/drug effects/*physiology MH - Enkephalins/*pharmacology MH - Female MH - Inhibitory Postsynaptic Potentials/drug effects/physiology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Receptors, Opioid, delta/*physiology MH - Receptors, Opioid, mu/*physiology PMC - PMC4698909 MID - NIHMS744027 EDAT- 2015/12/17 06:00 MHDA- 2016/04/29 06:00 CRDT- 2015/12/17 06:00 PHST- 2015/07/14 00:00 [received] PHST- 2015/10/09 00:00 [revised] PHST- 2015/11/05 00:00 [accepted] PHST- 2015/12/17 06:00 [entrez] PHST- 2015/12/17 06:00 [pubmed] PHST- 2016/04/29 06:00 [medline] AID - S0896-6273(15)01016-8 [pii] AID - 10.1016/j.neuron.2015.11.010 [doi] PST - ppublish SO - Neuron. 2015 Dec 16;88(6):1227-1239. doi: 10.1016/j.neuron.2015.11.010. Epub 2015 Dec 6. PMID- 26551563 OWN - NLM STAT- MEDLINE DCOM- 20161011 LR - 20230717 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 4 DP - 2015 Nov 9 TI - Neuromodulation of excitatory synaptogenesis in striatal development. LID - e10111 [pii] LID - 10.7554/eLife.10111 [doi] AB - Dopamine is released in the striatum during development and impacts the activity of Protein Kinase A (PKA) in striatal spiny projection neurons (SPNs). We examined whether dopaminergic neuromodulation regulates activity-dependent glutamatergic synapse formation in the developing striatum. Systemic in vivo treatment with Gαs-coupled G-protein receptors (GPCRs) agonists enhanced excitatory synapses on direct pathway striatal spiny projection neurons (dSPNs), whereas rapid production of excitatory synapses on indirect pathway neurons (iSPNs) required the activation of Gαs GPCRs in SPNs of both pathways. Nevertheless, in vitro Gαs activation was sufficient to enhance spinogenesis induced by glutamate photolysis in both dSPNs and iSPNs, suggesting that iSPNs in intact neural circuits have additional requirements for rapid synaptic development. We evaluated the in vivo effects of enhanced glutamate release from corticostriatal axons and postsynaptic PKA and discovered a mechanism of developmental plasticity wherein rapid synaptogenesis is promoted by the coordinated actions of glutamate and postsynaptic Gαs-coupled receptors. FAU - Kozorovitskiy, Yevgenia AU - Kozorovitskiy Y AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. AD - Department of Neurobiology, Northwestern University, Evanston, United States. FAU - Peixoto, Rui AU - Peixoto R AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Wang, Wengang AU - Wang W AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Saunders, Arpiar AU - Saunders A AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151109 PL - England TA - Elife JT - eLife JID - 101579614 RN - 0 (Dopamine Agents) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (Receptors, Glutamate) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) SB - IM MH - Animals MH - Cyclic AMP-Dependent Protein Kinases/metabolism MH - Dopamine Agents/*administration & dosage MH - Mice, Inbred C57BL MH - Neuronal Plasticity/*drug effects MH - Receptors, G-Protein-Coupled/metabolism MH - Receptors, Glutamate/metabolism MH - Visual Cortex/*physiology PMC - PMC4716836 OTO - NOTNLM OT - basal ganglia OT - circuit development OT - corticostriatal OT - dopamine OT - mouse OT - neuroscience OT - pka COIS- The authors declare that no competing interests exist. EDAT- 2015/11/10 06:00 MHDA- 2016/10/12 06:00 CRDT- 2015/11/10 06:00 PHST- 2015/07/15 00:00 [received] PHST- 2015/11/08 00:00 [accepted] PHST- 2015/11/10 06:00 [entrez] PHST- 2015/11/10 06:00 [pubmed] PHST- 2016/10/12 06:00 [medline] AID - e10111 [pii] AID - 10111 [pii] AID - 10.7554/eLife.10111 [doi] PST - epublish SO - Elife. 2015 Nov 9;4:e10111. doi: 10.7554/eLife.10111. PMID- 26504650 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20151027 LR - 20200930 IS - 2156-7085 (Print) IS - 2156-7085 (Electronic) IS - 2156-7085 (Linking) VI - 6 IP - 10 DP - 2015 Oct 1 TI - Modal demultiplexing properties of tapered and nanostructured optical fibers for in vivo optogenetic control of neural activity. PG - 4014-26 LID - 10.1364/BOE.6.004014 [doi] AB - Optogenetic approaches to manipulate neural activity have revolutionized the ability of neuroscientists to uncover the functional connectivity underlying brain function. At the same time, the increasing complexity of in vivo optogenetic experiments has increased the demand for new techniques to precisely deliver light into the brain, in particular to illuminate selected portions of the neural tissue. Tapered and nanopatterned gold-coated optical fibers were recently proposed as minimally invasive multipoint light delivery devices, allowing for site-selective optogenetic stimulation in the mammalian brain [Pisanello , Neuron82, 1245 (2014)]. Here we demonstrate that the working principle behind these devices is based on the mode-selective photonic properties of the fiber taper. Using analytical and ray tracing models we model the finite conductance of the metal coating, and show that single or multiple optical windows located at specific taper sections can outcouple only specific subsets of guided modes injected into the fiber. FAU - Pisanello, Marco AU - Pisanello M AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti SNC, 73010 Arnesano (LE), Italy ; Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Via per Monteroni, 73100 Lecce, Italy ; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA ; These authors contributed equally to this work. FAU - Della Patria, Andrea AU - Della Patria A AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti SNC, 73010 Arnesano (LE), Italy ; These authors contributed equally to this work. FAU - Sileo, Leonardo AU - Sileo L AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti SNC, 73010 Arnesano (LE), Italy. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. FAU - De Vittorio, Massimo AU - De Vittorio M AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti SNC, 73010 Arnesano (LE), Italy ; Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Via per Monteroni, 73100 Lecce, Italy. FAU - Pisanello, Ferruccio AU - Pisanello F AD - Istituto Italiano di Tecnologia (IIT), Center for Biomolecular Nanotechnologies, Via Barsanti SNC, 73010 Arnesano (LE), Italy. LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20150917 PL - United States TA - Biomed Opt Express JT - Biomedical optics express JID - 101540630 PMC - PMC4605059 OTO - NOTNLM OT - (170.0170) Medical optics and biotechnology OT - (220.0220) Optical design and fabrication EDAT- 2015/10/28 06:00 MHDA- 2015/10/28 06:01 CRDT- 2015/10/28 06:00 PHST- 2015/07/13 00:00 [received] PHST- 2015/09/11 00:00 [revised] PHST- 2015/09/12 00:00 [accepted] PHST- 2015/10/28 06:00 [entrez] PHST- 2015/10/28 06:00 [pubmed] PHST- 2015/10/28 06:01 [medline] AID - 245815 [pii] AID - 10.1364/BOE.6.004014 [doi] PST - epublish SO - Biomed Opt Express. 2015 Sep 17;6(10):4014-26. doi: 10.1364/BOE.6.004014. eCollection 2015 Oct 1. PMID- 26131660 OWN - NLM STAT- MEDLINE DCOM- 20160913 LR - 20191125 IS - 1934-8576 (Electronic) IS - 1934-8584 (Print) IS - 1934-8576 (Linking) VI - 72 DP - 2015 Jul 1 TI - Cre Activated and Inactivated Recombinant Adeno-Associated Viral Vectors for Neuronal Anatomical Tracing or Activity Manipulation. PG - 1.24.1-1.24.15 LID - 10.1002/0471142301.ns0124s72 [doi] AB - Recombinant adeno-associated viruses (rAAVs) transcriptionally activated by Cre recombinase (Cre-On) are powerful tools for determining the anatomy and function of genetically defined neuronal types in transgenic Cre driver mice. Here we describe how rAAVs transcriptionally inactivated by Cre (Cre-Off) can be used in conjunction with Cre-On rAAVs or genomic Cre-reporter alleles to study brain circuits. Intracranial injection of Cre-On/Cre-Off rAAVs into spatially intermingled Cre(+) and Cre(-) neurons allows these populations to be differentially labeled or manipulated within individual animals. This comparison helps define the unique properties of Cre(+) neurons, highlighting the specialized role they play in their constituent brain circuits. This protocol touches on the conceptual and experimental background of Cre-Off rAAV systems, including caveats and methods of validation. CI - Copyright © 2015 John Wiley & Sons, Inc. FAU - Saunders, Arpiar AU - Saunders A AD - Department of Neurobiology, Harvard Medical School, Howard Hughes Medical Institute, Boston, Massachusetts. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Harvard Medical School, Howard Hughes Medical Institute, Boston, Massachusetts. LA - eng GR - F31 NS074842/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review DEP - 20150701 PL - United States TA - Curr Protoc Neurosci JT - Current protocols in neuroscience JID - 9706581 RN - 0 (Luminescent Proteins) RN - EC 2.7.7.- (Cre recombinase) RN - EC 2.7.7.- (Integrases) SB - IM MH - Animals MH - Dependovirus/*genetics MH - Genetic Vectors/genetics/*metabolism MH - Integrases/genetics/*metabolism MH - Luminescent Proteins/genetics/metabolism MH - Mice MH - Mice, Transgenic MH - Neurons/*metabolism MH - Transduction, Genetic PMC - PMC4545963 MID - NIHMS706771 OTO - NOTNLM OT - AAV OT - Cre-dependent virus OT - Cre-lox OT - rAAV OT - viral tracer EDAT- 2015/07/02 06:00 MHDA- 2016/09/14 06:00 CRDT- 2015/07/02 06:00 PHST- 2015/07/02 06:00 [entrez] PHST- 2015/07/02 06:00 [pubmed] PHST- 2016/09/14 06:00 [medline] AID - 10.1002/0471142301.ns0124s72 [doi] PST - epublish SO - Curr Protoc Neurosci. 2015 Jul 1;72:1.24.1-1.24.15. doi: 10.1002/0471142301.ns0124s72. PMID- 26050037 OWN - NLM STAT- MEDLINE DCOM- 20150824 LR - 20181113 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 86 IP - 5 DP - 2015 Jun 3 TI - Antagonistic but Not Symmetric Regulation of Primary Motor Cortex by Basal Ganglia Direct and Indirect Pathways. PG - 1174-81 LID - S0896-6273(15)00415-8 [pii] LID - 10.1016/j.neuron.2015.05.008 [doi] AB - Motor cortex, basal ganglia (BG), and thalamus are arranged in a recurrent loop whose activity guides motor actions. In the dominant model of the function of the BG and their role in Parkinson's disease, direct (dSPNs) and indirect (iSPNs) striatal projection neurons are proposed to oppositely modulate cortical activity via BG outputs to thalamus. Here, we test this model by determining how striatal activity modulates primary motor cortex in awake head-restrained mice. We find that, within 200 ms, dSPN and iSPN activation exert robust and opposite effects on the majority of cortical neurons. However, these effects are heterogeneous, with certain cortical neurons biphasically modulated by iSPN stimulation. Moreover, these striatal effects are diminished when the animal performs a motor action. Thus, the effects of dSPN and iSPN activity on cortex are at times antagonistic, consistent with classic models, whereas in other contexts these effects can be occluded or coactive. CI - Copyright © 2015 Elsevier Inc. All rights reserved. FAU - Oldenburg, Ian A AU - Oldenburg IA AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bsabatini@hms.harvard.edu. LA - eng GR - F31 MH093026/MH/NIMH NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - F31-MH093026-01A1/MH/NIMH NIH HHS/United States GR - R01-NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - United States TA - Neuron JT - Neuron JID - 8809320 SB - IM MH - Animals MH - Basal Ganglia/*physiology MH - Electric Stimulation/methods MH - Male MH - Mice MH - Mice, Transgenic MH - Motor Cortex/*physiology MH - Nerve Net/*physiology MH - Neural Pathways/physiology PMC - PMC4458709 MID - NIHMS689080 EDAT- 2015/06/08 06:00 MHDA- 2015/08/25 06:00 CRDT- 2015/06/08 06:00 PHST- 2014/10/14 00:00 [received] PHST- 2015/01/12 00:00 [revised] PHST- 2015/04/29 00:00 [accepted] PHST- 2015/06/08 06:00 [entrez] PHST- 2015/06/08 06:00 [pubmed] PHST- 2015/08/25 06:00 [medline] AID - S0896-6273(15)00415-8 [pii] AID - 10.1016/j.neuron.2015.05.008 [doi] PST - ppublish SO - Neuron. 2015 Jun 3;86(5):1174-81. doi: 10.1016/j.neuron.2015.05.008. PMID- 25739505 OWN - NLM STAT- MEDLINE DCOM- 20160602 LR - 20220330 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 521 IP - 7550 DP - 2015 May 7 TI - A direct GABAergic output from the basal ganglia to frontal cortex. PG - 85-9 LID - 10.1038/nature14179 [doi] AB - The basal ganglia are phylogenetically conserved subcortical nuclei necessary for coordinated motor action and reward learning. Current models postulate that the basal ganglia modulate cerebral cortex indirectly via an inhibitory output to thalamus, bidirectionally controlled by direct- and indirect-pathway striatal projection neurons (dSPNs and iSPNs, respectively). The basal ganglia thalamic output sculpts cortical activity by interacting with signals from sensory and motor systems. Here we describe a direct projection from the globus pallidus externus (GP), a central nucleus of the basal ganglia, to frontal regions of the cerebral cortex (FC). Two cell types make up the GP-FC projection, distinguished by their electrophysiological properties, cortical projections and expression of choline acetyltransferase (ChAT), a synthetic enzyme for the neurotransmitter acetylcholine (ACh). Despite these differences, ChAT(+) cells, which have been historically identified as an extension of the nucleus basalis, as well as ChAT(-) cells, release the inhibitory neurotransmitter GABA (γ-aminobutyric acid) and are inhibited by iSPNs and dSPNs of dorsal striatum. Thus, GP-FC cells comprise a direct GABAergic/cholinergic projection under the control of striatum that activates frontal cortex in vivo. Furthermore, iSPN inhibition of GP-FC cells is sensitive to dopamine 2 receptor signalling, revealing a pathway by which drugs that target dopamine receptors for the treatment of neuropsychiatric disorders can act in the basal ganglia to modulate frontal cortices. FAU - Saunders, Arpiar AU - Saunders A AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. FAU - Oldenburg, Ian A AU - Oldenburg IA AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. FAU - Berezovskii, Vladimir K AU - Berezovskii VK AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. FAU - Johnson, Caroline A AU - Johnson CA AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. FAU - Kingery, Nathan D AU - Kingery ND AD - Neurobiology Imaging Facility, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. FAU - Elliott, Hunter L AU - Elliott HL AD - Image and Data Analysis Core, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. FAU - Xie, Tiao AU - Xie T AD - Image and Data Analysis Core, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. FAU - Gerfen, Charles R AU - Gerfen CR AD - Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, Maryland 20892, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. LA - eng GR - F31 MH093026/MH/NIMH NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - F31-MH093026-01A1/MH/NIMH NIH HHS/United States GR - NS072030/NS/NINDS NIH HHS/United States GR - P30 EY12196/EY/NEI NIH HHS/United States GR - P30 EY012196/EY/NEI NIH HHS/United States GR - P30 EY002520/EY/NEI NIH HHS/United States GR - F31 NS074842/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150304 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Antipsychotic Agents) RN - 0 (Receptors, Dopamine D2) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - EC 2.3.1.6 (Choline O-Acetyltransferase) RN - N9YNS0M02X (Acetylcholine) SB - IM MH - Acetylcholine/metabolism MH - Animals MH - Antipsychotic Agents/pharmacology MH - Basal Nucleus of Meynert/cytology/metabolism MH - Choline O-Acetyltransferase/metabolism MH - Electrophysiological Phenomena MH - Female MH - Frontal Lobe/cytology/drug effects/*metabolism MH - Globus Pallidus/cytology/drug effects/enzymology/*metabolism MH - Macaca mulatta MH - Male MH - Mice MH - Neural Pathways MH - Receptors, Dopamine D2/metabolism MH - Signal Transduction MH - gamma-Aminobutyric Acid/*metabolism PMC - PMC4425585 MID - NIHMS651677 COIS- The authors declare no competing financial interests. EDAT- 2015/03/06 06:00 MHDA- 2016/06/03 06:00 CRDT- 2015/03/06 06:00 PHST- 2014/11/03 00:00 [received] PHST- 2014/12/23 00:00 [accepted] PHST- 2015/03/06 06:00 [entrez] PHST- 2015/03/06 06:00 [pubmed] PHST- 2016/06/03 06:00 [medline] AID - nature14179 [pii] AID - 10.1038/nature14179 [doi] PST - ppublish SO - Nature. 2015 May 7;521(7550):85-9. doi: 10.1038/nature14179. Epub 2015 Mar 4. PMID- 25723967 OWN - NLM STAT- MEDLINE DCOM- 20160120 LR - 20181202 IS - 2050-084X (Electronic) IS - 2050-084X (Print) IS - 2050-084X (Linking) VI - 4 DP - 2015 Feb 27 TI - Corelease of acetylcholine and GABA from cholinergic forebrain neurons. LID - 10.7554/eLife.06412 [doi] LID - e06412 AB - Neurotransmitter corelease is emerging as a common theme of central neuromodulatory systems. Though corelease of glutamate or GABA with acetylcholine has been reported within the cholinergic system, the full extent is unknown. To explore synaptic signaling of cholinergic forebrain neurons, we activated choline acetyltransferase expressing neurons using channelrhodopsin while recording post-synaptic currents (PSCs) in layer 1 interneurons. Surprisingly, we observed PSCs mediated by GABAA receptors in addition to nicotinic acetylcholine receptors. Based on PSC latency and pharmacological sensitivity, our results suggest monosynaptic release of both GABA and ACh. Anatomical analysis showed that forebrain cholinergic neurons express the GABA synthetic enzyme Gad2 and the vesicular GABA transporter (Slc32a1). We confirmed the direct release of GABA by knocking out Slc32a1 from cholinergic neurons. Our results identify GABA as an overlooked fast neurotransmitter utilized throughout the forebrain cholinergic system. GABA/ACh corelease may have major implications for modulation of cortical function by cholinergic neurons. FAU - Saunders, Arpiar AU - Saunders A AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Granger, Adam J AU - Granger AJ AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. LA - eng GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20150227 PL - England TA - Elife JT - eLife JID - 101579614 RN - 0 (Potassium Channel Blockers) RN - 0 (Receptors, GABA-A) RN - 0 (Receptors, Nicotinic) RN - 0 (Sodium Channel Blockers) RN - 0 (Vesicular Inhibitory Amino Acid Transport Proteins) RN - 0 (Viaat protein, mouse) RN - 4368-28-9 (Tetrodotoxin) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - BH3B64OKL9 (4-Aminopyridine) RN - EC 2.3.1.6 (Choline O-Acetyltransferase) RN - EC 4.1.1.15 (Glutamate Decarboxylase) RN - EC 4.1.1.15 (glutamate decarboxylase 2) RN - N9YNS0M02X (Acetylcholine) SB - IM MH - 4-Aminopyridine/pharmacology MH - Acetylcholine/*metabolism MH - Animals MH - Choline O-Acetyltransferase/genetics/metabolism MH - Cholinergic Neurons/*metabolism/physiology MH - Excitatory Postsynaptic Potentials/drug effects MH - Glutamate Decarboxylase/genetics/metabolism MH - Membrane Potentials/drug effects MH - Mice, Transgenic MH - Microscopy, Confocal MH - Microscopy, Fluorescence, Multiphoton MH - Patch-Clamp Techniques MH - Potassium Channel Blockers/pharmacology MH - Prosencephalon/cytology/*metabolism/physiology MH - Receptors, GABA-A/metabolism MH - Receptors, Nicotinic/metabolism MH - Sodium Channel Blockers/pharmacology MH - Synaptic Transmission/drug effects/physiology MH - Tetrodotoxin/pharmacology MH - Vesicular Inhibitory Amino Acid Transport Proteins/genetics/metabolism MH - gamma-Aminobutyric Acid/*metabolism PMC - PMC4371381 OTO - NOTNLM OT - cholinergic system OT - mouse OT - neural circuits OT - neuromodulator OT - neuroscience OT - neurotransmitter corelease COIS- The authors declare that no competing interests exist. EDAT- 2015/02/28 06:00 MHDA- 2016/01/21 06:00 CRDT- 2015/02/28 06:00 PHST- 2015/01/09 00:00 [received] PHST- 2015/02/26 00:00 [accepted] PHST- 2015/02/28 06:00 [entrez] PHST- 2015/02/28 06:00 [pubmed] PHST- 2016/01/21 06:00 [medline] AID - 06412 [pii] AID - 10.7554/eLife.06412 [doi] PST - epublish SO - Elife. 2015 Feb 27;4:e06412. doi: 10.7554/eLife.06412. PMID- 25567906 OWN - NLM STAT- MEDLINE DCOM- 20150212 LR - 20230815 IS - 1095-9203 (Electronic) IS - 0036-8075 (Print) IS - 0036-8075 (Linking) VI - 347 IP - 6218 DP - 2015 Jan 9 TI - Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. PG - 188-94 LID - 10.1126/science.1257132 [doi] AB - The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Here, we identify SLC38A9, an uncharacterized protein with sequence similarity to amino acid transporters, as a lysosomal transmembrane protein that interacts with the Rag guanosine triphosphatases (GTPases) and Ragulator in an amino acid-sensitive fashion. SLC38A9 transports arginine with a high Michaelis constant, and loss of SLC38A9 represses mTORC1 activation by amino acids, particularly arginine. Overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity. Thus, SLC38A9 functions upstream of the Rag GTPases and is an excellent candidate for being an arginine sensor for the mTORC1 pathway. CI - Copyright © 2015, American Association for the Advancement of Science. FAU - Wang, Shuyu AU - Wang S AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. FAU - Tsun, Zhi-Yang AU - Tsun ZY AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. FAU - Wolfson, Rachel L AU - Wolfson RL AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. FAU - Shen, Kuang AU - Shen K AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. FAU - Wyant, Gregory A AU - Wyant GA AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. FAU - Plovanich, Molly E AU - Plovanich ME AD - Harvard Medical School, 260 Longwood Avenue, Boston, MA 02115, USA. FAU - Yuan, Elizabeth D AU - Yuan ED AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. FAU - Jones, Tony D AU - Jones TD AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. FAU - Chantranupong, Lynne AU - Chantranupong L AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. FAU - Comb, William AU - Comb W AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. FAU - Wang, Tim AU - Wang T AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. FAU - Bar-Peled, Liron AU - Bar-Peled L AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. FAU - Zoncu, Roberto AU - Zoncu R AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. FAU - Straub, Christoph AU - Straub C AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Kim, Choah AU - Kim C AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. FAU - Park, Jiwon AU - Park J AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Sabatini, David M AU - Sabatini DM AD - Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. sabatini@wi.mit.edu. LA - eng GR - R01 AI047389/AI/NIAID NIH HHS/United States GR - R01 CA103866/CA/NCI NIH HHS/United States GR - T32 GM007287/GM/NIGMS NIH HHS/United States GR - T32 GM007753/GM/NIGMS NIH HHS/United States GR - F31 CA180271/CA/NCI NIH HHS/United States GR - R37 AI047389/AI/NIAID NIH HHS/United States GR - Howard Hughes Medical Institute/United States GR - F30 CA180754/CA/NCI NIH HHS/United States GR - F31 CA189437/CA/NCI NIH HHS/United States GR - F31 AG044064/AG/NIA NIH HHS/United States GR - AI47389/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20150107 PL - United States TA - Science JT - Science (New York, N.Y.) JID - 0404511 RN - 0 (Amino Acid Transport Systems) RN - 0 (Multiprotein Complexes) RN - 0 (SLC38A9 protein, human) RN - 94ZLA3W45F (Arginine) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.6.5.2 (Monomeric GTP-Binding Proteins) SB - IM CIN - Science. 2015 Jan 9;347(6218):128-9. PMID: 25574008 MH - Amino Acid Sequence MH - Amino Acid Transport Systems/chemistry/genetics/*metabolism MH - Arginine/deficiency/*metabolism MH - HEK293 Cells MH - Humans MH - Lysosomes/*enzymology MH - Mechanistic Target of Rapamycin Complex 1 MH - Molecular Sequence Data MH - Monomeric GTP-Binding Proteins/*metabolism MH - Multiprotein Complexes/*metabolism MH - Protein Structure, Tertiary MH - Signal Transduction MH - TOR Serine-Threonine Kinases/*metabolism PMC - PMC4295826 MID - NIHMS654406 EDAT- 2015/01/09 06:00 MHDA- 2015/02/13 06:00 CRDT- 2015/01/09 06:00 PHST- 2015/01/09 06:00 [entrez] PHST- 2015/01/09 06:00 [pubmed] PHST- 2015/02/13 06:00 [medline] AID - science.1257132 [pii] AID - 10.1126/science.1257132 [doi] PST - ppublish SO - Science. 2015 Jan 9;347(6218):188-94. doi: 10.1126/science.1257132. Epub 2015 Jan 7. PMID- 25141172 OWN - NLM STAT- MEDLINE DCOM- 20150511 LR - 20211021 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 9 IP - 8 DP - 2014 TI - A direct projection from mouse primary visual cortex to dorsomedial striatum. PG - e104501 LID - 10.1371/journal.pone.0104501 [doi] LID - e104501 AB - The mammalian striatum receives inputs from many cortical areas, but the existence of a direct axonal projection from the primary visual cortex (V1) is controversial. In this study we use anterograde and retrograde tracing techniques to demonstrate that V1 directly innervates a topographically defined longitudinal strip of dorsomedial striatum in mice. We find that this projection forms functional excitatory synapses with direct and indirect pathway striatal projection neurons (SPNs) and engages feed-forward inhibition onto these cells. Importantly, stimulation of V1 afferents is sufficient to evoke phasic firing in SPNs. These findings therefore identify a striatal region that is functionally innervated by V1 and suggest that early visual processing may play an important role in striatal-based behaviors. FAU - Khibnik, Lena A AU - Khibnik LA AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Tritsch, Nicolas X AU - Tritsch NX AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - NS007484/NS/NINDS NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - T32 NS007484/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140820 PL - United States TA - PLoS One JT - PloS one JID - 101285081 SB - IM MH - Animals MH - Axons/physiology MH - Corpus Striatum/*anatomy & histology/physiology MH - Mice MH - Neural Pathways/anatomy & histology/physiology MH - Neurons/*cytology/physiology MH - Visual Cortex/*anatomy & histology/physiology PMC - PMC4139305 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2014/08/21 06:00 MHDA- 2015/05/12 06:00 CRDT- 2014/08/21 06:00 PHST- 2014/04/02 00:00 [received] PHST- 2014/07/11 00:00 [accepted] PHST- 2014/08/21 06:00 [entrez] PHST- 2014/08/21 06:00 [pubmed] PHST- 2015/05/12 06:00 [medline] AID - PONE-D-14-14783 [pii] AID - 10.1371/journal.pone.0104501 [doi] PST - epublish SO - PLoS One. 2014 Aug 20;9(8):e104501. doi: 10.1371/journal.pone.0104501. eCollection 2014. PMID- 25140704 OWN - NLM STAT- MEDLINE DCOM- 20151109 LR - 20211021 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 9 IP - 8 DP - 2014 TI - CRISPR/Cas9-mediated gene knock-down in post-mitotic neurons. PG - e105584 LID - 10.1371/journal.pone.0105584 [doi] LID - e105584 AB - The prokaryotic adaptive immune system CRISPR/Cas9 has recently been adapted for genome editing in eukaryotic cells. This technique allows for sequence-specific induction of double-strand breaks in genomic DNA of individual cells, effectively resulting in knock-out of targeted genes. It thus promises to be an ideal candidate for application in neuroscience where constitutive genetic modifications are frequently either lethal or ineffective due to adaptive changes of the brain. Here we use CRISPR/Cas9 to knock-out Grin1, the gene encoding the obligatory NMDA receptor subunit protein GluN1, in a sparse population of mouse pyramidal neurons. Within this genetically mosaic tissue, manipulated cells lack synaptic current mediated by NMDA-type glutamate receptors consistent with complete knock-out of the targeted gene. Our results show the first proof-of-principle demonstration of CRISPR/Cas9-mediated knock-down in neurons in vivo, where it can be a useful tool to study the function of specific proteins in neuronal circuits. FAU - Straub, Christoph AU - Straub C AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Granger, Adam J AU - Granger AJ AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Saulnier, Jessica L AU - Saulnier JL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. LA - eng GR - R01 NS077907/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - NS077907/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140820 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Gprin1 protein, mouse) RN - 0 (Nerve Tissue Proteins) RN - 0 (Receptors, N-Methyl-D-Aspartate) SB - IM MH - Animals MH - *CRISPR-Cas Systems MH - Gene Knockdown Techniques/*methods MH - Mice MH - Nerve Tissue Proteins/*genetics/metabolism MH - Pyramidal Cells/*metabolism/physiology MH - Receptors, N-Methyl-D-Aspartate/*genetics/metabolism MH - Synaptic Potentials PMC - PMC4139396 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2014/08/21 06:00 MHDA- 2015/11/10 06:00 CRDT- 2014/08/21 06:00 PHST- 2014/05/19 00:00 [received] PHST- 2014/07/22 00:00 [accepted] PHST- 2014/08/21 06:00 [entrez] PHST- 2014/08/21 06:00 [pubmed] PHST- 2015/11/10 06:00 [medline] AID - PONE-D-14-21576 [pii] AID - 10.1371/journal.pone.0105584 [doi] PST - epublish SO - PLoS One. 2014 Aug 20;9(8):e105584. doi: 10.1371/journal.pone.0105584. eCollection 2014. PMID- 24952910 OWN - NLM STAT- MEDLINE DCOM- 20140929 LR - 20220711 IS - 1548-7105 (Electronic) IS - 1548-7091 (Print) IS - 1548-7091 (Linking) VI - 11 IP - 8 DP - 2014 Aug TI - All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins. PG - 825-33 LID - 10.1038/nmeth.3000 [doi] AB - All-optical electrophysiology-spatially resolved simultaneous optical perturbation and measurement of membrane voltage-would open new vistas in neuroscience research. We evolved two archaerhodopsin-based voltage indicators, QuasAr1 and QuasAr2, which show improved brightness and voltage sensitivity, have microsecond response times and produce no photocurrent. We engineered a channelrhodopsin actuator, CheRiff, which shows high light sensitivity and rapid kinetics and is spectrally orthogonal to the QuasArs. A coexpression vector, Optopatch, enabled cross-talk-free genetically targeted all-optical electrophysiology. In cultured rat neurons, we combined Optopatch with patterned optical excitation to probe back-propagating action potentials (APs) in dendritic spines, synaptic transmission, subcellular microsecond-timescale details of AP propagation, and simultaneous firing of many neurons in a network. Optopatch measurements revealed homeostatic tuning of intrinsic excitability in human stem cell-derived neurons. In rat brain slices, Optopatch induced and reported APs and subthreshold events with high signal-to-noise ratios. The Optopatch platform enables high-throughput, spatially resolved electrophysiology without the use of conventional electrodes. FAU - Hochbaum, Daniel R AU - Hochbaum DR AD - 1] Applied Physics Program, School of Engineering and Applied Science, Harvard University, Cambridge, Massachusetts, USA. [2]. FAU - Zhao, Yongxin AU - Zhao Y AUID- ORCID: 0000000341885725 AD - 1] Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada. [2]. FAU - Farhi, Samouil L AU - Farhi SL AD - Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA. FAU - Klapoetke, Nathan AU - Klapoetke N AD - 1] The MIT Media Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Biological Engineering, MIT, Cambridge, Massachusetts, USA. [3] Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA. [4] McGovern Institute for Brain Research, MIT, Cambridge, Massachusetts, USA. FAU - Werley, Christopher A AU - Werley CA AD - Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA. FAU - Kapoor, Vikrant AU - Kapoor V AD - Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA. FAU - Zou, Peng AU - Zou P AD - Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA. FAU - Kralj, Joel M AU - Kralj JM AD - Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA. FAU - Maclaurin, Dougal AU - Maclaurin D AD - Department of Physics, Harvard University, Cambridge, Massachusetts, USA. FAU - Smedemark-Margulies, Niklas AU - Smedemark-Margulies N AD - Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA. FAU - Saulnier, Jessica L AU - Saulnier JL AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. FAU - Boulting, Gabriella L AU - Boulting GL AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. FAU - Straub, Christoph AU - Straub C AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. FAU - Cho, Yong Ku AU - Cho YK AD - 1] The MIT Media Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Biological Engineering, MIT, Cambridge, Massachusetts, USA. [3] Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA. [4] McGovern Institute for Brain Research, MIT, Cambridge, Massachusetts, USA. FAU - Melkonian, Michael AU - Melkonian M AD - Institute of Botany, Cologne Biocenter, University of Cologne, Cologne, Germany. FAU - Wong, Gane Ka-Shu AU - Wong GK AD - 1] Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada. [2] Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. [3] Beijing Genomics Institute-Shenzhen, Shenzhen, China. FAU - Harrison, D Jed AU - Harrison DJ AD - Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada. FAU - Murthy, Venkatesh N AU - Murthy VN AD - Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - 1] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. [2] Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts, USA. FAU - Boyden, Edward S AU - Boyden ES AD - 1] The MIT Media Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Biological Engineering, MIT, Cambridge, Massachusetts, USA. [3] Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA. [4] McGovern Institute for Brain Research, MIT, Cambridge, Massachusetts, USA. [5]. FAU - Campbell, Robert E AU - Campbell RE AUID- ORCID: 000000030604092X AD - 1] Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada. [2]. FAU - Cohen, Adam E AU - Cohen AE AD - 1] Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Department of Physics, Harvard University, Cambridge, Massachusetts, USA. [3] Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts, USA. LA - eng GR - 1-R01-EB012498-01/EB/NIBIB NIH HHS/United States GR - DP2 OD007428/OD/NIH HHS/United States GR - CAPMC/CIHR/Canada GR - R01 DC011291/DC/NIDCD NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R01 NS039059/NS/NINDS NIH HHS/United States GR - P30 ES002109/ES/NIEHS NIH HHS/United States GR - R01 DC013329/DC/NIDCD NIH HHS/United States GR - R01 EB012498/EB/NIBIB NIH HHS/United States GR - 1-DP2-OD007428/OD/NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20140622 PL - United States TA - Nat Methods JT - Nature methods JID - 101215604 RN - 0 (Recombinant Proteins) RN - 9009-81-8 (Rhodopsin) SB - IM MH - Animals MH - Directed Molecular Evolution MH - Mammals/*physiology MH - Neurons/*physiology MH - Recombinant Proteins/metabolism MH - Rhodopsin/*physiology MH - Synaptic Transmission PMC - PMC4117813 MID - NIHMS600566 EDAT- 2014/06/24 06:00 MHDA- 2014/09/30 06:00 CRDT- 2014/06/23 06:00 PHST- 2013/12/15 00:00 [received] PHST- 2014/05/17 00:00 [accepted] PHST- 2014/06/23 06:00 [entrez] PHST- 2014/06/24 06:00 [pubmed] PHST- 2014/09/30 06:00 [medline] AID - nmeth.3000 [pii] AID - 10.1038/nmeth.3000 [doi] PST - ppublish SO - Nat Methods. 2014 Aug;11(8):825-33. doi: 10.1038/nmeth.3000. Epub 2014 Jun 22. PMID- 24948810 OWN - NLM STAT- MEDLINE DCOM- 20140812 LR - 20211021 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 34 IP - 25 DP - 2014 Jun 18 TI - Multiphasic modulation of cholinergic interneurons by nigrostriatal afferents. PG - 8557-69 LID - 10.1523/JNEUROSCI.0589-14.2014 [doi] AB - The motor and learning functions of the striatum are critically dependent on synaptic transmission from midbrain dopamine neurons and striatal cholinergic interneurons (CINs). Both neural populations alter their discharge in vivo in response to salient sensory stimuli, albeit in opposite directions. Whereas midbrain dopamine neurons respond to salient stimuli with a brief burst of activity, CINs exhibit a distinct pause in firing that is often followed by a period of increased excitability. Although this "pause-rebound" sensory response requires dopaminergic signaling, the precise mechanisms underlying the modulation of CIN firing by dopaminergic afferents remain unclear. Here, we show that phasic activation of nigrostriatal afferents in a mouse striatal slice preparation is sufficient to evoke a pause-rebound response in CINs. Using a combination of optogenetic, electrophysiological, and pharmacological approaches, we demonstrate that synaptically released dopamine inhibits CINs through type 2 dopamine receptors, while another unidentified transmitter mediates the delayed excitation. These findings imply that, in addition to their direct effects on striatal projection neurons, midbrain dopamine neurons indirectly modulate striatal output by dynamically controlling cholinergic tone. In addition, our data suggest that phasic dopaminergic activity may directly participate in the characteristic pause-rebound sensory response that CINs exhibit in vivo in response to salient and conditioned stimuli. CI - Copyright © 2014 the authors 0270-6474/14/338557-13$15.00/0. FAU - Straub, Christoph AU - Straub C AD - Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115. FAU - Tritsch, Nicolas X AU - Tritsch NX AD - Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115. FAU - Hagan, Nellwyn A AU - Hagan NA AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115. FAU - Gu, Chenghua AU - Gu C AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115 bernardo_sabatini@hms.harvard.edu. LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States GR - R01NSO64583/PHS HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 SB - IM MH - Action Potentials/*physiology MH - Afferent Pathways/physiology MH - Animals MH - Cholinergic Neurons/*metabolism/physiology MH - Corpus Striatum/*physiology MH - Female MH - Gene Knock-In Techniques MH - Interneurons/*physiology MH - Male MH - Mice MH - Mice, Transgenic MH - Substantia Nigra/*physiology PMC - PMC4061393 OTO - NOTNLM OT - acetylcholine OT - basal ganglia OT - dopamine EDAT- 2014/06/21 06:00 MHDA- 2014/08/13 06:00 CRDT- 2014/06/21 06:00 PHST- 2014/06/21 06:00 [entrez] PHST- 2014/06/21 06:00 [pubmed] PHST- 2014/08/13 06:00 [medline] AID - 34/25/8557 [pii] AID - 0589-14 [pii] AID - 10.1523/JNEUROSCI.0589-14.2014 [doi] PST - ppublish SO - J Neurosci. 2014 Jun 18;34(25):8557-69. doi: 10.1523/JNEUROSCI.0589-14.2014. PMID- 24881834 OWN - NLM STAT- MEDLINE DCOM- 20140812 LR - 20211021 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 82 IP - 6 DP - 2014 Jun 18 TI - Multipoint-emitting optical fibers for spatially addressable in vivo optogenetics. PG - 1245-54 LID - S0896-6273(14)00356-0 [pii] LID - 10.1016/j.neuron.2014.04.041 [doi] AB - Optical stimulation and silencing of neural activity is a powerful technique for elucidating the structure and function of neural circuitry. In most in vivo optogenetic experiments, light is delivered into the brain through a single optical fiber. However, this approach limits illumination to a fixed volume of the brain. Here a focused ion beam is used to pattern multiple light windows on a tapered optical fiber. We show that such fibers allow selective and dynamic illumination of different brain regions along the taper. Site selection is achieved by a simple coupling strategy at the fiber input, and the use of a single tapered waveguide minimizes the implant invasiveness. We demonstrate the effectiveness of this approach for multipoint optical stimulation in the mammalian brain in vivo by coupling the fiber to a microelectrode array and performing simultaneous extracellular recording and stimulation at multiple sites in the mouse striatum and cerebral cortex. CI - Copyright © 2014 Elsevier Inc. All rights reserved. FAU - Pisanello, Ferruccio AU - Pisanello F AD - Istituto Italiano di Tecnologia (IIT), Center for Bio-Molecular Nanotechnologies, Via Barsanti sn, 73010 Arnesano (Lecce), Italy; Center for Neuroscience and Cognitive Systems@UniTn, Istituto Italiano di Tecnologia. corso Bettini 31, 38068 Rovereto (TN), Italy. Electronic address: ferruccio.pisanello@iit.it. FAU - Sileo, Leonardo AU - Sileo L AD - Istituto Italiano di Tecnologia (IIT), Center for Bio-Molecular Nanotechnologies, Via Barsanti sn, 73010 Arnesano (Lecce), Italy; Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Istituto Nanoscienze-CNR, NNL-National Nanotechnology Laboratory, via per Monteroni, 73100 Lecce, Italy. FAU - Oldenburg, Ian A AU - Oldenburg IA AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. FAU - Pisanello, Marco AU - Pisanello M AD - Istituto Italiano di Tecnologia (IIT), Center for Bio-Molecular Nanotechnologies, Via Barsanti sn, 73010 Arnesano (Lecce), Italy; Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Istituto Nanoscienze-CNR, NNL-National Nanotechnology Laboratory, via per Monteroni, 73100 Lecce, Italy. FAU - Martiradonna, Luigi AU - Martiradonna L AD - Istituto Italiano di Tecnologia (IIT), Center for Bio-Molecular Nanotechnologies, Via Barsanti sn, 73010 Arnesano (Lecce), Italy. FAU - Assad, John A AU - Assad JA AD - Center for Neuroscience and Cognitive Systems@UniTn, Istituto Italiano di Tecnologia. corso Bettini 31, 38068 Rovereto (TN), Italy; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. FAU - De Vittorio, Massimo AU - De Vittorio M AD - Istituto Italiano di Tecnologia (IIT), Center for Bio-Molecular Nanotechnologies, Via Barsanti sn, 73010 Arnesano (Lecce), Italy; Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Istituto Nanoscienze-CNR, NNL-National Nanotechnology Laboratory, via per Monteroni, 73100 Lecce, Italy. LA - eng GR - F31 MH093026/MH/NIMH NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - F31-MH093026-01A1/MH/NIMH NIH HHS/United States GR - NS072030/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140529 PL - United States TA - Neuron JT - Neuron JID - 8809320 SB - IM MH - Animals MH - Brain/*physiology MH - *Electrodes, Implanted MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - *Microelectrodes MH - Nerve Net/physiology MH - *Optical Fibers MH - Optogenetics/instrumentation/*methods MH - Photic Stimulation/*methods PMC - PMC4256382 MID - NIHMS602008 EDAT- 2014/06/03 06:00 MHDA- 2014/08/13 06:00 CRDT- 2014/06/03 06:00 PHST- 2014/04/15 00:00 [accepted] PHST- 2014/06/03 06:00 [entrez] PHST- 2014/06/03 06:00 [pubmed] PHST- 2014/08/13 06:00 [medline] AID - S0896-6273(14)00356-0 [pii] AID - 10.1016/j.neuron.2014.04.041 [doi] PST - ppublish SO - Neuron. 2014 Jun 18;82(6):1245-54. doi: 10.1016/j.neuron.2014.04.041. Epub 2014 May 29. PMID- 24847215 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20140521 LR - 20211021 IS - 1662-5129 (Print) IS - 1662-5129 (Electronic) IS - 1662-5129 (Linking) VI - 8 DP - 2014 TI - Super-resolution 2-photon microscopy reveals that the morphology of each dendritic spine correlates with diffusive but not synaptic properties. PG - 29 LID - 10.3389/fnana.2014.00029 [doi] LID - 29 AB - The structure of dendritic spines suggests a specialized function in compartmentalizing synaptic signals near active synapses. Indeed, theoretical and experimental analyses indicate that the diffusive resistance of the spine neck is sufficient to effectively compartmentalize some signaling molecules in a spine for the duration of their activated lifetime. Here we describe the application of 2-photon microscopy combined with stimulated emission depletion (STED-2P) to the biophysical study of the relationship between synaptic signals and spine morphology, demonstrating the utility of combining STED-2P with modern optical and electrophysiological techniques. Morphological determinants of fluorescence recovery time were identified and evaluated within the context of a simple compartmental model describing diffusive transfer between spine and dendrite. Correlations between the neck geometry and the amplitude of synaptic potentials and calcium transients evoked by 2-photon glutamate uncaging were also investigated. FAU - Takasaki, Kevin AU - Takasaki K AD - Department of Neurobiology, Harvard Medical School, Howard Hughes Medical Institute Boston, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Harvard Medical School, Howard Hughes Medical Institute Boston, MA, USA. LA - eng GR - RC1 NS068917/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20140507 PL - Switzerland TA - Front Neuroanat JT - Frontiers in neuroanatomy JID - 101477943 PMC - PMC4019874 OTO - NOTNLM OT - 2-photon microscopy OT - dendritic spine OT - stimulated emission microscopy OT - super resolution microscopy OT - synaptic transmission EDAT- 2014/05/23 06:00 MHDA- 2014/05/23 06:01 CRDT- 2014/05/22 06:00 PHST- 2014/02/08 00:00 [received] PHST- 2014/04/20 00:00 [accepted] PHST- 2014/05/22 06:00 [entrez] PHST- 2014/05/23 06:00 [pubmed] PHST- 2014/05/23 06:01 [medline] AID - 10.3389/fnana.2014.00029 [doi] PST - epublish SO - Front Neuroanat. 2014 May 7;8:29. doi: 10.3389/fnana.2014.00029. eCollection 2014. PMID- 24843012 OWN - NLM STAT- MEDLINE DCOM- 20151110 LR - 20230701 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 3 DP - 2014 Apr 24 TI - Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis. PG - e01936 LID - 10.7554/eLife.01936 [doi] LID - e01936 AB - Synaptic transmission between midbrain dopamine neurons and target neurons in the striatum is essential for the selection and reinforcement of movements. Recent evidence indicates that nigrostriatal dopamine neurons inhibit striatal projection neurons by releasing a neurotransmitter that activates GABAA receptors. Here, we demonstrate that this phenomenon extends to mesolimbic afferents, and confirm that the released neurotransmitter is GABA. However, the GABA synthetic enzymes GAD65 and GAD67 are not detected in midbrain dopamine neurons. Instead, these cells express the membrane GABA transporters mGAT1 (Slc6a1) and mGAT4 (Slc6a11) and inhibition of these transporters prevents GABA co-release. These findings therefore indicate that GABA co-release is a general feature of midbrain dopaminergic neurons that relies on GABA uptake from the extracellular milieu as opposed to de novo synthesis. This atypical mechanism may confer dopaminergic neurons the flexibility to differentially control GABAergic transmission in a target-dependent manner across their extensive axonal arbors.DOI: http://dx.doi.org/10.7554/eLife.01936.001. CI - Copyright © 2014, Tritsch et al. FAU - Tritsch, Nicolas X AU - Tritsch NX AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States. FAU - Oh, Won-Jong AU - Oh WJ AD - Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Gu, Chenghua AU - Gu C AD - Department of Neurobiology, Harvard Medical School, Boston, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States bsabatini@hms.harvard.edu. LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - NS064583/NS/NINDS NIH HHS/United States GR - R01 NS064583/NS/NINDS NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140424 PL - England TA - Elife JT - eLife JID - 101579614 RN - 0 (GABA Agents) RN - 0 (GABA Plasma Membrane Transport Proteins) RN - 0 (Slc6a1 protein, mouse) RN - 0 (Slc6a11 protein, mouse) RN - 56-12-2 (gamma-Aminobutyric Acid) SB - IM CIN - Nat Rev Neurosci. 2014 Jun;15(6):350. PMID: 24840794 MH - Animals MH - Biological Transport MH - Corpus Striatum/cytology/drug effects/*metabolism MH - Dopaminergic Neurons/drug effects/*metabolism MH - GABA Agents/pharmacology MH - GABA Plasma Membrane Transport Proteins/metabolism MH - Inhibitory Postsynaptic Potentials MH - Mesencephalon/cytology/drug effects/*metabolism MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - *Neural Inhibition/drug effects MH - Synapses/drug effects/*metabolism MH - *Synaptic Transmission/drug effects MH - Time Factors MH - gamma-Aminobutyric Acid/*metabolism PMC - PMC4001323 OTO - NOTNLM OT - GABA OT - GAT OT - basal ganglia OT - co-release OT - dopamine OT - striatum COIS- The authors declare that no competing interests exist. EDAT- 2014/05/21 06:00 MHDA- 2014/05/21 06:01 CRDT- 2014/05/21 06:00 PHST- 2014/05/21 06:00 [entrez] PHST- 2014/05/21 06:00 [pubmed] PHST- 2014/05/21 06:01 [medline] AID - 01936 [pii] AID - 10.7554/eLife.01936 [doi] PST - epublish SO - Elife. 2014 Apr 24;3:e01936. doi: 10.7554/eLife.01936. PMID- 24742454 OWN - NLM STAT- MEDLINE DCOM- 20140605 LR - 20181202 IS - 1097-4199 (Electronic) IS - 0896-6273 (Linking) VI - 82 IP - 2 DP - 2014 Apr 16 TI - How to grow a synapse. PG - 256-7 LID - S0896-6273(14)00290-6 [pii] LID - 10.1016/j.neuron.2014.03.033 [doi] AB - Activity-dependent alterations in the strength of an individual glutamatergic synapse are often accompanied by changes in the size and shape of the postsynaptic terminal. Two studies in this issue of Neuron, Meyer et al. (2014) and Bosch et al. (2014), shed new light on the mechanisms and signaling pathways underlying structural long-term potentiation. CI - Copyright © 2014 Elsevier Inc. All rights reserved. FAU - Straub, Christoph AU - Straub C AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. Electronic address: bernardo_sabatini@hms.harvard.edu. LA - eng PT - Comment PT - Journal Article PL - United States TA - Neuron JT - Neuron JID - 8809320 SB - IM CON - Neuron. 2014 Apr 16;82(2):430-43. PMID: 24742464 CON - Neuron. 2014 Apr 16;82(2):444-59. PMID: 24742465 MH - Animals MH - Dendritic Spines/*physiology MH - Hippocampus/*cytology MH - Humans MH - Long-Term Potentiation/*physiology MH - Neuronal Plasticity/*physiology MH - Neurons/*cytology/*physiology/*ultrastructure MH - Synapses/*physiology EDAT- 2014/04/20 06:00 MHDA- 2014/06/06 06:00 CRDT- 2014/04/19 06:00 PHST- 2014/04/19 06:00 [entrez] PHST- 2014/04/20 06:00 [pubmed] PHST- 2014/06/06 06:00 [medline] AID - S0896-6273(14)00290-6 [pii] AID - 10.1016/j.neuron.2014.03.033 [doi] PST - ppublish SO - Neuron. 2014 Apr 16;82(2):256-7. doi: 10.1016/j.neuron.2014.03.033. PMID- 24765076 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20140425 LR - 20211021 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 5 DP - 2014 TI - A PKA activity sensor for quantitative analysis of endogenous GPCR signaling via 2-photon FRET-FLIM imaging. PG - 56 LID - 10.3389/fphar.2014.00056 [doi] LID - 56 AB - Neuromodulators have profound effects on behavior, but the dynamics of their intracellular effectors has remained unclear. Most neuromodulators exert their function via G-protein-coupled receptors (GPCRs). One major challenge for understanding neuromodulator action is the lack of dynamic readouts of the biochemical signals produced by GPCR activation. The adenylate cyclase/cyclic AMP/protein kinase A (PKA) module is a central component of such biochemical signaling. This module is regulated by several behaviorally important neuromodulator receptors. Furthermore, PKA activity is necessary for the induction of many forms of synaptic plasticity as well as for the formation of long-term memory. In order to monitor PKA activity in brain tissue, we have developed a 2-photon fluorescence lifetime imaging microscopy (2pFLIM) compatible PKA sensor termed FLIM-AKAR, which is based on the ratiometric FRET sensor AKAR3. FLIM-AKAR shows a large dynamic range and little pH sensitivity. In addition, it is a rapidly diffusible cytoplasmic protein that specifically reports net PKA activity in situ. FLIM-AKAR expresses robustly in various brain regions with multiple transfection methods, can be targeted to genetically identified cell types, and responds to activation of both endogenous GPCRs and spatial-temporally specific delivery of glutamate. Initial experiments reveal differential regulation of PKA activity across subcellular compartments in response to neuromodulator inputs. Therefore, the reporter FLIM-AKAR, coupled with 2pFLIM, enables the study of PKA activity in response to neuromodulator inputs in genetically identified neurons in the brain, and sheds light on the intracellular dynamics of endogenous GPCR activation. FAU - Chen, Yao AU - Chen Y AD - Howard Hughes Medical Institute Boston, MA, USA ; Department of Neurobiology, Harvard Medical School Boston, MA, USA. FAU - Saulnier, Jessica L AU - Saulnier JL AD - Howard Hughes Medical Institute Boston, MA, USA ; Department of Neurobiology, Harvard Medical School Boston, MA, USA. FAU - Yellen, Gary AU - Yellen G AD - Department of Neurobiology, Harvard Medical School Boston, MA, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute Boston, MA, USA ; Department of Neurobiology, Harvard Medical School Boston, MA, USA. LA - eng GR - DP1 EB016985/EB/NIBIB NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - T32 NS007484/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20140402 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 EIN - Front Pharmacol. 2016;7:46. PMID: 26941646 PMC - PMC3980114 OTO - NOTNLM OT - FLIM OT - FLIM-AKAR OT - GPCR OT - PKA OT - cAMP OT - dendritic spine OT - glutamate OT - neuromodulation EDAT- 2014/04/26 06:00 MHDA- 2014/04/26 06:01 CRDT- 2014/04/26 06:00 PHST- 2014/01/30 00:00 [received] PHST- 2014/03/14 00:00 [accepted] PHST- 2014/04/26 06:00 [entrez] PHST- 2014/04/26 06:00 [pubmed] PHST- 2014/04/26 06:01 [medline] AID - 10.3389/fphar.2014.00056 [doi] PST - epublish SO - Front Pharmacol. 2014 Apr 2;5:56. doi: 10.3389/fphar.2014.00056. eCollection 2014. PMID- 24633176 OWN - NLM STAT- MEDLINE DCOM- 20141228 LR - 20220321 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 9 IP - 3 DP - 2014 TI - High content image analysis identifies novel regulators of synaptogenesis in a high-throughput RNAi screen of primary neurons. PG - e91744 LID - 10.1371/journal.pone.0091744 [doi] LID - e91744 AB - The formation of synapses, the specialized points of chemical communication between neurons, is a highly regulated developmental process fundamental to establishing normal brain circuitry. Perturbations of synapse formation and function causally contribute to human developmental and degenerative neuropsychiatric disorders, such as Alzheimer's disease, intellectual disability, and autism spectrum disorders. Many genes controlling synaptogenesis have been identified, but lack of facile experimental systems has made systematic discovery of regulators of synaptogenesis challenging. Thus, we created a high-throughput platform to study excitatory and inhibitory synapse development in primary neuronal cultures and used a lentiviral RNA interference library to identify novel regulators of synapse formation. This methodology is broadly applicable for high-throughput screening of genes and drugs that may rescue or improve synaptic dysfunction associated with cognitive function and neurological disorders. FAU - Nieland, Thomas J F AU - Nieland TJ AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America. FAU - Logan, David J AU - Logan DJ AD - Imaging Platform at the Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America. FAU - Saulnier, Jessica AU - Saulnier J AD - Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Lam, Daniel AU - Lam D AD - RNAi Platform, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America. FAU - Johnson, Caroline AU - Johnson C AD - Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Root, David E AU - Root DE AD - RNAi Platform, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America. FAU - Carpenter, Anne E AU - Carpenter AE AD - Imaging Platform at the Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America. FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. LA - eng GR - R01 GM089652/GM/NIGMS NIH HHS/United States GR - MH095096/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20140314 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (RNA, Small Interfering) SB - IM MH - Algorithms MH - Animals MH - Automation, Laboratory MH - Gene Expression Regulation MH - *High-Throughput Screening Assays MH - Mice MH - *Microscopy, Fluorescence MH - Neurons/*metabolism MH - *RNA Interference MH - RNA, Small Interfering/genetics/metabolism MH - Synapses/*metabolism PMC - PMC3954765 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2014/03/19 06:00 MHDA- 2014/12/30 06:00 CRDT- 2014/03/18 06:00 PHST- 2013/11/04 00:00 [received] PHST- 2014/02/15 00:00 [accepted] PHST- 2014/03/18 06:00 [entrez] PHST- 2014/03/19 06:00 [pubmed] PHST- 2014/12/30 06:00 [medline] AID - PONE-D-13-45000 [pii] AID - 10.1371/journal.pone.0091744 [doi] PST - epublish SO - PLoS One. 2014 Mar 14;9(3):e91744. doi: 10.1371/journal.pone.0091744. eCollection 2014. PMID- 24431445 OWN - NLM STAT- MEDLINE DCOM- 20140313 LR - 20211021 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 34 IP - 3 DP - 2014 Jan 15 TI - Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines. PG - 869-79 LID - 10.1523/JNEUROSCI.4538-13.2014 [doi] AB - The NMDA-type glutamate receptor (NMDAR) is essential for synaptogenesis, synaptic plasticity, and higher cognitive function. Emerging evidence indicates that NMDAR Ca(2+) permeability is under the control of cAMP/protein kinase A (PKA) signaling. Whereas the functional impact of PKA on NMDAR-dependent Ca(2+) signaling is well established, the molecular target remains unknown. Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca(2+) permeation and Ca(2+) signaling in spines. Activation of β-adrenergic and D1/D5-dopamine receptors induces Ser1166 phosphorylation. Loss of this single phosphorylation site abolishes PKA-dependent potentiation of NMDAR Ca(2+) permeation, synaptic currents, and Ca(2+) rises in dendritic spines. We further show that adverse experience in the form of forced swim, but not exposure to fox urine, elicits striking phosphorylation of Ser1166 in vivo, indicating differential impact of different forms of stress. Our data identify a novel molecular and functional target of PKA essential to NMDAR-mediated Ca(2+) signaling at synapses and regulated by the emotional response to stress. FAU - Murphy, Jessica A AU - Murphy JA AD - Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, Department of Pharmacology, University of California, Davis, California 95616, Department of Neurobiology, HHMI, Harvard Medical School, Boston, Massachusetts 02115, and Department of Biochemistry, University of Buffalo, State University of New York, Buffalo, New York 14214. FAU - Stein, Ivar S AU - Stein IS FAU - Lau, C Geoffrey AU - Lau CG FAU - Peixoto, Rui T AU - Peixoto RT FAU - Aman, Teresa K AU - Aman TK FAU - Kaneko, Naoki AU - Kaneko N FAU - Aromolaran, Kelly AU - Aromolaran K FAU - Saulnier, Jessica L AU - Saulnier JL FAU - Popescu, Gabriela K AU - Popescu GK FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Hell, Johannes W AU - Hell JW FAU - Zukin, R Suzanne AU - Zukin RS LA - eng GR - R01 NS052669/NS/NINDS NIH HHS/United States GR - R01 NS046742/NS/NINDS NIH HHS/United States GR - R01 NS097016/NS/NINDS NIH HHS/United States GR - F32 NS077622/NS/NINDS NIH HHS/United States GR - R01 NS078792/NS/NINDS NIH HHS/United States GR - T32 GM099608/GM/NIGMS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (NR2B NMDA receptor) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 452VLY9402 (Serine) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) SB - IM MH - Animals MH - Animals, Newborn MH - Calcium Signaling/*physiology MH - Cells, Cultured MH - Cyclic AMP-Dependent Protein Kinases/genetics/*metabolism MH - Dendritic Spines/genetics/*metabolism MH - Foxes MH - HEK293 Cells MH - Hippocampus/metabolism MH - Humans MH - Neural Inhibition/physiology MH - Phosphorylation/physiology MH - Rats, Sprague-Dawley MH - Receptors, N-Methyl-D-Aspartate/genetics/*metabolism/physiology MH - Serine/genetics/*metabolism MH - Stress, Psychological/genetics/metabolism MH - Synapses/*physiology PMC - PMC3891964 EDAT- 2014/01/17 06:00 MHDA- 2014/03/14 06:00 CRDT- 2014/01/17 06:00 PHST- 2014/01/17 06:00 [entrez] PHST- 2014/01/17 06:00 [pubmed] PHST- 2014/03/14 06:00 [medline] AID - 34/3/869 [pii] AID - 4538-13 [pii] AID - 10.1523/JNEUROSCI.4538-13.2014 [doi] PST - ppublish SO - J Neurosci. 2014 Jan 15;34(3):869-79. doi: 10.1523/JNEUROSCI.4538-13.2014. PMID- 23960100 OWN - NLM STAT- MEDLINE DCOM- 20131217 LR - 20230620 IS - 1521-0111 (Electronic) IS - 0026-895X (Print) IS - 0026-895X (Linking) VI - 84 IP - 5 DP - 2013 Nov TI - Caged naloxone reveals opioid signaling deactivation kinetics. PG - 687-95 LID - 10.1124/mol.113.088096 [doi] AB - The spatiotemporal dynamics of opioid signaling in the brain remain poorly defined. Photoactivatable opioid ligands provide a means to quantitatively measure these dynamics and their underlying mechanisms in brain tissue. Although activation kinetics can be assessed using caged agonists, deactivation kinetics are obscured by slow clearance of agonist in tissue. To reveal deactivation kinetics of opioid signaling we developed a caged competitive antagonist that can be quickly photoreleased in sufficient concentrations to render agonist dissociation effectively irreversible. Carboxynitroveratryl-naloxone (CNV-NLX), a caged analog of the competitive opioid antagonist NLX, was readily synthesized from commercially available NLX in good yield and found to be devoid of antagonist activity at heterologously expressed opioid receptors. Photolysis in slices of rat locus coeruleus produced a rapid inhibition of the ionic currents evoked by multiple agonists of the μ-opioid receptor (MOR), but not of α-adrenergic receptors, which activate the same pool of ion channels. Using the high-affinity peptide agonist dermorphin, we established conditions under which light-driven deactivation rates are independent of agonist concentration and thus intrinsic to the agonist-receptor complex. Under these conditions, some MOR agonists yielded deactivation rates that are limited by G protein signaling, whereas others appeared limited by agonist dissociation. Therefore, the choice of agonist determines which feature of receptor signaling is unmasked by CNV-NLX photolysis. FAU - Banghart, Matthew R AU - Banghart MR AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts (M.R.B., R.C.S., B.L.S.); Vollum Institute, Oregon Health & Science University, Portland, Oregon (J.T.W.); and Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia (L.D.L.). FAU - Williams, John T AU - Williams JT FAU - Shah, Ruchir C AU - Shah RC FAU - Lavis, Luke D AU - Lavis LD FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 MH085498/MH/NIMH NIH HHS/United States GR - R00 DA034648/DA/NIDA NIH HHS/United States GR - DA08163/DA/NIDA NIH HHS/United States GR - DA034648/DA/NIDA NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - MH085498/MH/NIMH NIH HHS/United States GR - R01 DA008163/DA/NIDA NIH HHS/United States GR - K99 DA034648/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20130819 PL - United States TA - Mol Pharmacol JT - Molecular pharmacology JID - 0035623 RN - 0 (Narcotic Antagonists) RN - 0 (Receptors, Opioid, mu) RN - 100929-53-1 (Enkephalin, Ala(2)-MePhe(4)-Gly(5)-) RN - 36B82AMQ7N (Naloxone) SB - IM MH - Animals MH - Brain/drug effects MH - Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology MH - Humans MH - Kinetics MH - Naloxone/*pharmacology MH - Narcotic Antagonists/*pharmacology MH - Rats MH - Receptors, Opioid, mu/drug effects MH - Signal Transduction/*drug effects PMC - PMC3807075 EDAT- 2013/08/21 06:00 MHDA- 2013/12/18 06:00 CRDT- 2013/08/21 06:00 PHST- 2013/08/21 06:00 [entrez] PHST- 2013/08/21 06:00 [pubmed] PHST- 2013/12/18 06:00 [medline] AID - mol.113.088096 [pii] AID - MOL_088096 [pii] AID - 10.1124/mol.113.088096 [doi] PST - ppublish SO - Mol Pharmacol. 2013 Nov;84(5):687-95. doi: 10.1124/mol.113.088096. Epub 2013 Aug 19. PMID- 24117060 OWN - NLM STAT- MEDLINE DCOM- 20140528 LR - 20211021 IS - 1520-5126 (Electronic) IS - 0002-7863 (Print) IS - 0002-7863 (Linking) VI - 135 IP - 42 DP - 2013 Oct 23 TI - Spectral evolution of a photochemical protecting group for orthogonal two-color uncaging with visible light. PG - 15948-54 LID - 10.1021/ja408225k [doi] AB - Caged compounds are molecules rendered functionally inert by derivatization with a photochemical protecting group. We describe the design logic behind the development of a diethylaminocoumarin (DEAC) caging chromophore, DEAC450, that absorbs blue light strongly (ε450 = 43,000 M(-1) cm(-1)) and violet light 11-fold more weakly. The absorption minimum is in the wavelength range (340-360 nm) that is traditionally used for photolysis of many widely used nitroaromatic caged compounds (e.g., 4-carboxymethoxy-5,7-dinitroindolinyl(CDNI)-GABA). We used this chromophore to synthesize DEAC450-caged cAMP and found this probe was very stable toward aqueous hydrolysis in the electronic ground state but was photolyzed with a quantum efficiency of 0.78. When DEAC450-cAMP and CDNI-GABA where co-applied to striatal cholinergic interneurons, the caged compounds were photolyzed in an chromatically orthogonal manner using blue and violet light so as to modulate the neuronal firing rate in a bidirectional way. FAU - Olson, Jeremy P AU - Olson JP AD - Department of Neuroscience, Mount Sinai School of Medicine , New York, New York 10029, United States. FAU - Banghart, Matthew R AU - Banghart MR FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Ellis-Davies, Graham C R AU - Ellis-Davies GC LA - eng GR - R01 MH085498/MH/NIMH NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - MH085498/MH/NIMH NIH HHS/United States GR - K99 DA034648/DA/NIDA NIH HHS/United States GR - NS069720/NS/NINDS NIH HHS/United States GR - R01 NS069720/NS/NINDS NIH HHS/United States GR - GM053395/GM/NIGMS NIH HHS/United States GR - R01 GM053395/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20131011 PL - United States TA - J Am Chem Soc JT - Journal of the American Chemical Society JID - 7503056 RN - 0 (Aminocoumarins) RN - 0 (Coumarins) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - E0399OZS9N (Cyclic AMP) SB - IM MH - Aminocoumarins/*chemistry MH - *Color MH - Coumarins/*chemistry MH - Cyclic AMP/chemistry MH - Hydrolysis MH - *Light MH - Molecular Structure MH - Photochemical Processes MH - gamma-Aminobutyric Acid/chemistry PMC - PMC4097017 MID - NIHMS531378 EDAT- 2013/10/15 06:00 MHDA- 2014/05/29 06:00 CRDT- 2013/10/15 06:00 PHST- 2013/10/15 06:00 [entrez] PHST- 2013/10/15 06:00 [pubmed] PHST- 2014/05/29 06:00 [medline] AID - 10.1021/ja408225k [doi] PST - ppublish SO - J Am Chem Soc. 2013 Oct 23;135(42):15948-54. doi: 10.1021/ja408225k. Epub 2013 Oct 11. PMID- 24065881 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20130925 LR - 20211021 IS - 1662-5099 (Print) IS - 1662-5099 (Electronic) IS - 1662-5099 (Linking) VI - 6 DP - 2013 TI - Temporal dynamics of a homeostatic pathway controlling neural network activity. PG - 28 LID - 10.3389/fnmol.2013.00028 [doi] LID - 28 AB - Neurons use a variety of mechanisms to homeostatically regulate neural network activity in order to maintain firing in a bounded range. One such process involves the bi-directional modulation of excitatory synaptic drive in response to chronic changes in network activity. Down-scaling of excitatory synapses in response to high activity requires Arc-dependent endocytosis of glutamate receptors. However, the temporal dynamics and signaling pathways regulating Arc during homeostatic plasticity are not well understood. Here we determine the relative contribution of transcriptional and translational control in the regulation of Arc, the signaling pathways responsible for the activity-dependent production of Arc, and the time course of these signaling events as they relate to the homeostatic adjustment of network activity in hippocampal neurons. We find that an ERK1/2-dependent transcriptional pathway active within 1-2 h of up-regulated network activity induces Arc leading to a restoration of network spiking rates within 12 h. Under basal and low activity conditions, specialized mechanisms are in place to rapidly degrade Arc mRNA and protein such that they have half-lives of less than 1 h. In addition, we find that while mTOR signaling is regulated by network activity on a similar time scale, mTOR-dependent translational control is not a major regulator of Arc production or degradation suggesting that the signaling pathways underlying homeostatic plasticity are distinct from those mediating synapse-specific forms of synaptic depression. FAU - Bateup, Helen S AU - Bateup HS AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School Boston, MA, USA. FAU - Denefrio, Cassandra L AU - Denefrio CL FAU - Johnson, Caroline A AU - Johnson CA FAU - Saulnier, Jessica L AU - Saulnier JL FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS052707/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20130918 PL - Switzerland TA - Front Mol Neurosci JT - Frontiers in molecular neuroscience JID - 101477914 PMC - PMC3776619 OTO - NOTNLM OT - Arc OT - ERK signaling OT - TSC/mTOR OT - activity-dependent gene regulation OT - hippocampus OT - homeostatic plasticity OT - multi-electrode array OT - network activity EDAT- 2013/09/26 06:00 MHDA- 2013/09/26 06:01 CRDT- 2013/09/26 06:00 PHST- 2013/07/29 00:00 [received] PHST- 2013/08/24 00:00 [accepted] PHST- 2013/09/26 06:00 [entrez] PHST- 2013/09/26 06:00 [pubmed] PHST- 2013/09/26 06:01 [medline] AID - 10.3389/fnmol.2013.00028 [doi] PST - epublish SO - Front Mol Neurosci. 2013 Sep 18;6:28. doi: 10.3389/fnmol.2013.00028. eCollection 2013. PMID- 23953120 OWN - NLM STAT- MEDLINE DCOM- 20131112 LR - 20230425 IS - 1097-4172 (Electronic) IS - 0092-8674 (Print) IS - 0092-8674 (Linking) VI - 154 IP - 4 DP - 2013 Aug 15 TI - A nanobody-based system using fluorescent proteins as scaffolds for cell-specific gene manipulation. PG - 928-39 LID - S0092-8674(13)00892-1 [pii] LID - 10.1016/j.cell.2013.07.021 [doi] AB - Fluorescent proteins are commonly used to label cells across organisms, but the unmodified forms cannot control biological activities. Using GFP-binding proteins derived from Camelid antibodies, we co-opted GFP as a scaffold for inducing formation of biologically active complexes, developing a library of hybrid transcription factors that control gene expression only in the presence of GFP or its derivatives. The modular design allows for variation in key properties such as DNA specificity, transcriptional potency, and drug dependency. Production of GFP controlled cell-specific gene expression and facilitated functional perturbations in the mouse retina and brain. Further, retrofitting existing transgenic GFP mouse and zebrafish lines for GFP-dependent transcription enabled applications such as optogenetic probing of neural circuits. This work establishes GFP as a multifunctional scaffold and opens the door to selective manipulation of diverse GFP-labeled cells across transgenic lines. This approach may also be extended to exploit other intracellular products as cell-specific scaffolds in multicellular organisms. CI - Copyright © 2013 Elsevier Inc. All rights reserved. FAU - Tang, Jonathan C Y AU - Tang JC AD - Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. FAU - Szikra, Tamas AU - Szikra T FAU - Kozorovitskiy, Yevgenia AU - Kozorovitskiy Y FAU - Teixiera, Miguel AU - Teixiera M FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Roska, Botond AU - Roska B FAU - Cepko, Constance L AU - Cepko CL LA - eng GR - HHMI_/Howard Hughes Medical Institute/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Cell JT - Cell JID - 0413066 RN - 0 (Recombinant Fusion Proteins) RN - 0 (Transcription Factors) RN - 147336-22-9 (Green Fluorescent Proteins) SB - IM CIN - Nat Methods. 2013 Oct;10(10):930-1. PMID: 24161972 MH - Animals MH - Animals, Genetically Modified MH - Electrophysiological Phenomena MH - *Genetic Techniques MH - Green Fluorescent Proteins/genetics/*metabolism MH - Humans MH - Mice MH - Recombinant Fusion Proteins/genetics/metabolism MH - Transcription Factors/metabolism MH - *Transcription, Genetic MH - Zebrafish PMC - PMC4096992 MID - NIHMS600460 OID - NLM: HHMIMS600460 EDAT- 2013/08/21 06:00 MHDA- 2013/11/13 06:00 CRDT- 2013/08/20 06:00 PHST- 2012/10/31 00:00 [received] PHST- 2013/05/31 00:00 [revised] PHST- 2013/07/15 00:00 [accepted] PHST- 2013/08/20 06:00 [entrez] PHST- 2013/08/21 06:00 [pubmed] PHST- 2013/11/13 06:00 [medline] AID - S0092-8674(13)00892-1 [pii] AID - 10.1016/j.cell.2013.07.021 [doi] PST - ppublish SO - Cell. 2013 Aug 15;154(4):928-39. doi: 10.1016/j.cell.2013.07.021. PMID- 23791193 OWN - NLM STAT- MEDLINE DCOM- 20130830 LR - 20211021 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 78 IP - 6 DP - 2013 Jun 19 TI - Recombinant probes for visualizing endogenous synaptic proteins in living neurons. PG - 971-85 LID - S0896-6273(13)00319-X [pii] LID - 10.1016/j.neuron.2013.04.017 [doi] AB - The ability to visualize endogenous proteins in living neurons provides a powerful means to interrogate neuronal structure and function. Here we generate recombinant antibody-like proteins, termed Fibronectin intrabodies generated with mRNA display (FingRs), that bind endogenous neuronal proteins PSD-95 and Gephyrin with high affinity and that, when fused to GFP, allow excitatory and inhibitory synapses to be visualized in living neurons. Design of the FingR incorporates a transcriptional regulation system that ties FingR expression to the level of the target and reduces background fluorescence. In dissociated neurons and brain slices, FingRs generated against PSD-95 and Gephyrin did not affect the expression patterns of their endogenous target proteins or the number or strength of synapses. Together, our data indicate that PSD-95 and Gephyrin FingRs can report the localization and amount of endogenous synaptic proteins in living neurons and thus may be used to study changes in synaptic strength in vivo. CI - Copyright © 2013 Elsevier Inc. All rights reserved. FAU - Gross, Garrett G AU - Gross GG AD - Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA. FAU - Junge, Jason A AU - Junge JA FAU - Mora, Rudy J AU - Mora RJ FAU - Kwon, Hyung-Bae AU - Kwon HB FAU - Olson, C Anders AU - Olson CA FAU - Takahashi, Terry T AU - Takahashi TT FAU - Liman, Emily R AU - Liman ER FAU - Ellis-Davies, Graham C R AU - Ellis-Davies GC FAU - McGee, Aaron W AU - McGee AW FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Roberts, Richard W AU - Roberts RW FAU - Arnold, Don B AU - Arnold DB LA - eng GR - OD 006117/OD/NIH HHS/United States GR - NS-046579/NS/NINDS NIH HHS/United States GR - GM 060416/GM/NIGMS NIH HHS/United States GR - R01 GM060416/GM/NIGMS NIH HHS/United States GR - R01 CA170820/CA/NCI NIH HHS/United States GR - R01 AI085583/AI/NIAID NIH HHS/United States GR - MH-086381/MH/NIMH NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R01 NS069720/NS/NINDS NIH HHS/United States GR - R01 GM053395/GM/NIGMS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - GM-083898/GM/NIGMS NIH HHS/United States GR - GM53395/GM/NIGMS NIH HHS/United States GR - R01 MH086381/MH/NIMH NIH HHS/United States GR - R01 GM083898/GM/NIGMS NIH HHS/United States GR - NS69720/NS/NINDS NIH HHS/United States GR - R01 NS081678/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Carrier Proteins) RN - 0 (DLG4 protein, human) RN - 0 (Disks Large Homolog 4 Protein) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Membrane Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (Recombinant Proteins) RN - 0 (gephyrin) SB - IM CIN - Nat Methods. 2013 Aug;10(8):696-7. PMID: 24058978 MH - Animals MH - COS Cells MH - Carrier Proteins/*analysis/genetics MH - Chlorocebus aethiops MH - Disks Large Homolog 4 Protein MH - Gene Expression Profiling/*methods MH - Intracellular Signaling Peptides and Proteins/*analysis/genetics MH - Membrane Proteins/*analysis/genetics MH - Nerve Tissue Proteins/analysis/genetics MH - Neurons/*chemistry/physiology MH - Recombinant Proteins/*analysis/genetics MH - Synapses/chemistry/physiology PMC - PMC3779638 MID - NIHMS512565 COIS- Conflict of interest statement. One of us (GCRE-D) has filed a preliminary patent declaration on the synthesis of dinitroindolinyl-caged neurotransmitters. EDAT- 2013/06/26 06:00 MHDA- 2013/08/31 06:00 CRDT- 2013/06/25 06:00 PHST- 2013/04/10 00:00 [accepted] PHST- 2013/06/25 06:00 [entrez] PHST- 2013/06/26 06:00 [pubmed] PHST- 2013/08/31 06:00 [medline] AID - S0896-6273(13)00319-X [pii] AID - 10.1016/j.neuron.2013.04.017 [doi] PST - ppublish SO - Neuron. 2013 Jun 19;78(6):971-85. doi: 10.1016/j.neuron.2013.04.017. PMID- 23664616 OWN - NLM STAT- MEDLINE DCOM- 20130709 LR - 20220309 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 78 IP - 3 DP - 2013 May 8 TI - Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. PG - 510-22 LID - S0896-6273(13)00264-X [pii] LID - 10.1016/j.neuron.2013.03.017 [doi] AB - Neural circuits are regulated by activity-dependent feedback systems that tightly control network excitability and which are thought to be crucial for proper brain development. Defects in the ability to establish and maintain network homeostasis may be central to the pathogenesis of neurodevelopmental disorders. Here, we examine the function of the tuberous sclerosis complex (TSC)-mTOR signaling pathway, a common target of mutations associated with epilepsy and autism spectrum disorder, in regulating activity-dependent processes in the mouse hippocampus. We find that the TSC-mTOR pathway is a central component of a positive feedback loop that promotes network activity by repressing inhibitory synapses onto excitatory neurons. In Tsc1 KO neurons, weakened inhibition caused by deregulated mTOR alters the balance of excitatory and inhibitory synaptic transmission, leading to hippocampal hyperexcitability. These findings identify the TSC-mTOR pathway as a regulator of neural network activity and have implications for the neurological dysfunction in disorders exhibiting deregulated mTOR signaling. CI - Copyright © 2013 Elsevier Inc. All rights reserved. FAU - Bateup, Helen S AU - Bateup HS AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. FAU - Johnson, Caroline A AU - Johnson CA FAU - Denefrio, Cassandra L AU - Denefrio CL FAU - Saulnier, Jessica L AU - Saulnier JL FAU - Kornacker, Karl AU - Kornacker K FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS052707/NS/NINDS NIH HHS/United States GR - NS052707/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Tsc1 protein, mouse) RN - 0 (Tuberous Sclerosis Complex 1 Protein) RN - 0 (Tumor Suppressor Proteins) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Disease Models, Animal MH - Hippocampus/metabolism/*physiopathology MH - Mice MH - Mice, Knockout MH - Nerve Net/metabolism/physiopathology MH - Signal Transduction/physiology MH - Synapses/*physiology MH - TOR Serine-Threonine Kinases/genetics/metabolism MH - Tuberous Sclerosis/genetics/metabolism/*physiopathology MH - Tuberous Sclerosis Complex 1 Protein MH - Tumor Suppressor Proteins/genetics/*metabolism PMC - PMC3690324 MID - NIHMS473737 EDAT- 2013/05/15 06:00 MHDA- 2013/07/10 06:00 CRDT- 2013/05/14 06:00 PHST- 2013/03/20 00:00 [accepted] PHST- 2013/05/14 06:00 [entrez] PHST- 2013/05/15 06:00 [pubmed] PHST- 2013/07/10 06:00 [medline] AID - S0896-6273(13)00264-X [pii] AID - 10.1016/j.neuron.2013.03.017 [doi] PST - ppublish SO - Neuron. 2013 May 8;78(3):510-22. doi: 10.1016/j.neuron.2013.03.017. PMID- 23577752 OWN - NLM STAT- MEDLINE DCOM- 20131107 LR - 20211021 IS - 1520-5126 (Electronic) IS - 0002-7863 (Print) IS - 0002-7863 (Linking) VI - 135 IP - 16 DP - 2013 Apr 24 TI - Optically selective two-photon uncaging of glutamate at 900 nm. PG - 5954-7 LID - 10.1021/ja4019379 [doi] AB - We have synthesized a 7-diethylaminocoumarin (DEAC) derivative that allows wavelength-selective two-photon uncaging at 900 nm versus 720 nm. This new caging chromophore, called DEAC450, has an extended π-electron moiety at the 3-position that shifts the absorption spectrum maximum of DEAC from 375 to 450 nm. Two-photon excitation at 900 nm was more than 60-fold greater than at 720 nm. Two-photon uncaging of DEAC450-Glu at 900 nm at spine heads on pyramidal neurons in acutely isolated brain slices generated postsynaptic responses that were similar to spontaneous postsynaptic excitatory miniature currents, whereas significantly higher energies at 720 nm evoked no currents. Since many nitroaromatic caged compounds are two-photon active at 720 nm, optically selective uncaging of DEAC450-caged biomolecules at 900 nm may allow facile two-color optical interrogation of bimodal signaling pathways in living tissue with high resolution for the first time. FAU - Olson, Jeremy P AU - Olson JP AD - Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA. FAU - Kwon, Hyung-Bae AU - Kwon HB FAU - Takasaki, Kevin T AU - Takasaki KT FAU - Chiu, Chiayu Q AU - Chiu CQ FAU - Higley, Michael J AU - Higley MJ FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Ellis-Davies, Graham C R AU - Ellis-Davies GC LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - MH099045/MH/NIMH NIH HHS/United States GR - NS069720/NS/NINDS NIH HHS/United States GR - R01 MH099045/MH/NIMH NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R01 NS069720/NS/NINDS NIH HHS/United States GR - GM053395/GM/NIGMS NIH HHS/United States GR - R01 GM053395/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20130411 PL - United States TA - J Am Chem Soc JT - Journal of the American Chemical Society JID - 7503056 RN - 0 (Coumarins) RN - 0 (Indicators and Reagents) RN - 3KX376GY7L (Glutamic Acid) SB - IM MH - Animals MH - Brain Chemistry MH - Coumarins/chemistry MH - Excitatory Postsynaptic Potentials/drug effects MH - Glutamic Acid/*chemistry MH - Hydrogen-Ion Concentration MH - In Vitro Techniques MH - Indicators and Reagents MH - Mice MH - Neuroimaging/*methods MH - Patch-Clamp Techniques MH - Photolysis MH - Pyramidal Cells/drug effects MH - Signal Transduction/drug effects/physiology MH - Spectrophotometry, Ultraviolet PMC - PMC4079120 MID - NIHMS467326 EDAT- 2013/04/13 06:00 MHDA- 2013/11/08 06:00 CRDT- 2013/04/13 06:00 PHST- 2013/04/13 06:00 [entrez] PHST- 2013/04/13 06:00 [pubmed] PHST- 2013/11/08 06:00 [medline] AID - 10.1021/ja4019379 [doi] PST - ppublish SO - J Am Chem Soc. 2013 Apr 24;135(16):5954-7. doi: 10.1021/ja4019379. Epub 2013 Apr 11. PMID- 23442955 OWN - NLM STAT- MEDLINE DCOM- 20130809 LR - 20211021 IS - 1542-0086 (Electronic) IS - 0006-3495 (Print) IS - 0006-3495 (Linking) VI - 104 IP - 4 DP - 2013 Feb 19 TI - Live-cell superresolution imaging by pulsed STED two-photon excitation microscopy. PG - 770-7 LID - S0006-3495(13)00073-8 [pii] LID - 10.1016/j.bpj.2012.12.053 [doi] AB - Two-photon laser scanning microscopy (2PLSM) allows fluorescence imaging in thick biological samples where absorption and scattering typically degrade resolution and signal collection of one-photon imaging approaches. The spatial resolution of conventional 2PLSM is limited by diffraction, and the near-infrared wavelengths used for excitation in 2PLSM preclude the accurate imaging of many small subcellular compartments of neurons. Stimulated emission depletion (STED) microscopy is a superresolution imaging modality that overcomes the resolution limit imposed by diffraction and allows fluorescence imaging of nanoscale features. Here, we describe the design and operation of a superresolution two-photon microscope using pulsed excitation and STED lasers. We examine the depth dependence of STED imaging in acute tissue slices and find enhancement of 2P resolution ranging from approximately fivefold at 20 μm to approximately twofold at 90-μm deep. The depth dependence of resolution is found to be consistent with the depth dependence of depletion efficiency, suggesting resolution is limited by STED laser propagation through turbid tissue. Finally, we achieve live imaging of dendritic spines with 60-nm resolution and demonstrate that our technique allows accurate quantification of neuronal morphology up to 30-μm deep in living brain tissue. CI - Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved. FAU - Takasaki, Kevin T AU - Takasaki KT AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA. FAU - Ding, Jun B AU - Ding JB FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - RC1NS068917/NS/NINDS NIH HHS/United States GR - R00 NS075136/NS/NINDS NIH HHS/United States GR - RC1 NS068917/NS/NINDS NIH HHS/United States GR - P30 HD018655/HD/NICHD NIH HHS/United States GR - T90 DA022759/DA/NIDA NIH HHS/United States GR - R90 DA023427/DA/NIDA NIH HHS/United States GR - R90DA023427/DA/NIDA NIH HHS/United States GR - T90DA022759/DA/NIDA NIH HHS/United States GR - T32 NS007484/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - United States TA - Biophys J JT - Biophysical journal JID - 0370626 SB - IM CIN - Biophys J. 2013 Feb 19;104(4):741-3. PMID: 23442950 MH - Animals MH - CA1 Region, Hippocampal/cytology MH - Dendritic Spines/*ultrastructure MH - Mice MH - Mice, Inbred C57BL MH - Microscopy, Confocal/methods MH - Microscopy, Fluorescence, Multiphoton/*methods MH - Nanospheres PMC - PMC3576532 EDAT- 2013/02/28 06:00 MHDA- 2013/08/10 06:00 CRDT- 2013/02/28 06:00 PHST- 2012/08/15 00:00 [received] PHST- 2012/11/20 00:00 [revised] PHST- 2012/12/17 00:00 [accepted] PHST- 2013/02/28 06:00 [entrez] PHST- 2013/02/28 06:00 [pubmed] PHST- 2013/08/10 06:00 [medline] AID - S0006-3495(13)00073-8 [pii] AID - BPJ4520 [pii] AID - 10.1016/j.bpj.2012.12.053 [doi] PST - ppublish SO - Biophys J. 2013 Feb 19;104(4):770-7. doi: 10.1016/j.bpj.2012.12.053. PMID- 23403489 OWN - NLM STAT- MEDLINE DCOM- 20140519 LR - 20211021 IS - 1662-5110 (Print) IS - 1662-5110 (Electronic) IS - 1662-5110 (Linking) VI - 7 DP - 2013 TI - Vesicular stomatitis virus with the rabies virus glycoprotein directs retrograde transsynaptic transport among neurons in vivo. PG - 11 LID - 10.3389/fncir.2013.00011 [doi] LID - 11 AB - Defining the connections among neurons is critical to our understanding of the structure and function of the nervous system. Recombinant viruses engineered to transmit across synapses provide a powerful approach for the dissection of neuronal circuitry in vivo. We recently demonstrated that recombinant vesicular stomatitis virus (VSV) can be endowed with anterograde or retrograde transsynaptic tracing ability by providing the virus with different glycoproteins. Here we extend the characterization of the transmission and gene expression of recombinant VSV (rVSV) with the rabies virus glycoprotein (RABV-G), and provide examples of its activity relative to the anterograde transsynaptic tracer form of rVSV. rVSV with RABV-G was found to drive strong expression of transgenes and to spread rapidly from neuron to neuron in only a retrograde manner. Depending upon how the RABV-G was delivered, VSV served as a polysynaptic or monosynaptic tracer, or was able to define projections through axonal uptake and retrograde transport. In animals co-infected with rVSV in its anterograde form, rVSV with RABV-G could be used to begin to characterize the similarities and differences in connections to different areas. rVSV with RABV-G provides a flexible, rapid, and versatile tracing tool that complements the previously described VSV-based anterograde transsynaptic tracer. FAU - Beier, Kevin T AU - Beier KT AD - Department of Genetics and Department of Ophthalmology, Harvard Medical School, Harvard University and Howard Hughes Medical Institute Boston, MA, USA. FAU - Saunders, Arpiar B AU - Saunders AB FAU - Oldenburg, Ian A AU - Oldenburg IA FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Cepko, Constance L AU - Cepko CL LA - eng GR - F31 MH093026/MH/NIMH NIH HHS/United States GR - F31 NS068012/NS/NINDS NIH HHS/United States GR - P30 HD018655/HD/NICHD NIH HHS/United States GR - T32 MH020017/MH/NIMH NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20130207 PL - Switzerland TA - Front Neural Circuits JT - Frontiers in neural circuits JID - 101477940 RN - 0 (G protein, vesicular stomatitis virus) RN - 0 (Membrane Glycoproteins) RN - 0 (Viral Envelope Proteins) SB - IM MH - Animals MH - Animals, Newborn MH - HEK293 Cells MH - Humans MH - Membrane Glycoproteins/*physiology MH - Mice MH - Neurons/*physiology/virology MH - Organ Culture Techniques MH - Protein Transport/physiology MH - Rabies virus/*physiology MH - Rats MH - Rats, Sprague-Dawley MH - Synapses/chemistry/*physiology/virology MH - Viral Envelope Proteins/*physiology PMC - PMC3566411 OTO - NOTNLM OT - in vivo OT - polysynaptic OT - rabies OT - retrograde transneuronal tracing OT - technology OT - transsynaptic infection OT - vesicular stomatitis virus EDAT- 2013/02/14 06:00 MHDA- 2013/02/14 06:01 CRDT- 2013/02/14 06:00 PHST- 2012/10/26 00:00 [received] PHST- 2013/01/20 00:00 [accepted] PHST- 2013/02/14 06:00 [entrez] PHST- 2013/02/14 06:00 [pubmed] PHST- 2013/02/14 06:01 [medline] AID - 10.3389/fncir.2013.00011 [doi] PST - epublish SO - Front Neural Circuits. 2013 Feb 7;7:11. doi: 10.3389/fncir.2013.00011. eCollection 2013. PMID- 23143522 OWN - NLM STAT- MEDLINE DCOM- 20130129 LR - 20211021 IS - 1546-1726 (Electronic) IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 15 IP - 12 DP - 2012 Dec TI - Neuroligin-1-dependent competition regulates cortical synaptogenesis and synapse number. PG - 1667-74 LID - 10.1038/nn.3256 [doi] AB - Members of the neuroligin family of cell-adhesion proteins are found at excitatory and inhibitory synapses and are mutated in some familial forms of autism spectrum disorders. Although they display synaptogenic properties in heterologous systems, the function of neuroligins in vivo in the regulation of synapse formation and synapse number has been difficult to establish. We found that neuroligin-1 (NL1), which is located at excitatory postsynaptic densities, regulates activity-dependent synaptogenesis and mature synapse number on cortical layer 2/3 pyramidal neurons in vivo. However, synapse number was not sensitive to absolute NL1 levels but instead depended on transcellular differences in the relative amounts of NL1. These effects were independent of the cell-autonomous regulation of NMDA-type glutamate receptors by absolute levels of NL1. Our data indicate that transcellular competitive processes govern synapse formation and number in developing cortex and that NL1 has a central function in these processes. FAU - Kwon, Hyung-Bae AU - Kwon HB AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. FAU - Kozorovitskiy, Yevgenia AU - Kozorovitskiy Y FAU - Oh, Won-Jong AU - Oh WJ FAU - Peixoto, Rui T AU - Peixoto RT FAU - Akhtar, Nazia AU - Akhtar N FAU - Saulnier, Jessica L AU - Saulnier JL FAU - Gu, Chenghua AU - Gu C FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R01 NS064583/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - R01NS064583/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20121111 PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 0 (Cell Adhesion Molecules, Neuronal) RN - 0 (neuroligin 1) SB - IM CIN - Nat Neurosci. 2012 Dec;15(12):1609-11. PMID: 23187691 MH - Animals MH - Cell Adhesion Molecules, Neuronal/*physiology MH - Cell Communication/physiology MH - Cell Count MH - Cells, Cultured MH - Cerebral Cortex/cytology/*embryology/*physiology MH - Coculture Techniques MH - Female MH - HEK293 Cells MH - Humans MH - Male MH - Mice MH - Mice, 129 Strain MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Neurogenesis/*physiology MH - Organ Culture Techniques MH - Pregnancy MH - Rats MH - Rats, Sprague-Dawley MH - Synapses/*physiology PMC - PMC3536444 MID - NIHMS414299 EDAT- 2012/11/13 06:00 MHDA- 2013/01/30 06:00 CRDT- 2012/11/13 06:00 PHST- 2012/09/10 00:00 [received] PHST- 2012/10/11 00:00 [accepted] PHST- 2012/11/13 06:00 [entrez] PHST- 2012/11/13 06:00 [pubmed] PHST- 2013/01/30 06:00 [medline] AID - nn.3256 [pii] AID - 10.1038/nn.3256 [doi] PST - ppublish SO - Nat Neurosci. 2012 Dec;15(12):1667-74. doi: 10.1038/nn.3256. Epub 2012 Nov 11. PMID- 23083741 OWN - NLM STAT- MEDLINE DCOM- 20130102 LR - 20231213 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 76 IP - 2 DP - 2012 Oct 18 TI - Transsynaptic signaling by activity-dependent cleavage of neuroligin-1. PG - 396-409 LID - S0896-6273(12)00655-1 [pii] LID - 10.1016/j.neuron.2012.07.006 [doi] AB - Adhesive contact between pre- and postsynaptic neurons initiates synapse formation during brain development and provides a natural means of transsynaptic signaling. Numerous adhesion molecules and their role during synapse development have been described in detail. However, once established, the mechanisms of adhesive disassembly and its function in regulating synaptic transmission have been unclear. Here, we report that synaptic activity induces acute proteolytic cleavage of neuroligin-1 (NLG1), a postsynaptic adhesion molecule at glutamatergic synapses. NLG1 cleavage is triggered by NMDA receptor activation, requires Ca2+ /calmodulin-dependent protein kinase, and is mediated by proteolytic activity of matrix metalloprotease 9 (MMP9). Cleavage of NLG1 occurs at single activated spines, is regulated by neural activity in vivo, and causes rapid destabilization of its presynaptic partner neurexin-1β (NRX1β). In turn, NLG1 cleavage depresses synaptic transmission by abruptly reducing presynaptic release probability. Thus, local proteolytic control of synaptic adhesion tunes synaptic transmission during brain development and plasticity. CI - Copyright © 2012 Elsevier Inc. All rights reserved. FAU - Peixoto, Rui T AU - Peixoto RT AD - Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA. FAU - Kunz, Portia A AU - Kunz PA FAU - Kwon, Hyungbae AU - Kwon H FAU - Mabb, Angela M AU - Mabb AM FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Philpot, Benjamin D AU - Philpot BD FAU - Ehlers, Michael D AU - Ehlers MD LA - eng GR - R01 MH064748/MH/NIMH NIH HHS/United States GR - R01 NS047574/NS/NINDS NIH HHS/United States GR - T32 HD040127/HD/NICHD NIH HHS/United States GR - T32HD040127/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20121017 PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Calcium-Binding Proteins) RN - 0 (Cell Adhesion Molecules, Neuronal) RN - 0 (Enzyme Inhibitors) RN - 0 (Excitatory Amino Acid Agents) RN - 0 (FM 4-64) RN - 0 (Luminescent Proteins) RN - 0 (Muscarinic Agonists) RN - 0 (Neural Cell Adhesion Molecules) RN - 0 (Nrxn1 protein, mouse) RN - 0 (Plant Lectins) RN - 0 (Pyridinium Compounds) RN - 0 (Quaternary Ammonium Compounds) RN - 0 (Vesicular Glutamate Transport Protein 1) RN - 0 (neuroligin 1) RN - 0 (tomato lectin) RN - 01MI4Q9DI3 (Pilocarpine) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 2ZD004190S (Threonine) RN - 3KX376GY7L (Glutamic Acid) RN - 660YQ98I10 (Potassium Chloride) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - EC 3.4.24.35 (Mmp9 protein, mouse) SB - IM EIN - Neuron. 2012 Nov 8;76(3):667 CIN - Nat Rev Neurosci. 2012 Dec;13(12):811. PMID: 23165251 MH - Animals MH - Animals, Newborn MH - Biotinylation MH - Calcium-Binding Proteins MH - Cell Adhesion Molecules, Neuronal/genetics/*metabolism MH - Cells, Cultured MH - Cerebral Cortex/cytology MH - Chlorocebus aethiops MH - Dark Adaptation/genetics MH - Dendrites/metabolism/ultrastructure MH - Disease Models, Animal MH - Electric Stimulation MH - Electroporation MH - Enzyme Inhibitors/pharmacology MH - Excitatory Amino Acid Agents/pharmacology MH - Excitatory Postsynaptic Potentials/drug effects/genetics MH - Female MH - Glutamic Acid/pharmacology MH - Green Fluorescent Proteins/genetics MH - Hippocampus/*cytology MH - Luminescent Proteins/genetics/metabolism MH - Matrix Metalloproteinase 9/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Microscopy, Confocal MH - Muscarinic Agonists/toxicity MH - Mutation/genetics MH - Neural Cell Adhesion Molecules/metabolism MH - Neurons/cytology/drug effects/*physiology MH - Organ Culture Techniques MH - Patch-Clamp Techniques MH - Photons MH - Pilocarpine/toxicity MH - Plant Lectins/genetics/metabolism MH - Potassium Chloride/pharmacology MH - Pregnancy MH - Pyridinium Compounds/metabolism MH - Quaternary Ammonium Compounds/metabolism MH - Signal Transduction/drug effects/genetics/*physiology MH - Status Epilepticus/chemically induced MH - Synaptic Transmission/drug effects/genetics/*physiology MH - Threonine/genetics/metabolism MH - Transfection MH - Vesicular Glutamate Transport Protein 1/metabolism MH - Red Fluorescent Protein PMC - PMC3783515 MID - NIHMS417818 EDAT- 2012/10/23 06:00 MHDA- 2013/01/03 06:00 CRDT- 2012/10/23 06:00 PHST- 2012/07/03 00:00 [accepted] PHST- 2012/10/23 06:00 [entrez] PHST- 2012/10/23 06:00 [pubmed] PHST- 2013/01/03 06:00 [medline] AID - S0896-6273(12)00655-1 [pii] AID - 10.1016/j.neuron.2012.07.006 [doi] PST - ppublish SO - Neuron. 2012 Oct 18;76(2):396-409. doi: 10.1016/j.neuron.2012.07.006. Epub 2012 Oct 17. PMID- 23034651 OWN - NLM STAT- MEDLINE DCOM- 20121106 LR - 20230701 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 490 IP - 7419 DP - 2012 Oct 11 TI - Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. PG - 262-6 LID - 10.1038/nature11466 [doi] AB - The substantia nigra pars compacta and ventral tegmental area contain the two largest populations of dopamine-releasing neurons in the mammalian brain. These neurons extend elaborate projections in the striatum, a large subcortical structure implicated in motor planning and reward-based learning. Phasic activation of dopaminergic neurons in response to salient or reward-predicting stimuli is thought to modulate striatal output through the release of dopamine to promote and reinforce motor action. Here we show that activation of dopamine neurons in striatal slices rapidly inhibits action potential firing in both direct- and indirect-pathway striatal projection neurons through vesicular release of the inhibitory transmitter GABA (γ-aminobutyric acid). GABA is released directly from dopaminergic axons but in a manner that is independent of the vesicular GABA transporter VGAT. Instead, GABA release requires activity of the vesicular monoamine transporter VMAT2, which is the vesicular transporter for dopamine. Furthermore, VMAT2 expression in GABAergic neurons lacking VGAT is sufficient to sustain GABA release. Thus, these findings expand the repertoire of synaptic mechanisms used by dopamine neurons to influence basal ganglia circuits, show a new substrate whose transport is dependent on VMAT2 and demonstrate that GABA can function as a bona fide co-transmitter in monoaminergic neurons. FAU - Tritsch, Nicolas X AU - Tritsch NX AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. FAU - Ding, Jun B AU - Ding JB FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - 4R00NS075136/NS/NINDS NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - R00 NS075136/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - T32 NS007484/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20121003 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (GABA Plasma Membrane Transport Proteins) RN - 0 (Slc18a2 protein, mouse) RN - 0 (Vesicular Monoamine Transport Proteins) RN - 56-12-2 (gamma-Aminobutyric Acid) SB - IM CIN - Nature. 2012 Oct 11;490(7419):178-9. PMID: 23060181 CIN - Nat Rev Neurosci. 2012 Dec;13(12):815. PMID: 23095838 MH - Animals MH - Corpus Striatum/cytology/*metabolism MH - Dopaminergic Neurons/*metabolism MH - GABA Plasma Membrane Transport Proteins/*metabolism MH - Gene Expression Profiling MH - Gene Expression Regulation MH - Gene Knock-In Techniques MH - Mice MH - Mice, Transgenic MH - Vesicular Monoamine Transport Proteins/metabolism MH - gamma-Aminobutyric Acid/*metabolism PMC - PMC3944587 MID - NIHMS397093 EDAT- 2012/10/05 06:00 MHDA- 2012/11/07 06:00 CRDT- 2012/10/05 06:00 PHST- 2012/05/15 00:00 [received] PHST- 2012/07/27 00:00 [accepted] PHST- 2012/10/05 06:00 [entrez] PHST- 2012/10/05 06:00 [pubmed] PHST- 2012/11/07 06:00 [medline] AID - nature11466 [pii] AID - 10.1038/nature11466 [doi] PST - ppublish SO - Nature. 2012 Oct 11;490(7419):262-6. doi: 10.1038/nature11466. Epub 2012 Oct 3. PMID- 23040805 OWN - NLM STAT- MEDLINE DCOM- 20121210 LR - 20230708 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 76 IP - 1 DP - 2012 Oct 4 TI - Dopaminergic modulation of synaptic transmission in cortex and striatum. PG - 33-50 LID - S0896-6273(12)00858-6 [pii] LID - 10.1016/j.neuron.2012.09.023 [doi] AB - Among the many neuromodulators used by the mammalian brain to regulate circuit function and plasticity, dopamine (DA) stands out as one of the most behaviorally powerful. Perturbations of DA signaling are implicated in the pathogenesis or exploited in the treatment of many neuropsychiatric diseases, including Parkinson's disease (PD), addiction, schizophrenia, obsessive compulsive disorder, and Tourette's syndrome. Although the precise mechanisms employed by DA to exert its control over behavior are not fully understood, DA is known to regulate many electrical and biochemical aspects of neuronal function including excitability, synaptic transmission, integration and plasticity, protein trafficking, and gene transcription. In this Review, we discuss the actions of DA on ionic and synaptic signaling in neurons of the prefrontal cortex and striatum, brain areas in which dopaminergic dysfunction is thought to be central to disease. CI - Copyright © 2012 Elsevier Inc. All rights reserved. FAU - Tritsch, Nicolas X AU - Tritsch NX AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - VTD58H1Z2X (Dopamine) SB - IM CIN - Mov Disord. 2013 Aug;28(9):1211. PMID: 23925922 MH - Animals MH - Brain/*physiology MH - Dopamine/*metabolism MH - Humans MH - Neurons/*metabolism MH - Synaptic Transmission/*physiology PMC - PMC4386589 MID - NIHMS478968 EDAT- 2012/10/09 06:00 MHDA- 2012/12/12 06:00 CRDT- 2012/10/09 06:00 PHST- 2012/10/09 06:00 [entrez] PHST- 2012/10/09 06:00 [pubmed] PHST- 2012/12/12 06:00 [medline] AID - S0896-6273(12)00858-6 [pii] AID - 10.1016/j.neuron.2012.09.023 [doi] PST - ppublish SO - Neuron. 2012 Oct 4;76(1):33-50. doi: 10.1016/j.neuron.2012.09.023. PMID- 22998875 OWN - NLM STAT- MEDLINE DCOM- 20121203 LR - 20220309 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 75 IP - 6 DP - 2012 Sep 20 TI - Transient sodium current at subthreshold voltages: activation by EPSP waveforms. PG - 1081-93 LID - S0896-6273(12)00770-2 [pii] LID - 10.1016/j.neuron.2012.08.033 [doi] AB - Tetrodotoxin (TTX)-sensitive sodium channels carry large transient currents during action potentials and also "persistent" sodium current, a noninactivating TTX-sensitive current present at subthreshold voltages. We examined gating of subthreshold sodium current in dissociated cerebellar Purkinje neurons and hippocampal CA1 neurons, studied at 37°C with near-physiological ionic conditions. Unexpectedly, in both cell types small voltage steps at subthreshold voltages activated a substantial component of transient sodium current as well as persistent current. Subthreshold EPSP-like waveforms also activated a large component of transient sodium current, but IPSP-like waveforms engaged primarily persistent sodium current with only a small additional transient component. Activation of transient as well as persistent sodium current at subthreshold voltages produces amplification of EPSPs that is sensitive to the rate of depolarization and can help account for the dependence of spike threshold on depolarization rate, as previously observed in vivo. CI - Copyright © 2012 Elsevier Inc. All rights reserved. FAU - Carter, Brett C AU - Carter BC AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Giessel, Andrew J AU - Giessel AJ FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Bean, Bruce P AU - Bean BP LA - eng GR - F31 NS065647/NS/NINDS NIH HHS/United States GR - F31 NS064630/NS/NINDS NIH HHS/United States GR - F31-NS065647/NS/NINDS NIH HHS/United States GR - R01 NS036855/NS/NINDS NIH HHS/United States GR - R01-NS036855/NS/NINDS NIH HHS/United States GR - F31-NS064630/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R01-NS046579/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Sodium Channel Blockers) RN - 0 (Sodium Channels) RN - 3KX376GY7L (Glutamic Acid) RN - 4368-28-9 (Tetrodotoxin) SB - IM EIN - Neuron. 2015 Aug 19;87(4):906 MH - Animals MH - Animals, Newborn MH - Biophysical Phenomena/drug effects/*physiology MH - Cerebellum/cytology MH - Electric Stimulation MH - Excitatory Postsynaptic Potentials/drug effects/*physiology MH - Glutamic Acid/pharmacology MH - Hippocampus/cytology MH - In Vitro Techniques MH - Markov Chains MH - Mice MH - Mice, Inbred C57BL MH - Models, Neurological MH - Neurons/drug effects/*physiology MH - Patch-Clamp Techniques MH - Sodium Channel Blockers/pharmacology MH - Sodium Channels/drug effects/*metabolism MH - Tetrodotoxin/pharmacology PMC - PMC3460524 MID - NIHMS404557 EDAT- 2012/09/25 06:00 MHDA- 2012/12/10 06:00 CRDT- 2012/09/25 06:00 PHST- 2012/08/21 00:00 [accepted] PHST- 2012/09/25 06:00 [entrez] PHST- 2012/09/25 06:00 [pubmed] PHST- 2012/12/10 06:00 [medline] AID - S0896-6273(12)00770-2 [pii] AID - 10.1016/j.neuron.2012.08.033 [doi] PST - ppublish SO - Neuron. 2012 Sep 20;75(6):1081-93. doi: 10.1016/j.neuron.2012.08.033. PMID- 22866029 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20121002 LR - 20211021 IS - 1662-5110 (Electronic) IS - 1662-5110 (Linking) VI - 6 DP - 2012 TI - Novel recombinant adeno-associated viruses for Cre activated and inactivated transgene expression in neurons. PG - 47 LID - 10.3389/fncir.2012.00047 [doi] LID - 47 AB - Understanding the organization of the nervous system requires methods for dissecting the contributions of each component cell type to circuit function. One widely used approach combines genetic targeting of Cre recombinase to specific cell populations with infection of recombinant adeno-associated viruses (rAAVs) whose transgene expression is activated by Cre ("Cre-On"). Distinguishing how the Cre-expressing neurons differ functionally from neighboring Cre-negative neurons requires rAAVs that are inactivated by Cre ("Cre-Off") and can be used in tandem with Cre-On viruses. Here we introduce two rAAV vectors that are inactivated by Cre and carry different fluorophore and optogenetic constructs. We demonstrate single and dual rAAV systems to achieve Cre-On and Cre-Off expression in spatially-intermingled cell populations of the striatum. Using these systems, we uncovered cryptic genomic interactions that occur between multiple Cre-sensitive rAAVs or between Cre-sensitive rAAVs and somatic Cre-conditional alleles and devised methods to avoid these interactions. Our data highlight both important experimental caveats associated with Cre-dependent rAAV use as well as opportunities for the development of improved rAAVs for gene delivery. FAU - Saunders, Arpiar AU - Saunders A AD - Department of Neurobiology, Harvard Medical School, Howard Hughes Medical Institute Boston, MA, USA. FAU - Johnson, Caroline A AU - Johnson CA FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - F31 NS074842/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20120727 PL - Switzerland TA - Front Neural Circuits JT - Frontiers in neural circuits JID - 101477940 PMC - PMC3406316 OTO - NOTNLM OT - Cre recombinase OT - circuits OT - optogenetics OT - tracing OT - transgenic OT - viruses EDAT- 2012/08/07 06:00 MHDA- 2012/08/07 06:01 CRDT- 2012/08/07 06:00 PHST- 2012/06/06 00:00 [received] PHST- 2012/07/06 00:00 [accepted] PHST- 2012/08/07 06:00 [entrez] PHST- 2012/08/07 06:00 [pubmed] PHST- 2012/08/07 06:01 [medline] AID - 10.3389/fncir.2012.00047 [doi] PST - epublish SO - Front Neural Circuits. 2012 Jul 27;6:47. doi: 10.3389/fncir.2012.00047. eCollection 2012. PMID- 22459689 OWN - NLM STAT- MEDLINE DCOM- 20121119 LR - 20211021 IS - 1873-6882 (Electronic) IS - 0959-4388 (Print) IS - 0959-4388 (Linking) VI - 22 IP - 3 DP - 2012 Jun TI - Signaling in dendritic spines and spine microdomains. PG - 389-96 LID - 10.1016/j.conb.2012.03.003 [doi] AB - The specialized morphology of dendritic spines creates an isolated compartment that allows for localized biochemical signaling. Recent studies have revealed complexity in the function of the spine head as a signaling domain and indicate that (1) the spine is functionally subdivided into multiple independent microdomains and (2) not all biochemical signals are equally compartmentalized within the spine. Here we review these findings as well as the developments in fluorescence microscopy that are making possible direct monitoring of signaling within spines and, in the future, within sub-spine microdomains. CI - Copyright © 2012 Elsevier Ltd. All rights reserved. FAU - Chen, Yao AU - Chen Y AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, United States. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R01 NS046579-09/NS/NINDS NIH HHS/United States GR - T32 NS007484/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20120327 PL - England TA - Curr Opin Neurobiol JT - Current opinion in neurobiology JID - 9111376 SB - IM MH - Animals MH - Dendritic Spines/*physiology/*ultrastructure MH - Membrane Microdomains/*physiology/ultrastructure MH - Models, Biological MH - Signal Transduction/*physiology MH - Synapses/classification/physiology/ultrastructure PMC - PMC3391315 MID - NIHMS366854 EDAT- 2012/03/31 06:00 MHDA- 2012/12/10 06:00 CRDT- 2012/03/31 06:00 PHST- 2011/12/13 00:00 [received] PHST- 2012/03/05 00:00 [revised] PHST- 2012/03/05 00:00 [accepted] PHST- 2012/03/31 06:00 [entrez] PHST- 2012/03/31 06:00 [pubmed] PHST- 2012/12/10 06:00 [medline] AID - S0959-4388(12)00041-4 [pii] AID - 10.1016/j.conb.2012.03.003 [doi] PST - ppublish SO - Curr Opin Neurobiol. 2012 Jun;22(3):389-96. doi: 10.1016/j.conb.2012.03.003. Epub 2012 Mar 27. PMID- 22660328 OWN - NLM STAT- MEDLINE DCOM- 20120712 LR - 20220309 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 485 IP - 7400 DP - 2012 May 13 TI - Recurrent network activity drives striatal synaptogenesis. PG - 646-50 LID - 10.1038/nature11052 [doi] AB - Neural activity during development critically shapes postnatal wiring of the mammalian brain. This is best illustrated by the sensory systems, in which the patterned feed-forward excitation provided by sensory organs and experience drives the formation of mature topographic circuits capable of extracting specific features of sensory stimuli. In contrast, little is known about the role of early activity in the development of the basal ganglia, a phylogenetically ancient group of nuclei fundamentally important for complex motor action and reward-based learning. These nuclei lack direct sensory input and are only loosely topographically organized, forming interlocking feed-forward and feed-back inhibitory circuits without laminar structure. Here we use transgenic mice and viral gene transfer methods to modulate neurotransmitter release and neuronal activity in vivo in the developing striatum. We find that the balance of activity between the two inhibitory and antagonist pathways in the striatum regulates excitatory innervation of the basal ganglia during development. These effects indicate that the propagation of activity through a multi-stage network regulates the wiring of the basal ganglia, revealing an important role of positive feedback in driving network maturation. FAU - Kozorovitskiy, Yevgenia AU - Kozorovitskiy Y AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, USA. FAU - Saunders, Arpiar AU - Saunders A FAU - Johnson, Caroline A AU - Johnson CA FAU - Lowell, Bradford B AU - Lowell BB FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 DK089044/DK/NIDDK NIH HHS/United States GR - F31 NS074842-02/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - R01 NS046579-09/NS/NINDS NIH HHS/United States GR - T32 MH020017/MH/NIMH NIH HHS/United States GR - F31 NS074842/NS/NINDS NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20120513 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Vesicular Inhibitory Amino Acid Transport Proteins) RN - 0 (Viaat protein, mouse) RN - 56-12-2 (gamma-Aminobutyric Acid) SB - IM EIN - Nature. 2012 Sep 13;489(7415):326 MH - Animals MH - Basal Ganglia/cytology/*embryology/*physiology MH - Cerebral Cortex/cytology/physiology MH - Feedback, Physiological MH - Female MH - Male MH - Mice MH - Mice, Transgenic MH - Models, Neurological MH - Neostriatum/cytology/*embryology/*physiology MH - Neural Inhibition MH - Neural Pathways/*physiology MH - Synapses/*metabolism MH - Thalamus/cytology/physiology MH - Vesicular Inhibitory Amino Acid Transport Proteins/deficiency/genetics/metabolism MH - gamma-Aminobutyric Acid/metabolism PMC - PMC3367801 MID - NIHMS365353 EDAT- 2012/06/05 06:00 MHDA- 2012/07/13 06:00 CRDT- 2012/06/05 06:00 PHST- 2012/01/31 00:00 [received] PHST- 2012/03/20 00:00 [accepted] PHST- 2012/06/05 06:00 [entrez] PHST- 2012/06/05 06:00 [pubmed] PHST- 2012/07/13 06:00 [medline] AID - nature11052 [pii] AID - 10.1038/nature11052 [doi] PST - epublish SO - Nature. 2012 May 13;485(7400):646-50. doi: 10.1038/nature11052. PMID- 22491782 OWN - NLM STAT- MEDLINE DCOM- 20120820 LR - 20220309 IS - 1943-0264 (Electronic) IS - 1943-0264 (Linking) VI - 4 IP - 5 DP - 2012 May 1 TI - Synapses and Alzheimer's disease. LID - 10.1101/cshperspect.a005777 [doi] LID - a005777 AB - Alzheimer's disease (AD) is a major cause of dementia in the elderly. Pathologically, AD is characterized by the accumulation of insoluble aggregates of Aβ-peptides that are proteolytic cleavage products of the amyloid-β precursor protein ("plaques") and by insoluble filaments composed of hyperphosphorylated tau protein ("tangles"). Familial forms of AD often display increased production of Aβ peptides and/or altered activity of presenilins, the catalytic subunits of γ-secretase that produce Aβ peptides. Although the pathogenesis of AD remains unclear, recent studies have highlighted two major themes that are likely important. First, oligomeric Aβ species have strong detrimental effects on synapse function and structure, particularly on the postsynaptic side. Second, decreased presenilin function impairs synaptic transmission and promotes neurodegeneration. The mechanisms underlying these processes are beginning to be elucidated, and, although their relevance to AD remains debated, understanding these processes will likely allow new therapeutic avenues to AD. FAU - Sheng, Morgan AU - Sheng M AD - Department of Neuroscience, Genentech Inc., South San Francisco, California 94080, USA. sheng.morgan@gene.com FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Südhof, Thomas C AU - Südhof TC LA - eng GR - RC2 AG036614/AG/NIA NIH HHS/United States GR - R01 NS040057/NS/NINDS NIH HHS/United States GR - RC2AG036614/AG/NIA NIH HHS/United States GR - R01 NS077906/NS/NINDS NIH HHS/United States GR - P01AG0107701/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review DEP - 20120501 PL - United States TA - Cold Spring Harb Perspect Biol JT - Cold Spring Harbor perspectives in biology JID - 101513680 RN - 0 (Amyloid beta-Peptides) RN - 0 (Presenilins) RN - 0 (tau Proteins) SB - IM MH - Alzheimer Disease/pathology/*physiopathology MH - Amyloid beta-Peptides/*metabolism/toxicity MH - Gene Transfer Techniques/trends MH - Humans MH - *Models, Biological MH - Presenilins/*deficiency MH - Synapses/*pathology/physiology MH - Synaptic Transmission/*physiology MH - tau Proteins/*metabolism PMC - PMC3331702 MID - NIHMS464311 EDAT- 2012/04/12 06:00 MHDA- 2012/08/21 06:00 CRDT- 2012/04/12 06:00 PHST- 2012/04/12 06:00 [entrez] PHST- 2012/04/12 06:00 [pubmed] PHST- 2012/08/21 06:00 [medline] AID - cshperspect.a005777 [pii] AID - a005777 [pii] AID - 10.1101/cshperspect.a005777 [doi] PST - epublish SO - Cold Spring Harb Perspect Biol. 2012 May 1;4(5):a005777. doi: 10.1101/cshperspect.a005777. PMID- 22338091 OWN - NLM STAT- MEDLINE DCOM- 20120726 LR - 20211021 IS - 1943-0264 (Electronic) IS - 1943-0264 (Linking) VI - 4 IP - 4 DP - 2012 Apr 1 TI - Calcium signaling in dendritic spines. PG - a005686 LID - 10.1101/cshperspect.a005686 [doi] LID - a005686 AB - Calcium (Ca(2+)) is a ubiquitous signaling molecule that accumulates in the cytoplasm in response to diverse classes of stimuli and, in turn, regulates many aspects of cell function. In neurons, Ca(2+) influx in response to action potentials or synaptic stimulation triggers neurotransmitter release, modulates ion channels, induces synaptic plasticity, and activates transcription. In this article, we discuss the factors that regulate Ca(2+) signaling in mammalian neurons with a particular focus on Ca(2+) signaling within dendritic spines. This includes consideration of the routes of entry and exit of Ca(2+), the cellular mechanisms that establish the temporal and spatial profile of Ca(2+) signaling, and the biophysical criteria that determine which downstream signals are activated when Ca(2+) accumulates in a spine. Furthermore, we also briefly discuss the technical advances that made possible the quantitative study of Ca(2+) signaling in dendritic spines. FAU - Higley, Michael J AU - Higley MJ AD - Department of Neurobiology, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale School of Medicine, New Haven, Connecticut 06520, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20120401 PL - United States TA - Cold Spring Harb Perspect Biol JT - Cold Spring Harbor perspectives in biology JID - 101513680 SB - IM MH - Action Potentials MH - Animals MH - *Calcium Signaling MH - Dendritic Spines/*metabolism MH - Mammals MH - Neuronal Plasticity PMC - PMC3312680 EDAT- 2012/02/18 06:00 MHDA- 2012/07/27 06:00 CRDT- 2012/02/17 06:00 PHST- 2012/02/17 06:00 [entrez] PHST- 2012/02/18 06:00 [pubmed] PHST- 2012/07/27 06:00 [medline] AID - cshperspect.a005686 [pii] AID - a005686 [pii] AID - 10.1101/cshperspect.a005686 [doi] PST - epublish SO - Cold Spring Harb Perspect Biol. 2012 Apr 1;4(4):a005686. doi: 10.1101/cshperspect.a005686. PMID- 22325203 OWN - NLM STAT- MEDLINE DCOM- 20120405 LR - 20230605 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 73 IP - 3 DP - 2012 Feb 9 TI - Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. PG - 511-22 LID - 10.1016/j.neuron.2011.11.027 [doi] AB - AgRP neuron activity drives feeding and weight gain whereas that of nearby POMC neurons does the opposite. However, the role of excitatory glutamatergic input in controlling these neurons is unknown. To address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC neurons. Deletion of NMDARs from AgRP neurons markedly reduced weight, body fat and food intake whereas deletion from POMC neurons had no effect. Activation of AgRP neurons by fasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs, depolarization and firing rates, required NMDARs. Furthermore, AgRP but not POMC neurons have dendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleled by an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis. Thus glutamatergic synaptic transmission and its modulation by NMDARs play key roles in controlling AgRP neurons and determining the cellular and behavioral response to fasting. CI - Copyright © 2012 Elsevier Inc. All rights reserved. FAU - Liu, Tiemin AU - Liu T AD - Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA. FAU - Kong, Dong AU - Kong D FAU - Shah, Bhavik P AU - Shah BP FAU - Ye, Chianping AU - Ye C FAU - Koda, Shuichi AU - Koda S FAU - Saunders, Arpiar AU - Saunders A FAU - Ding, Jun B AU - Ding JB FAU - Yang, Zongfang AU - Yang Z FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Lowell, Bradford B AU - Lowell BB LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - R01 DK089044/DK/NIDDK NIH HHS/United States GR - K99 NS075136/NS/NINDS NIH HHS/United States GR - R01 DK089044-03/DK/NIDDK NIH HHS/United States GR - R01 DK075632-07/DK/NIDDK NIH HHS/United States GR - P30 DK057521/DK/NIDDK NIH HHS/United States GR - P30 DK046200-20/DK/NIDDK NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States GR - R01 DK096010/DK/NIDDK NIH HHS/United States GR - F31 NS074842-02/NS/NINDS NIH HHS/United States GR - R01 DK071051-08/DK/NIDDK NIH HHS/United States GR - R37 DK053477/DK/NIDDK NIH HHS/United States GR - R01 DK071051/DK/NIDDK NIH HHS/United States GR - R01 NS046579-09/NS/NINDS NIH HHS/United States GR - P30 DK046200/DK/NIDDK NIH HHS/United States GR - R37 DK053477-16/DK/NIDDK NIH HHS/United States GR - K99 NS075136-02/NS/NINDS NIH HHS/United States GR - R01 DK075632/DK/NIDDK NIH HHS/United States GR - F31 NS074842/NS/NINDS NIH HHS/United States GR - P30 DK057521-13/DK/NIDDK NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - T32 NS007484/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Agouti-Related Protein) RN - 0 (Agrp protein, mouse) RN - 0 (Carrier Proteins) RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (GABA Antagonists) RN - 0 (Gprin1 protein, mouse) RN - 0 (Nerve Tissue Proteins) RN - 0 (Neuropeptide Y) RN - 0 (Proto-Oncogene Proteins c-fos) RN - 0 (RNA, Messenger) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 124-87-8 (Picrotoxin) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 66796-54-1 (Pro-Opiomelanocortin) RN - 6OTE87SCCW (6-Cyano-7-nitroquinoxaline-2,3-dione) RN - 76726-92-6 (2-Amino-5-phosphonovalerate) SB - IM CIN - Cell Metab. 2012 Mar 7;15(3):275-6. PMID: 22342702 MH - 2-Amino-5-phosphonovalerate/pharmacology MH - 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology MH - Age Factors MH - Agouti-Related Protein/deficiency/*metabolism MH - Animals MH - Body Composition/drug effects/genetics MH - Brain/cytology MH - Carrier Proteins/genetics MH - Dendritic Spines/drug effects/*physiology MH - Eating/drug effects/physiology MH - Energy Metabolism/drug effects/genetics MH - Excitatory Amino Acid Antagonists/pharmacology MH - Excitatory Postsynaptic Potentials/drug effects/genetics MH - *Fasting MH - Female MH - GABA Antagonists/pharmacology MH - Gene Expression Regulation/drug effects/genetics MH - Green Fluorescent Proteins/genetics MH - In Vitro Techniques MH - Male MH - Membrane Potentials/drug effects/genetics MH - Mice MH - Mice, Transgenic MH - Nerve Tissue Proteins/deficiency/genetics MH - Neurons/*cytology/drug effects MH - Neuropeptide Y/genetics MH - Patch-Clamp Techniques MH - Picrotoxin/pharmacology MH - Pro-Opiomelanocortin/genetics MH - Proto-Oncogene Proteins c-fos/metabolism MH - RNA, Messenger MH - Receptors, N-Methyl-D-Aspartate/deficiency MH - Time Factors PMC - PMC3278709 MID - NIHMS349096 EDAT- 2012/02/14 06:00 MHDA- 2012/04/06 06:00 CRDT- 2012/02/14 06:00 PHST- 2011/11/22 00:00 [accepted] PHST- 2012/02/14 06:00 [entrez] PHST- 2012/02/14 06:00 [pubmed] PHST- 2012/04/06 06:00 [medline] AID - S0896-6273(12)00031-1 [pii] AID - 10.1016/j.neuron.2011.11.027 [doi] PST - ppublish SO - Neuron. 2012 Feb 9;73(3):511-22. doi: 10.1016/j.neuron.2011.11.027. PMID- 22051692 OWN - NLM STAT- MEDLINE DCOM- 20120622 LR - 20211020 IS - 1873-6882 (Electronic) IS - 0959-4388 (Linking) VI - 22 IP - 1 DP - 2012 Feb TI - Optical super-resolution microscopy in neurobiology. PG - 86-93 LID - 10.1016/j.conb.2011.10.014 [doi] AB - Understanding the highly plastic nature of neurons requires the dynamic visualization of their molecular and cellular organization in a native context. However, due to the limited resolution of standard light microscopy, many of the structural specializations of neurons cannot be resolved. A recent revolution in light microscopy has given rise to several super-resolution light microscopy methods yielding 2-10-fold higher resolution than conventional microscopy. We here describe the principles behind these techniques as well as their application to the analysis of the molecular architecture of the synapse. Furthermore, we discuss the potential for continued development of super-resolution microscopy as necessary for live imaging of neuronal structure and function in the brain. CI - Copyright © 2011 Elsevier Ltd. All rights reserved. FAU - Sigrist, Stephan J AU - Sigrist SJ AD - Cluster of Excellence NeuroCure, Institute for Biology, Freie Universität Berlin, Germany. stephan.sigrist@fu-berlin.de FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - RC1 NS068917/NS/NINDS NIH HHS/United States GR - RC1 NS068917-01/NS/NINDS NIH HHS/United States PT - Journal Article PT - Review DEP - 20111101 PL - England TA - Curr Opin Neurobiol JT - Current opinion in neurobiology JID - 9111376 SB - IM MH - Animals MH - Brain/*physiology MH - Diagnostic Imaging/*methods MH - Humans MH - Microscopy/*methods MH - Neurons/*physiology MH - Neurosciences/*methods MH - Optics and Photonics/methods EDAT- 2011/11/05 06:00 MHDA- 2012/06/23 06:00 CRDT- 2011/11/05 06:00 PHST- 2011/07/21 00:00 [received] PHST- 2011/08/30 00:00 [revised] PHST- 2011/10/12 00:00 [accepted] PHST- 2011/11/05 06:00 [entrez] PHST- 2011/11/05 06:00 [pubmed] PHST- 2012/06/23 06:00 [medline] AID - S0959-4388(11)00180-2 [pii] AID - 10.1016/j.conb.2011.10.014 [doi] PST - ppublish SO - Curr Opin Neurobiol. 2012 Feb;22(1):86-93. doi: 10.1016/j.conb.2011.10.014. Epub 2011 Nov 1. PMID- 22284180 OWN - NLM STAT- MEDLINE DCOM- 20120719 LR - 20211021 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 73 IP - 2 DP - 2012 Jan 26 TI - Photoactivatable neuropeptides for spatiotemporally precise delivery of opioids in neural tissue. PG - 249-59 LID - 10.1016/j.neuron.2011.11.016 [doi] AB - Neuropeptides activate G protein-coupled receptors to acutely modulate cellular excitability and synaptic transmission. However, due to the lack of reagents for precise delivery of peptides within dense brain tissue, the spatiotemporal scale over which neuropeptides act is unknown. To achieve rapid and spatially delimited delivery of neuropeptides in mammalian brain tissue, we developed photoactivatable analogs of two opioids: [Leu⁵]-enkephalin (LE) and the 8 amino acid form of Dynorphin A (Dyn-8). These peptides are functionally inactive prior to photolysis, and exposure to ultraviolet (UV) light causes clean release of LE and Dyn-8. Recordings from acute slices of rat locus coeruleus (LC) demonstrated that photorelease of LE activates mu opioid receptor-coupled K+ channels with kinetics that approach the limits imposed by G protein-mediated signaling. Temporally precise and spatially delimited photorelease revealed the kinetics and ionic nature of the mu opioid response and the mechanisms that determine the spatial profile of enkephalinergic volume transmission in LC. CI - Copyright © 2012 Elsevier Inc. All rights reserved. FAU - Banghart, Matthew R AU - Banghart MR AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 MH085498/MH/NIMH NIH HHS/United States GR - R01 MH085498-04/MH/NIMH NIH HHS/United States GR - MH085498/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Analgesics, Opioid) RN - 0 (Enkephalins) RN - 0 (Neuropeptides) RN - 0 (Receptors, Opioid, mu) RN - 74913-18-1 (Dynorphins) SB - IM MH - Analgesics, Opioid/metabolism/*pharmacology MH - Animals MH - Dynorphins/metabolism/*pharmacology MH - Enkephalins/metabolism/*pharmacology MH - Neurons/metabolism MH - Neuropeptides/metabolism/*pharmacology MH - Rats MH - Receptors, Opioid, mu/metabolism MH - Ultraviolet Rays PMC - PMC3282187 MID - NIHMS353783 EDAT- 2012/01/31 06:00 MHDA- 2012/07/20 06:00 CRDT- 2012/01/31 06:00 PHST- 2011/11/08 00:00 [accepted] PHST- 2012/01/31 06:00 [entrez] PHST- 2012/01/31 06:00 [pubmed] PHST- 2012/07/20 06:00 [medline] AID - S0896-6273(11)01089-0 [pii] AID - 10.1016/j.neuron.2011.11.016 [doi] PST - ppublish SO - Neuron. 2012 Jan 26;73(2):249-59. doi: 10.1016/j.neuron.2011.11.016. PMID- 22179111 OWN - NLM STAT- MEDLINE DCOM- 20120319 LR - 20230605 IS - 1546-1726 (Electronic) IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 15 IP - 2 DP - 2011 Dec 18 TI - Semaphorin 3E-Plexin-D1 signaling controls pathway-specific synapse formation in the striatum. PG - 215-23 LID - 10.1038/nn.3003 [doi] AB - The proper formation of synaptic connectivity in the mammalian brain is critical for complex behavior. In the striatum, balanced excitatory synaptic transmission from multiple sources onto two classes of principal neurons is required for coordinated and voluntary motor control. Here we show that the interaction between the secreted semaphorin 3E (Sema3E) and its receptor Plexin-D1 is a critical determinant of synaptic specificity in cortico-thalamo-striatal circuits in mice. We find that Sema3e (encoding Sema3E) is highly expressed in thalamostriatal projection neurons, whereas in the striatum Plxnd1 (encoding Plexin-D1) is selectively expressed in direct-pathway medium spiny neurons (MSNs). Despite physical intermingling of the MSNs, genetic ablation of Plxnd1 or Sema3e results in functional and anatomical rearrangement of thalamostriatal synapses specifically in direct-pathway MSNs without effects on corticostriatal synapses. Thus, our results demonstrate that Sema3E and Plexin-D1 specify the degree of glutamatergic connectivity between a specific source and target in the complex circuitry of the basal ganglia. FAU - Ding, Jun B AU - Ding JB AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. FAU - Oh, Won-Jong AU - Oh WJ FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Gu, Chenghua AU - Gu C LA - eng GR - K99 NS075136-01/NS/NINDS NIH HHS/United States GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - K99 NS075136/NS/NINDS NIH HHS/United States GR - R01 NS046579-09/NS/NINDS NIH HHS/United States GR - K99-NS075136/NS/NINDS NIH HHS/United States GR - R00 NS075136/NS/NINDS NIH HHS/United States GR - NS064583/NS/NINDS NIH HHS/United States GR - R01 NS064583-03/NS/NINDS NIH HHS/United States GR - R01 NS064583/NS/NINDS NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - T32 NS007484/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20111218 PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 0 (Cell Adhesion Molecules, Neuronal) RN - 0 (Channelrhodopsins) RN - 0 (Cytoskeletal Proteins) RN - 0 (Glycoproteins) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Luminescent Proteins) RN - 0 (Membrane Glycoproteins) RN - 0 (Membrane Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (Plxnd1 protein, mouse) RN - 0 (Receptors, AMPA) RN - 0 (Receptors, Dopamine D1) RN - 0 (Receptors, Dopamine D2) RN - 0 (Sema3e protein, mouse) RN - 0 (Semaphorins) RN - 0 (Slc17a6 protein, mouse) RN - 0 (Vesicular Glutamate Transport Protein 2) RN - 0 (dopamine D1A receptor) RN - TFZ3H25BS1 (glutamate receptor ionotropic, AMPA 1) SB - IM MH - Animals MH - Animals, Newborn MH - Biophysics MH - Brain/cytology/metabolism MH - Cell Adhesion Molecules, Neuronal/deficiency/*metabolism MH - Channelrhodopsins MH - Corpus Striatum/*cytology MH - Cytoskeletal Proteins MH - Dependovirus/genetics MH - Electric Stimulation/methods MH - Excitatory Postsynaptic Potentials/drug effects/genetics MH - Gene Expression Regulation, Developmental/genetics MH - Glycoproteins/deficiency/*metabolism MH - In Vitro Techniques MH - Intracellular Signaling Peptides and Proteins MH - Luminescent Proteins/genetics MH - Membrane Glycoproteins MH - Membrane Proteins/deficiency/*metabolism MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Nerve Tissue Proteins MH - Neurons/*physiology MH - Patch-Clamp Techniques MH - Receptors, AMPA/metabolism MH - Receptors, Dopamine D1/genetics/metabolism MH - Receptors, Dopamine D2/genetics MH - Semaphorins MH - Signal Transduction/genetics MH - Statistics, Nonparametric MH - Synapses/genetics/*physiology MH - Vesicular Glutamate Transport Protein 2/metabolism PMC - PMC3267860 MID - NIHMS337420 EDAT- 2011/12/20 06:00 MHDA- 2012/03/20 06:00 CRDT- 2011/12/20 06:00 PHST- 2011/09/14 00:00 [received] PHST- 2011/11/08 00:00 [accepted] PHST- 2011/12/20 06:00 [entrez] PHST- 2011/12/20 06:00 [pubmed] PHST- 2012/03/20 06:00 [medline] AID - nn.3003 [pii] AID - 10.1038/nn.3003 [doi] PST - epublish SO - Nat Neurosci. 2011 Dec 18;15(2):215-23. doi: 10.1038/nn.3003. PMID- 21677170 OWN - NLM STAT- MEDLINE DCOM- 20110822 LR - 20220309 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 31 IP - 24 DP - 2011 Jun 15 TI - Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. PG - 8862-9 LID - 10.1523/JNEUROSCI.1617-11.2011 [doi] AB - The autism spectrum disorder tuberous sclerosis complex (TSC) is caused by mutations in the Tsc1 or Tsc2 genes, whose protein products form a heterodimeric complex that negatively regulates mammalian target of rapamycin-dependent protein translation. Although several forms of synaptic plasticity, including metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), depend on protein translation at the time of induction, it is unknown whether these forms of plasticity require signaling through the Tsc1/2 complex. To examine this possibility, we postnatally deleted Tsc1 in vivo in a subset of hippocampal CA1 neurons using viral delivery of Cre recombinase in mice. We found that hippocampal mGluR-LTD was abolished by loss of Tsc1, whereas a protein synthesis-independent form of NMDA receptor-dependent LTD was preserved. Additionally, AMPA and NMDA receptor-mediated EPSCs and miniature spontaneous EPSC frequency were enhanced in Tsc1 KO neurons. These changes in synaptic function occurred in the absence of alterations in spine density, morphology, or presynaptic release probability. Our findings indicate that signaling through Tsc1/2 is required for the expression of specific forms of hippocampal synaptic plasticity as well as the maintenance of normal excitatory synaptic strength. Furthermore, these data suggest that perturbations of synaptic signaling may contribute to the pathogenesis of TSC. FAU - Bateup, Helen S AU - Bateup HS AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Takasaki, Kevin T AU - Takasaki KT FAU - Saulnier, Jessica L AU - Saulnier JL FAU - Denefrio, Cassandra L AU - Denefrio CL FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS052707/NS/NINDS NIH HHS/United States GR - R01 NS052707-04/NS/NINDS NIH HHS/United States GR - NS052707/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (Receptors, Glutamate) RN - 0 (Symporters) RN - 0 (Tscot protein, mouse) RN - 0 (enhanced green fluorescent protein) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 452VLY9402 (Serine) RN - 6384-92-5 (N-Methylaspartate) RN - 77521-29-0 (alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid) SB - IM MH - Animals MH - Animals, Newborn MH - CA1 Region, Hippocampal/*cytology MH - Dendritic Spines/metabolism MH - Excitatory Amino Acid Antagonists/pharmacology MH - Excitatory Postsynaptic Potentials/drug effects/genetics MH - Green Fluorescent Proteins/genetics MH - Long-Term Synaptic Depression/drug effects/*genetics MH - Mice MH - Mice, Transgenic MH - Microscopy, Confocal/methods MH - N-Methylaspartate/pharmacology MH - Neurons/cytology/drug effects/*physiology MH - Organ Culture Techniques MH - Receptors, Glutamate/genetics/*metabolism MH - Serine/genetics MH - Symporters/*deficiency MH - Synapses/drug effects/*physiology MH - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology PMC - PMC3133739 MID - NIHMS303535 EDAT- 2011/06/17 06:00 MHDA- 2011/08/23 06:00 CRDT- 2011/06/17 06:00 PHST- 2011/06/17 06:00 [entrez] PHST- 2011/06/17 06:00 [pubmed] PHST- 2011/08/23 06:00 [medline] AID - 31/24/8862 [pii] AID - 3703478 [pii] AID - 10.1523/JNEUROSCI.1617-11.2011 [doi] PST - ppublish SO - J Neurosci. 2011 Jun 15;31(24):8862-9. doi: 10.1523/JNEUROSCI.1617-11.2011. PMID- 21552280 OWN - NLM STAT- MEDLINE DCOM- 20110609 LR - 20220309 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 474 IP - 7349 DP - 2011 Jun 2 TI - Glutamate induces de novo growth of functional spines in developing cortex. PG - 100-4 LID - 10.1038/nature09986 [doi] AB - Mature cortical pyramidal neurons receive excitatory inputs onto small protrusions emanating from their dendrites called spines. Spines undergo activity-dependent remodelling, stabilization and pruning during development, and similar structural changes can be triggered by learning and changes in sensory experiences. However, the biochemical triggers and mechanisms of de novo spine formation in the developing brain and the functional significance of new spines to neuronal connectivity are largely unknown. Here we develop an approach to induce and monitor de novo spine formation in real time using combined two-photon laser-scanning microscopy and two-photon laser uncaging of glutamate. Our data demonstrate that, in mouse cortical layer 2/3 pyramidal neurons, glutamate is sufficient to trigger de novo spine growth from the dendrite shaft in a location-specific manner. We find that glutamate-induced spinogenesis requires opening of NMDARs (N-methyl-D-aspartate-type glutamate receptors) and activation of protein kinase A (PKA) but is independent of calcium-calmodulin-dependent kinase II (CaMKII) and tyrosine kinase receptor B (TrkB) receptors. Furthermore, newly formed spines express glutamate receptors and are rapidly functional such that they transduce presynaptic activity into postsynaptic signals. Together, our data demonstrate that early neural connectivity is shaped by activity in a spatially precise manner and that nascent dendrite spines are rapidly functionally incorporated into cortical circuits. FAU - Kwon, Hyung-Bae AU - Kwon HB AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R01 NS046579-06A1/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20110508 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Neurotransmitter Agents) RN - 3KX376GY7L (Glutamic Acid) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Calcium/metabolism MH - Cerebral Cortex/*drug effects/*embryology MH - Dendritic Spines/drug effects MH - Electric Stimulation MH - Glutamic Acid/*pharmacology MH - Mice MH - Mice, Inbred C57BL MH - Neurotransmitter Agents/*pharmacology MH - Pyramidal Cells/drug effects/embryology PMC - PMC3107907 MID - NIHMS278278 EDAT- 2011/05/10 06:00 MHDA- 2011/06/10 06:00 CRDT- 2011/05/10 06:00 PHST- 2010/10/25 00:00 [received] PHST- 2011/03/04 00:00 [accepted] PHST- 2011/05/10 06:00 [entrez] PHST- 2011/05/10 06:00 [pubmed] PHST- 2011/06/10 06:00 [medline] AID - nature09986 [pii] AID - 10.1038/nature09986 [doi] PST - ppublish SO - Nature. 2011 Jun 2;474(7349):100-4. doi: 10.1038/nature09986. Epub 2011 May 8. PMID- 21544206 OWN - NLM STAT- MEDLINE DCOM- 20110825 LR - 20220309 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 6 IP - 4 DP - 2011 Apr 22 TI - Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum. PG - e19155 LID - 10.1371/journal.pone.0019155 [doi] LID - e19155 AB - The neurotransmitter glutamate is released by excitatory projection neurons throughout the brain. However, non-glutamatergic cells, including cholinergic and monoaminergic neurons, express markers that suggest that they are also capable of vesicular glutamate release. Striatal cholinergic interneurons (CINs) express the Type-3 vesicular glutamate transporter (VGluT3), although whether they form functional glutamatergic synapses is unclear. To examine this possibility, we utilized mice expressing Cre-recombinase under control of the endogenous choline acetyltransferase locus and conditionally expressed light-activated Channelrhodopsin2 in CINs. Optical stimulation evoked action potentials in CINs and produced postsynaptic responses in medium spiny neurons that were blocked by glutamate receptor antagonists. CIN-mediated glutamatergic responses exhibited a large contribution of NMDA-type glutamate receptors, distinguishing them from corticostriatal inputs. CIN-mediated glutamatergic responses were insensitive to antagonists of acetylcholine receptors and were not seen in mice lacking VGluT3. Our results indicate that CINs are capable of mediating fast glutamatergic transmission, suggesting a new role for these cells in regulating striatal activity. FAU - Higley, Michael J AU - Higley MJ AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Gittis, Aryn H AU - Gittis AH FAU - Oldenburg, Ian A AU - Oldenburg IA FAU - Balthasar, Nina AU - Balthasar N FAU - Seal, Rebecca P AU - Seal RP FAU - Edwards, Robert H AU - Edwards RH FAU - Lowell, Bradford B AU - Lowell BB FAU - Kreitzer, Anatol C AU - Kreitzer AC FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - MH50712/MH/NIMH NIH HHS/United States GR - P30 DK046200/DK/NIDDK NIH HHS/United States GR - DK075632/DK/NIDDK NIH HHS/United States GR - R01 NS046579-08/NS/NINDS NIH HHS/United States GR - P30 DK057521/DK/NIDDK NIH HHS/United States GR - NS063663/NS/NINDS NIH HHS/United States GR - R01 DK075632/DK/NIDDK NIH HHS/United States GR - R37 MH050712/MH/NIMH NIH HHS/United States GR - R01 MH050712/MH/NIMH NIH HHS/United States GR - P01 DA010154/DA/NIDA NIH HHS/United States GR - DA10154/DA/NIDA NIH HHS/United States GR - F31 MH093026/MH/NIMH NIH HHS/United States GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - NS064984/NS/NINDS NIH HHS/United States GR - R01 NS064984/NS/NINDS NIH HHS/United States GR - F32 NS063663/NS/NINDS NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States GR - F32 MH068085/MH/NIMH NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20110422 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Amino Acid Transport Systems, Acidic) RN - 0 (Central Nervous System Stimulants) RN - 0 (Channelrhodopsins) RN - 0 (Receptors, Cholinergic) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (vesicular glutamate transporter 3, mouse) RN - 124-87-8 (Picrotoxin) RN - 6EE945D3OK (Mecamylamine) RN - DL48G20X8X (Scopolamine) SB - IM MH - Amino Acid Transport Systems, Acidic/*metabolism MH - Animals MH - Central Nervous System Stimulants/pharmacology MH - Channelrhodopsins MH - Corpus Striatum/drug effects/*metabolism MH - Evoked Potentials/drug effects MH - Female MH - Interneurons/drug effects/*metabolism MH - Male MH - Mecamylamine/pharmacology MH - Mice MH - Picrotoxin/pharmacology MH - Receptors, Cholinergic/metabolism MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Scopolamine/pharmacology PMC - PMC3081336 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2011/05/06 06:00 MHDA- 2011/08/27 06:00 CRDT- 2011/05/06 06:00 PHST- 2011/02/02 00:00 [received] PHST- 2011/03/19 00:00 [accepted] PHST- 2011/05/06 06:00 [entrez] PHST- 2011/05/06 06:00 [pubmed] PHST- 2011/08/27 06:00 [medline] AID - PONE-D-11-02633 [pii] AID - 10.1371/journal.pone.0019155 [doi] PST - epublish SO - PLoS One. 2011 Apr 22;6(4):e19155. doi: 10.1371/journal.pone.0019155. PMID- 21498068 OWN - NLM STAT- MEDLINE DCOM- 20110912 LR - 20220129 IS - 1873-6882 (Electronic) IS - 0959-4388 (Linking) VI - 21 IP - 2 DP - 2011 Apr TI - Synaptic function and regulation. PG - 205-7 LID - 10.1016/j.conb.2011.03.004 [doi] FAU - Goda, Yukiko AU - Goda Y FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - MC_U122669937/MRC_/Medical Research Council/United Kingdom PT - Editorial PT - Introductory Journal Article DEP - 20110415 PL - England TA - Curr Opin Neurobiol JT - Current opinion in neurobiology JID - 9111376 SB - IM MH - Animals MH - Humans MH - Neuronal Plasticity/*physiology MH - *Periodicals as Topic MH - Synapses/*physiology MH - Synaptic Transmission/*physiology EDAT- 2011/04/19 06:00 MHDA- 2011/09/13 06:00 CRDT- 2011/04/19 06:00 PHST- 2011/04/19 06:00 [entrez] PHST- 2011/04/19 06:00 [pubmed] PHST- 2011/09/13 06:00 [medline] AID - S0959-4388(11)00044-4 [pii] AID - 10.1016/j.conb.2011.03.004 [doi] PST - ppublish SO - Curr Opin Neurobiol. 2011 Apr;21(2):205-7. doi: 10.1016/j.conb.2011.03.004. Epub 2011 Apr 15. PMID- 21695265 OWN - NLM STAT- MEDLINE DCOM- 20111021 LR - 20211020 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 6 IP - 6 DP - 2011 TI - Boosting of synaptic potentials and spine Ca transients by the peptide toxin SNX-482 requires alpha-1E-encoded voltage-gated Ca channels. PG - e20939 LID - 10.1371/journal.pone.0020939 [doi] LID - e20939 AB - The majority of glutamatergic synapses formed onto principal neurons of the mammalian central nervous system are associated with dendritic spines. Spines are tiny protuberances that house the proteins that mediate the response of the postsynaptic cell to the presynaptic release of glutamate. Postsynaptic signals are regulated by an ion channel signaling cascade that is active in individual dendritic spines and involves voltage-gated calcium (Ca) channels, small conductance (SK)-type Ca-activated potassium channels, and NMDA-type glutamate receptors. Pharmacological studies using the toxin SNX-482 indicated that the voltage-gated Ca channels that signal within spines to open SK channels belong to the class Ca(V)2.3, which is encoded by the Alpha-1E pore-forming subunit. In order to specifically test this conclusion, we examined the effects of SNX-482 on synaptic signals in acute hippocampal slices from knock-out mice lacking the Alpha-1E gene. We find that in these mice, application of SNX-482 has no effect on glutamate-uncaging evoked synaptic potentials and Ca influx, indicating that that SNX-482 indeed acts via the Alpha-1E-encoded Ca(V)2.3 channel. FAU - Giessel, Andrew J AU - Giessel AJ AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R37 NS046579/NS/NINDS NIH HHS/United States GR - F31 NS065647/NS/NINDS NIH HHS/United States GR - R01 NS046579-08/NS/NINDS NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20110609 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Cacna1e protein, mouse) RN - 0 (Calcium Channels, R-Type) RN - 0 (Cation Transport Proteins) RN - 0 (Peptides) RN - 0 (SNX 482) RN - 0 (Spider Venoms) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Calcium/*metabolism MH - Calcium Channels, R-Type/deficiency/*genetics/*metabolism MH - Cation Transport Proteins/deficiency/*genetics/*metabolism MH - Dendritic Spines/*drug effects/metabolism MH - Gene Knockout Techniques MH - Mice MH - Peptides/*pharmacology MH - Signal Transduction/drug effects MH - Spider Venoms/*pharmacology MH - Synaptic Potentials/*drug effects PMC - PMC3111456 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2011/06/23 06:00 MHDA- 2011/10/22 06:00 CRDT- 2011/06/23 06:00 PHST- 2011/03/09 00:00 [received] PHST- 2011/05/13 00:00 [accepted] PHST- 2011/06/23 06:00 [entrez] PHST- 2011/06/23 06:00 [pubmed] PHST- 2011/10/22 06:00 [medline] AID - PONE-D-11-04595 [pii] AID - 10.1371/journal.pone.0020939 [doi] PST - ppublish SO - PLoS One. 2011;6(6):e20939. doi: 10.1371/journal.pone.0020939. Epub 2011 Jun 9. PMID- 21145006 OWN - NLM STAT- MEDLINE DCOM- 20110118 LR - 20220408 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 68 IP - 5 DP - 2010 Dec 9 TI - M1 muscarinic receptors boost synaptic potentials and calcium influx in dendritic spines by inhibiting postsynaptic SK channels. PG - 936-47 LID - 10.1016/j.neuron.2010.09.004 [doi] AB - Acetylcholine release and activation of muscarinic cholinergic receptors (mAChRs) enhance synaptic plasticity in vitro and cognition and memory in vivo. Within the hippocampus, mAChRs promote NMDA-type glutamate receptor-dependent forms of long-term potentiation. Here, we use calcium (Ca) imaging combined with two-photon laser glutamate uncaging at apical spines of CA1 pyramidal neurons to examine postsynaptic mechanisms of muscarinic modulation of glutamatergic transmission. Uncaging-evoked excitatory postsynaptic potentials and Ca transients are increased by muscarinic stimulation; however, this is not due to direct modulation of glutamate receptors. Instead, mAChRs modulate a negative feedback loop in spines that normally suppresses synaptic signals. mAChR activation reduces the Ca sensitivity of small conductance Ca-activated potassium (SK) channels that are found in the spine, resulting in increased synaptic potentials and Ca transients. These effects are mediated by M1-type muscarinic receptors and occur in a casein kinase-2-dependent manner. Thus, muscarinic modulation regulates synaptic transmission by tuning the activity of nonglutamatergic postsynaptic ion channels. CI - Copyright © 2010 Elsevier Inc. All rights reserved. FAU - Giessel, Andrew J AU - Giessel AJ AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - F31 NS065647/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - R01 NS046579-06A1/NS/NINDS NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Receptor, Muscarinic M1) RN - 0 (Small-Conductance Calcium-Activated Potassium Channels) RN - EC 2.7.11.1 (Casein Kinase II) RN - N9YNS0M02X (Acetylcholine) RN - SY7Q814VUP (Calcium) SB - IM CIN - Neuron. 2010 Dec 9;68(5):809-11. PMID: 21144995 CIN - Nat Rev Neurosci. 2011 Feb;12(2):62. PMID: 21309090 MH - Acetylcholine/metabolism MH - Animals MH - CA1 Region, Hippocampal/cytology/metabolism MH - Calcium/metabolism MH - Casein Kinase II/*metabolism MH - Dendritic Spines/*metabolism MH - Feedback, Physiological MH - In Vitro Techniques MH - Mice MH - Mice, Inbred C57BL MH - Pyramidal Cells/cytology/metabolism MH - Receptor Cross-Talk/*physiology MH - Receptor, Muscarinic M1/*metabolism MH - Second Messenger Systems/physiology MH - Signal Transduction/physiology MH - Small-Conductance Calcium-Activated Potassium Channels/*metabolism MH - Synaptic Potentials/physiology PMC - PMC3052967 MID - NIHMS237821 EDAT- 2010/12/15 06:00 MHDA- 2011/01/19 06:00 CRDT- 2010/12/15 06:00 PHST- 2010/08/10 00:00 [accepted] PHST- 2010/12/15 06:00 [entrez] PHST- 2010/12/15 06:00 [pubmed] PHST- 2011/01/19 06:00 [medline] AID - S0896-6273(10)00721-X [pii] AID - 10.1016/j.neuron.2010.09.004 [doi] PST - ppublish SO - Neuron. 2010 Dec 9;68(5):936-47. doi: 10.1016/j.neuron.2010.09.004. PMID- 20585900 OWN - NLM STAT- MEDLINE DCOM- 20110801 LR - 20211020 IS - 1559-0089 (Electronic) IS - 1539-2791 (Linking) VI - 8 IP - 3 DP - 2010 Oct TI - Oriented Markov random field based dendritic spine segmentation for fluorescence microscopy images. PG - 157-70 LID - 10.1007/s12021-010-9073-y [doi] AB - Dendritic spines have been shown to be closely related to various functional properties of the neuron. Usually dendritic spines are manually labeled to analyze their morphological changes, which is very time-consuming and susceptible to operator bias, even with the assistance of computers. To deal with these issues, several methods have been recently proposed to automatically detect and measure the dendritic spines with little human interaction. However, problems such as degraded detection performance for images with larger pixel size (e.g. 0.125 μm/pixel instead of 0.08 μm/pixel) still exist in these methods. Moreover, the shapes of detected spines are also distorted. For example, the "necks" of some spines are missed. Here we present an oriented Markov random field (OMRF) based algorithm which improves spine detection as well as their geometric characterization. We begin with the identification of a region of interest (ROI) containing all the dendrites and spines to be analyzed. For this purpose, we introduce an adaptive procedure for identifying the image background. Next, the OMRF model is discussed within a statistical framework and the segmentation is solved as a maximum a posteriori estimation (MAP) problem, whose optimal solution is found by a knowledge-guided iterative conditional mode (KICM) algorithm. Compared with the existing algorithms, the proposed algorithm not only provides a more accurate representation of the spine shape, but also improves the detection performance by more than 50% with regard to reducing both the misses and false detection. FAU - Cheng, Jie AU - Cheng J AD - The Center for Bioengineering and Informatics, The Methodist Hospital Research Institute and Department of Radiology, The Methodist Hospital, Weill Cornell Medical College, Houston, TX 77030, USA. FAU - Zhou, Xiaobo AU - Zhou X FAU - Miller, Eric L AU - Miller EL FAU - Alvarez, Veronica A AU - Alvarez VA FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Wong, Stephen T C AU - Wong ST LA - eng GR - R01 NS052707/NS/NINDS NIH HHS/United States GR - R01 NS052707-04/NS/NINDS NIH HHS/United States GR - R01 LM008696/LM/NLM NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - United States TA - Neuroinformatics JT - Neuroinformatics JID - 101142069 SB - IM MH - *Algorithms MH - Animals MH - Cell Shape/physiology MH - Computer Simulation MH - Dendritic Spines/physiology/*ultrastructure MH - Hippocampus/*cytology/physiology MH - Image Cytometry/*methods MH - *Markov Chains MH - Microscopy, Fluorescence/*methods MH - Organ Culture Techniques MH - Pattern Recognition, Automated/methods/trends MH - Rats EDAT- 2010/06/30 06:00 MHDA- 2011/08/02 06:00 CRDT- 2010/06/30 06:00 PHST- 2010/06/30 06:00 [entrez] PHST- 2010/06/30 06:00 [pubmed] PHST- 2011/08/02 06:00 [medline] AID - 10.1007/s12021-010-9073-y [doi] PST - ppublish SO - Neuroinformatics. 2010 Oct;8(3):157-70. doi: 10.1007/s12021-010-9073-y. PMID- 20601948 OWN - NLM STAT- MEDLINE DCOM- 20100820 LR - 20211020 IS - 1546-1726 (Electronic) IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 13 IP - 8 DP - 2010 Aug TI - Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors. PG - 958-66 LID - 10.1038/nn.2592 [doi] AB - Striatal D2-type dopamine receptors (D2Rs) have been implicated in the pathophysiology of neuropsychiatric disorders, including Parkinson's disease and schizophrenia. Although these receptors regulate striatal synaptic plasticity, the mechanisms underlying dopaminergic modulation of glutamatergic synapses are unclear. We combined optogenetics, two-photon microscopy and glutamate uncaging to examine D2R-dependent modulation of glutamatergic synaptic transmission in mouse striatopallidal neurons. We found that D2R activation reduces corticostriatal glutamate release and attenuates both synaptic- and action potential-evoked Ca2+ influx into dendritic spines by approximately 50%. Modulation of Ca2+ signaling was mediated by a protein kinase A (PKA)-dependent regulation of Ca2+ entry through NMDA-type glutamate receptors that was inhibited by D2Rs and enhanced by activation of 2A-type adenosine receptors (A2ARs). D2Rs also produced a PKA- and A2AR-independent reduction in Ca2+ influx through R-type voltage-gated Ca2+ channels. These findings reveal that dopamine regulates spine Ca2+ by multiple pathways and that competitive modulation of PKA controls NMDAR-mediated Ca2+ signaling in the striatum. FAU - Higley, Michael J AU - Higley MJ AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - HHMI/Howard Hughes Medical Institute/United States GR - R01 NS046579-06A1/NS/NINDS NIH HHS/United States GR - NS063663/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - F32 NS063663/NS/NINDS NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20100704 PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 0 (Calcium Channels) RN - 0 (Receptor, Adenosine A2A) RN - 0 (Receptors, Dopamine D2) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Calcium/*metabolism MH - Calcium Channels/metabolism MH - Calcium Signaling/*physiology MH - Corpus Striatum/metabolism MH - Cyclic AMP-Dependent Protein Kinases/metabolism MH - Dendritic Spines/metabolism MH - Excitatory Postsynaptic Potentials/physiology MH - Female MH - Male MH - Mice MH - Microscopy, Confocal MH - Organ Culture Techniques MH - Patch-Clamp Techniques MH - Receptor, Adenosine A2A/*metabolism MH - Receptors, Dopamine D2/*metabolism MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Synapses/*metabolism MH - Synaptic Transmission/*physiology PMC - PMC2910780 MID - NIHMS211272 EDAT- 2010/07/06 06:00 MHDA- 2010/08/21 06:00 CRDT- 2010/07/06 06:00 PHST- 2010/04/21 00:00 [received] PHST- 2010/06/03 00:00 [accepted] PHST- 2010/07/06 06:00 [entrez] PHST- 2010/07/06 06:00 [pubmed] PHST- 2010/08/21 06:00 [medline] AID - nn.2592 [pii] AID - 10.1038/nn.2592 [doi] PST - ppublish SO - Nat Neurosci. 2010 Aug;13(8):958-66. doi: 10.1038/nn.2592. Epub 2010 Jul 4. PMID- 20510921 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20100617 LR - 20100531 IS - 1097-4172 (Electronic) IS - 0092-8674 (Linking) VI - 141 IP - 5 DP - 2010 May 28 TI - For synapses, it's depression not death. PG - 750-2 LID - 10.1016/j.cell.2010.05.013 [doi] AB - Long-term depression (LTD) of synaptic strength is an activity-dependent process in neurons that may be important for learning and memory. Li et al. (2010) now reveal a new apoptosis-independent role for mitochondrial-activated caspases in LTD suggesting that neurons have co-opted the canonical cell death pathway to perform a specialized function at synapses. CI - Copyright 2010 Elsevier Inc. All rights reserved. FAU - Bateup, Helen S AU - Bateup HS AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng PT - Comment PT - Journal Article PL - United States TA - Cell JT - Cell JID - 0413066 CON - Cell. 2010 May 28;141(5):859-71. PMID: 20510932 EDAT- 2010/06/01 06:00 MHDA- 2010/06/01 06:01 CRDT- 2010/06/01 06:00 PHST- 2010/06/01 06:00 [entrez] PHST- 2010/06/01 06:00 [pubmed] PHST- 2010/06/01 06:01 [medline] AID - S0092-8674(10)00549-0 [pii] AID - 10.1016/j.cell.2010.05.013 [doi] PST - ppublish SO - Cell. 2010 May 28;141(5):750-2. doi: 10.1016/j.cell.2010.05.013. PMID- 19828799 OWN - NLM STAT- MEDLINE DCOM- 20091030 LR - 20211020 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 29 IP - 41 DP - 2009 Oct 14 TI - Distinct domains within PSD-95 mediate synaptic incorporation, stabilization, and activity-dependent trafficking. PG - 12845-54 LID - 10.1523/JNEUROSCI.1841-09.2009 [doi] AB - The postsynaptic density (PSD) consists of a lattice-like array of interacting proteins that organizes and stabilizes receptors, ion channels, structural, and signaling proteins necessary for synaptic function. To study the stabilization of proteins within this structure and the contribution of these proteins to the integrity of the PSD, we tagged synaptic proteins with PAGFP (photoactivatable green fluorescent protein) and used combined two-photon laser-scanning microscopy and two-photon laser photoactivation to measure their rate of turnover in individual spines of rat CA1 pyramidal neurons. We find that PSD-95 is highly stable within the spine, more so than other PSD-associated proteins such as CaMKIIalpha, CaMKIIbeta, GluR2, and Stargazin. Analysis of a series of PSD-95 mutants revealed that distinct domains stabilize PSD-95 within the PSD and contribute to PSD formation. Stabilization of PSD-95 within the PSD requires N-terminal palmitoylation and protein interactions mediated by the first and second PDZ domains, whereas formation of a stable lattice of PSD-95 molecules within the PSD additionally requires the C-terminal SH3 domain. Furthermore, in a PDZ domain 1 and 2 dependent manner, activation of NMDA receptors with a chemical long-term depression protocol rapidly destabilizes PSD-95 and causes a subset of the PSD-95 molecules previously anchored in the spine to be released. Thus, through the analysis of rates of exchange of synaptic PSD-95, we determine separate domains of PSD-95 that play specific roles in establishing a stable postsynaptic lattice, in allowing proteins to enter this lattice, and in reorganizing this structure in response to plasticity-inducing stimuli. FAU - Sturgill, James F AU - Sturgill JF AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Steiner, Pascal AU - Steiner P FAU - Czervionke, Brian L AU - Czervionke BL FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS052707/NS/NINDS NIH HHS/United States GR - R01 NS052707-03/NS/NINDS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - NS052707/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Disks Large Homolog 4 Protein) RN - 0 (Dlg4 protein, rat) RN - 0 (Excitatory Amino Acid Agonists) RN - 0 (Immunosuppressive Agents) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Membrane Proteins) RN - 0 (Receptors, AMPA) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 6384-92-5 (N-Methylaspartate) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase) RN - P6W5IXV8V9 (glutamate receptor ionotropic, AMPA 2) RN - WM0HAQ4WNM (Tacrolimus) SB - IM MH - Animals MH - Animals, Newborn MH - Calcium-Calmodulin-Dependent Protein Kinase Kinase/genetics MH - Dendritic Spines/drug effects/genetics/metabolism MH - Disks Large Homolog 4 Protein MH - Excitatory Amino Acid Agonists/pharmacology MH - Green Fluorescent Proteins/genetics MH - Hippocampus/cytology MH - Immunosuppressive Agents/pharmacology MH - Intracellular Signaling Peptides and Proteins/genetics/*metabolism MH - Lipoylation/physiology MH - Membrane Proteins/genetics/*metabolism MH - Mutation/genetics MH - N-Methylaspartate/pharmacology MH - Organ Culture Techniques MH - PDZ Domains/genetics/*physiology MH - Protein Structure, Tertiary/genetics/physiology MH - Protein Transport/drug effects/genetics/physiology MH - Rats MH - Receptors, AMPA/genetics MH - Signal Transduction/drug effects/genetics/*physiology MH - Synapses/drug effects/*physiology MH - Tacrolimus/pharmacology MH - Time Factors MH - Transfection/methods PMC - PMC2787089 MID - NIHMS158050 EDAT- 2009/10/16 06:00 MHDA- 2009/10/31 06:00 CRDT- 2009/10/16 06:00 PHST- 2009/10/16 06:00 [entrez] PHST- 2009/10/16 06:00 [pubmed] PHST- 2009/10/31 06:00 [medline] AID - 29/41/12845 [pii] AID - 3534320 [pii] AID - 10.1523/JNEUROSCI.1841-09.2009 [doi] PST - ppublish SO - J Neurosci. 2009 Oct 14;29(41):12845-54. doi: 10.1523/JNEUROSCI.1841-09.2009. PMID- 19753104 OWN - NLM STAT- MEDLINE DCOM- 20091201 LR - 20220408 IS - 1545-7885 (Electronic) IS - 1544-9173 (Print) IS - 1544-9173 (Linking) VI - 7 IP - 9 DP - 2009 Sep TI - Biphasic synaptic Ca influx arising from compartmentalized electrical signals in dendritic spines. PG - e1000190 LID - 10.1371/journal.pbio.1000190 [doi] LID - e1000190 AB - Excitatory synapses on mammalian principal neurons are typically formed onto dendritic spines, which consist of a bulbous head separated from the parent dendrite by a thin neck. Although activation of voltage-gated channels in the spine and stimulus-evoked constriction of the spine neck can influence synaptic signals, the contribution of electrical filtering by the spine neck to basal synaptic transmission is largely unknown. Here we use spine and dendrite calcium (Ca) imaging combined with 2-photon laser photolysis of caged glutamate to assess the impact of electrical filtering imposed by the spine morphology on synaptic Ca transients. We find that in apical spines of CA1 hippocampal neurons, the spine neck creates a barrier to the propagation of current, which causes a voltage drop and results in spatially inhomogeneous activation of voltage-gated Ca channels (VGCCs) on a micron length scale. Furthermore, AMPA and NMDA-type glutamate receptors (AMPARs and NMDARs, respectively) that are colocalized on individual spine heads interact to produce two kinetically and mechanistically distinct phases of synaptically evoked Ca influx. Rapid depolarization of the spine triggers a brief and large Ca current whose amplitude is regulated in a graded manner by the number of open AMPARs and whose duration is terminated by the opening of small conductance Ca-activated potassium (SK) channels. A slower phase of Ca influx is independent of AMPAR opening and is determined by the number of open NMDARs and the post-stimulus potential in the spine. Biphasic synaptic Ca influx only occurs when AMPARs and NMDARs are coactive within an individual spine. These results demonstrate that the morphology of dendritic spines endows associated synapses with specialized modes of signaling and permits the graded and independent control of multiple phases of synaptic Ca influx. FAU - Bloodgood, Brenda L AU - Bloodgood BL AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Giessel, Andrew J AU - Giessel AJ FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R01 NS046579-06A1/NS/NINDS NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20090915 PL - United States TA - PLoS Biol JT - PLoS biology JID - 101183755 RN - 0 (Calcium Channels) RN - 0 (Receptors, AMPA) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 3KX376GY7L (Glutamic Acid) SB - IM MH - Animals MH - Calcium Channels/physiology MH - *Calcium Signaling MH - Dendritic Spines/*physiology/ultrastructure MH - Electrical Synapses/*physiology MH - Glutamic Acid/metabolism MH - Hippocampus/cytology/physiology MH - Mice MH - Neural Conduction MH - Receptors, AMPA/metabolism MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Synaptic Potentials MH - Synaptic Transmission PMC - PMC2734993 COIS- The authors have declared that no competing interests exist. EDAT- 2009/09/16 06:00 MHDA- 2009/12/16 06:00 CRDT- 2009/09/16 06:00 PHST- 2009/03/31 00:00 [received] PHST- 2009/07/30 00:00 [accepted] PHST- 2009/09/16 06:00 [entrez] PHST- 2009/09/16 06:00 [pubmed] PHST- 2009/12/16 06:00 [medline] AID - 09-PLBI-RA-1367R3 [pii] AID - 10.1371/journal.pbio.1000190 [doi] PST - ppublish SO - PLoS Biol. 2009 Sep;7(9):e1000190. doi: 10.1371/journal.pbio.1000190. Epub 2009 Sep 15. PMID- 19668198 OWN - NLM STAT- MEDLINE DCOM- 20090923 LR - 20211020 IS - 1546-1726 (Electronic) IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 12 IP - 9 DP - 2009 Sep TI - Cholinergic modulation of multivesicular release regulates striatal synaptic potency and integration. PG - 1121-8 LID - 10.1038/nn.2368 [doi] AB - The pleiotropic actions of neuromodulators on pre- and postsynaptic targets make disentangling the mechanisms underlying regulation of synaptic transmission challenging. In the striatum, acetylcholine modulates glutamate release via activation of muscarinic receptors (mAchRs), although the consequences for postsynaptic signaling are unclear. Using two-photon microscopy and glutamate uncaging to examine individual synapses in the rat striatum, we found that glutamatergic afferents have a high degree of multivesicular release (MVR) in the absence of postsynaptic receptor saturation. We found that mAchR activation decreased both the probability of release and the concentration of glutamate in the synaptic cleft. The corresponding decrease in synaptic potency reduced the duration of synaptic potentials and limited temporal summation of afferent inputs. These findings reveal a mechanism by which a combination of basal MVR and low receptor saturation allow the presynaptic actions of a neuromodulator to control the engagement of postsynaptic nonlinearities and regulate synaptic integration. FAU - Higley, Michael J AU - Higley MJ AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. FAU - Soler-Llavina, Gilberto J AU - Soler-Llavina GJ FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - F32 NS063663-01A1/NS/NINDS NIH HHS/United States GR - 1 F31NS049655-01/NS/NINDS NIH HHS/United States GR - F31 NS049655-03/NS/NINDS NIH HHS/United States GR - R01 NS046579-06A1/NS/NINDS NIH HHS/United States GR - F31 NS049655/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - F32 NS063663/NS/NINDS NIH HHS/United States GR - NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20090809 PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 0 (Calcium Channels, N-Type) RN - 0 (Receptors, Muscarinic) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 3KX376GY7L (Glutamic Acid) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Calcium/metabolism MH - Calcium Channels, N-Type/metabolism MH - Corpus Striatum/*physiology MH - Dendritic Spines/physiology MH - Excitatory Postsynaptic Potentials MH - Glutamic Acid/metabolism MH - In Vitro Techniques MH - Membrane Potentials/physiology MH - Presynaptic Terminals/physiology MH - Probability MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, Muscarinic/*metabolism MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Synapses/*physiology MH - Synaptic Transmission/*physiology MH - Synaptic Vesicles/*physiology MH - Time Factors PMC - PMC2733934 MID - NIHMS124696 EDAT- 2009/08/12 09:00 MHDA- 2009/09/24 06:00 CRDT- 2009/08/12 09:00 PHST- 2009/05/14 00:00 [received] PHST- 2009/06/11 00:00 [accepted] PHST- 2009/08/12 09:00 [entrez] PHST- 2009/08/12 09:00 [pubmed] PHST- 2009/09/24 06:00 [medline] AID - nn.2368 [pii] AID - 10.1038/nn.2368 [doi] PST - ppublish SO - Nat Neurosci. 2009 Sep;12(9):1121-8. doi: 10.1038/nn.2368. Epub 2009 Aug 9. PMID- 19709626 OWN - NLM STAT- MEDLINE DCOM- 20090921 LR - 20211020 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 63 IP - 4 DP - 2009 Aug 27 TI - Supraresolution imaging in brain slices using stimulated-emission depletion two-photon laser scanning microscopy. PG - 429-37 LID - 10.1016/j.neuron.2009.07.011 [doi] AB - Two-photon laser scanning microscopy (2PLSM) has allowed unprecedented fluorescence imaging of neuronal structure and function within neural tissue. However, the resolution of this approach is poor compared to that of conventional confocal microscopy. Here, we demonstrate supraresolution 2PLSM within brain slices. Imaging beyond the diffraction limit is accomplished by using near-infrared (NIR) lasers for both pulsed two-photon excitation and continuous wave stimulated emission depletion (STED). Furthermore, we demonstrate that Alexa Fluor 594, a bright fluorophore commonly used for both live cell and fixed tissue fluorescence imaging, is suitable for STED 2PLSM. STED 2PLSM supraresolution microscopy achieves approximately 3-fold improvement in resolution in the radial direction over conventional 2PLSM, revealing greater detail in the structure of dendritic spines located approximately 100 microns below the surface of brain slices. Further improvements in resolution are theoretically achievable, suggesting that STED 2PLSM will permit nanoscale imaging of neuronal structures located in relatively intact brain tissue. FAU - Ding, Jun B AU - Ding JB AD - Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. FAU - Takasaki, Kevin T AU - Takasaki KT FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R01 NS046579-06A1/NS/NINDS NIH HHS/United States GR - T32 NS007484/NS/NINDS NIH HHS/United States PT - Comparative Study PT - Journal Article PL - United States TA - Neuron JT - Neuron JID - 8809320 SB - IM MH - Animals MH - Brain/*ultrastructure MH - In Vitro Techniques MH - Mice MH - Mice, Inbred C57BL MH - Microscopy, Confocal/*instrumentation/*methods MH - Microscopy, Fluorescence, Multiphoton/*instrumentation/*methods PMC - PMC2756148 MID - NIHMS144057 EDAT- 2009/08/28 09:00 MHDA- 2009/09/22 06:00 CRDT- 2009/08/28 09:00 PHST- 2009/04/23 00:00 [received] PHST- 2009/06/22 00:00 [revised] PHST- 2009/07/15 00:00 [accepted] PHST- 2009/08/28 09:00 [entrez] PHST- 2009/08/28 09:00 [pubmed] PHST- 2009/09/22 06:00 [medline] AID - S0896-6273(09)00518-2 [pii] AID - 10.1016/j.neuron.2009.07.011 [doi] PST - ppublish SO - Neuron. 2009 Aug 27;63(4):429-37. doi: 10.1016/j.neuron.2009.07.011. PMID- 21204410 STAT- Publisher ISBN- 978-1-4200-4414-0 PB - CRC Press/Taylor & Francis CTI - Frontiers in Neuroscience DP - 2009 TI - NMDA Receptor-Mediated Calcium Transients in Dendritic Spines. BTI - Biology of the NMDA Receptor CP - Chapter 9 AB - In pyramidal neurons of the hippocampus and cortex, NMDA-type glutamate receptors (NMDARs) are the predominant sources of synaptically evoked calcium (Ca) signals [1–7] (Figure 9.1A through C). Ca influx through NMDARs regulates diverse processes including kinase and phosphatase activity, protein trafficking, structural and functional synaptic plasticity, cell growth, cell survival, and apoptosis [8–11]. Which of these many Ca-dependent processes are triggered when NMDARs open depend on the context of receptor activation and the magnitude, kinetics, timing, and spatial spread of the resulting Ca transients. This chapter reviews the features of NMDARs that determine Ca influx through the receptors and discusses how the context of NMDAR activation shapes synaptically evoked Ca transients. CI - Copyright © 2009, Taylor & Francis Group, LLC. FED - Van Dongen, Antonius M ED - Van Dongen AM AD - Duke University Medical Center, North Carolina FAU - Bloodgood, Brenda L AU - Bloodgood BL FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng PT - Review PT - Book Chapter PL - Boca Raton (FL) EDAT- 2009/01/01 00:00 CRDT- 2009/01/01 00:00 AID - NBK5276 [bookaccession] PMID- 19081375 OWN - NLM STAT- MEDLINE DCOM- 20090408 LR - 20220309 IS - 1097-4199 (Electronic) IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 60 IP - 5 DP - 2008 Dec 10 TI - Destabilization of the postsynaptic density by PSD-95 serine 73 phosphorylation inhibits spine growth and synaptic plasticity. PG - 788-802 LID - 10.1016/j.neuron.2008.10.014 [doi] AB - Long-term potentiation (LTP) is accompanied by dendritic spine growth and changes in the composition of the postsynaptic density (PSD). We find that activity-dependent growth of apical spines of CA1 pyramidal neurons is accompanied by destabilization of the PSD that results in transient loss and rapid replacement of PSD-95 and SHANK2. Signaling through PSD-95 is required for activity-dependent spine growth and trafficking of SHANK2. N-terminal PDZ and C-terminal guanylate kinase domains of PSD-95 are required for both processes, indicating that PSD-95 coordinates multiple signals to regulate morphological plasticity. Activity-dependent trafficking of PSD-95 is triggered by phosphorylation at serine 73, a conserved calcium/calmodulin-dependent protein kinase II (CaMKII) consensus phosphorylation site, which negatively regulates spine growth and potentiation of synaptic currents. We propose that PSD-95 and CaMKII act at multiple steps during plasticity induction to initially trigger and later terminate spine growth by trafficking growth-promoting PSD proteins out of the active spine. FAU - Steiner, Pascal AU - Steiner P AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Higley, Michael J AU - Higley MJ FAU - Xu, Weifeng AU - Xu W FAU - Czervionke, Brian L AU - Czervionke BL FAU - Malenka, Robert C AU - Malenka RC FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - NS05270/NS/NINDS NIH HHS/United States GR - MH063394/MH/NIMH NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - R37 MH063394-19/MH/NIMH NIH HHS/United States GR - K99 MH080310/MH/NIMH NIH HHS/United States GR - R37 MH063394/MH/NIMH NIH HHS/United States GR - R01 NS052707-02/NS/NINDS NIH HHS/United States GR - R00 MH080310/MH/NIMH NIH HHS/United States GR - R01 NS052707/NS/NINDS NIH HHS/United States GR - R01 MH063394/MH/NIMH NIH HHS/United States GR - MH080310/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (4-methoxy-7-nitroindolinyl-glutamate) RN - 0 (Disks Large Homolog 4 Protein) RN - 0 (Dlg4 protein, rat) RN - 0 (Enzyme Inhibitors) RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (Glutamates) RN - 0 (Indoles) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Membrane Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (Piperazines) RN - 0 (Shank2 protein, rat) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 452VLY9402 (Serine) RN - 63HM46XPOW (KN 62) RN - 84477-87-2 (1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine) RN - 98Y1I8ZD4M (3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) SB - IM EIN - Neuron. 2009 Jan 15;61(1):152 MH - 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives/pharmacology MH - Animals MH - Animals, Newborn MH - Dendritic Spines/drug effects/*physiology MH - Disks Large Homolog 4 Protein MH - Electric Stimulation/methods MH - Enzyme Inhibitors/pharmacology MH - Excitatory Amino Acid Antagonists/pharmacology MH - Glutamates/pharmacology MH - Green Fluorescent Proteins/biosynthesis/genetics MH - Hippocampus/cytology MH - Indoles/pharmacology MH - Intracellular Signaling Peptides and Proteins/genetics/*metabolism MH - Long-Term Potentiation/physiology MH - Membrane Proteins/genetics/*metabolism MH - Nerve Tissue Proteins/metabolism MH - Neuronal Plasticity/drug effects/*physiology MH - Neurons/*cytology/drug effects MH - Organ Culture Techniques MH - Patch-Clamp Techniques/methods MH - Phosphorylation/drug effects/physiology MH - Piperazines/pharmacology MH - Point Mutation MH - Protein Structure, Tertiary MH - Protein Transport/drug effects MH - Rats MH - Rats, Sprague-Dawley MH - Serine/*metabolism MH - Time Factors PMC - PMC2671083 MID - NIHMS99229 EDAT- 2008/12/17 09:00 MHDA- 2009/04/09 09:00 CRDT- 2008/12/17 09:00 PHST- 2008/03/18 00:00 [received] PHST- 2008/08/29 00:00 [revised] PHST- 2008/10/07 00:00 [accepted] PHST- 2008/12/17 09:00 [entrez] PHST- 2008/12/17 09:00 [pubmed] PHST- 2009/04/09 09:00 [medline] AID - S0896-6273(08)00887-8 [pii] AID - 10.1016/j.neuron.2008.10.014 [doi] PST - ppublish SO - Neuron. 2008 Dec 10;60(5):788-802. doi: 10.1016/j.neuron.2008.10.014. PMID- 18817730 OWN - NLM STAT- MEDLINE DCOM- 20081104 LR - 20220321 IS - 1097-4199 (Electronic) IS - 0896-6273 (Linking) VI - 59 IP - 6 DP - 2008 Sep 25 TI - Calcium signaling in dendrites and spines: practical and functional considerations. PG - 902-13 LID - 10.1016/j.neuron.2008.08.020 [doi] AB - Changes in intracellular calcium (Ca) concentration following synaptic and suprathreshold activity are mediated by a wide range of sources and contribute to the regulation of myriad neuronal functions. The development of Ca imaging techniques has dramatically increased our understanding of the complex interactions between different Ca sources and their ability to produce spatial and temporal specificity of signaling, even within small cellular compartments such as dendrites and dendritic spines. However, as the use of Ca imaging has become more prevalent, the need to exercise care in the experimental methodology and interpretation of data has also grown. In this review, we discuss the recent progress made using imaging methods in understanding dendritic Ca signaling and also describe a quantitative framework for using fluorescent indicators to experimentally measure and interpret changes in intracellular Ca. FAU - Higley, Michael J AU - Higley MJ AD - Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R01 NS046579-06A1/NS/NINDS NIH HHS/United States GR - Howard Hughes Medical Institute/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Calcium Channels) RN - 0 (Fluorescent Dyes) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Calcium/*metabolism MH - Calcium Channels/metabolism MH - Calcium Signaling/*physiology MH - Cytoplasm/metabolism MH - Dendrites/metabolism MH - Dendritic Spines/*metabolism MH - Fluorescent Dyes/metabolism MH - Humans MH - Membrane Microdomains/physiology MH - Models, Neurological MH - Second Messenger Systems/*physiology MH - Synaptic Transmission/physiology RF - 139 EDAT- 2008/09/27 09:00 MHDA- 2008/11/05 09:00 CRDT- 2008/09/27 09:00 PHST- 2008/08/06 00:00 [received] PHST- 2008/08/18 00:00 [revised] PHST- 2008/08/19 00:00 [accepted] PHST- 2008/09/27 09:00 [pubmed] PHST- 2008/11/05 09:00 [medline] PHST- 2008/09/27 09:00 [entrez] AID - S0896-6273(08)00744-7 [pii] AID - 10.1016/j.neuron.2008.08.020 [doi] PST - ppublish SO - Neuron. 2008 Sep 25;59(6):902-13. doi: 10.1016/j.neuron.2008.08.020. PMID- 18568035 OWN - NLM STAT- MEDLINE DCOM- 20080821 LR - 20220310 IS - 1546-170X (Electronic) IS - 1078-8956 (Print) IS - 1078-8956 (Linking) VI - 14 IP - 8 DP - 2008 Aug TI - Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. PG - 837-42 LID - 10.1038/nm1782 [doi] AB - Alzheimer's disease constitutes a rising threat to public health. Despite extensive research in cellular and animal models, identifying the pathogenic agent present in the human brain and showing that it confers key features of Alzheimer's disease has not been achieved. We extracted soluble amyloid-beta protein (Abeta) oligomers directly from the cerebral cortex of subjects with Alzheimer's disease. The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and reduced dendritic spine density in normal rodent hippocampus. Soluble Abeta from Alzheimer's disease brain also disrupted the memory of a learned behavior in normal rats. These various effects were specifically attributable to Abeta dimers. Mechanistically, metabotropic glutamate receptors were required for the LTD enhancement, and N-methyl D-aspartate receptors were required for the spine loss. Co-administering antibodies to the Abeta N-terminus prevented the LTP and LTD deficits, whereas antibodies to the midregion or C-terminus were less effective. Insoluble amyloid plaque cores from Alzheimer's disease cortex did not impair LTP unless they were first solubilized to release Abeta dimers, suggesting that plaque cores are largely inactive but sequester Abeta dimers that are synaptotoxic. We conclude that soluble Abeta oligomers extracted from Alzheimer's disease brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species. FAU - Shankar, Ganesh M AU - Shankar GM AD - Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. FAU - Li, Shaomin AU - Li S FAU - Mehta, Tapan H AU - Mehta TH FAU - Garcia-Munoz, Amaya AU - Garcia-Munoz A FAU - Shepardson, Nina E AU - Shepardson NE FAU - Smith, Imelda AU - Smith I FAU - Brett, Francesca M AU - Brett FM FAU - Farrell, Michael A AU - Farrell MA FAU - Rowan, Michael J AU - Rowan MJ FAU - Lemere, Cynthia A AU - Lemere CA FAU - Regan, Ciaran M AU - Regan CM FAU - Walsh, Dominic M AU - Walsh DM FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Selkoe, Dennis J AU - Selkoe DJ LA - eng GR - R01 AG027443-03/AG/NIA NIH HHS/United States GR - AG R01 027443/AG/NIA NIH HHS/United States GR - 067660/WT_/Wellcome Trust/United Kingdom GR - R01 NS046579-06A1/NS/NINDS NIH HHS/United States GR - R01 AG027443-01/AG/NIA NIH HHS/United States GR - R01 AG027443/AG/NIA NIH HHS/United States GR - R01 AG027443-04/AG/NIA NIH HHS/United States GR - R01 AG027443-02/AG/NIA NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20080622 PL - United States TA - Nat Med JT - Nature medicine JID - 9502015 RN - 0 (Amyloid beta-Peptides) SB - IM MH - Alzheimer Disease/*metabolism MH - Amyloid beta-Peptides/*chemistry MH - Animals MH - Brain/*metabolism/pathology MH - Dendritic Spines MH - Dimerization MH - Hippocampus/*metabolism MH - Humans MH - Learning MH - *Memory MH - Mice MH - Neuronal Plasticity MH - Neurons/metabolism MH - Rats MH - Synapses/*metabolism PMC - PMC2772133 MID - NIHMS154255 EDAT- 2008/06/24 09:00 MHDA- 2008/08/22 09:00 CRDT- 2008/06/24 09:00 PHST- 2007/10/15 00:00 [received] PHST- 2008/05/15 00:00 [accepted] PHST- 2008/06/24 09:00 [pubmed] PHST- 2008/08/22 09:00 [medline] PHST- 2008/06/24 09:00 [entrez] AID - nm1782 [pii] AID - 10.1038/nm1782 [doi] PST - ppublish SO - Nat Med. 2008 Aug;14(8):837-42. doi: 10.1038/nm1782. Epub 2008 Jun 22. PMID- 18308511 OWN - NLM STAT- MEDLINE DCOM- 20080929 LR - 20211203 IS - 0898-6568 (Print) IS - 0898-6568 (Linking) VI - 20 IP - 6 DP - 2008 Jun TI - Pam (Protein associated with Myc) functions as an E3 ubiquitin ligase and regulates TSC/mTOR signaling. PG - 1084-91 LID - 10.1016/j.cellsig.2008.01.020 [doi] AB - The tumor suppressor tuberin, encoded by the Tuberous Sclerosis Complex (TSC) gene TSC2, negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in the control of cell growth and proliferation. In addition to naturally occurring mutations, several kinases including Akt, RSK1, and ERK are known to phosphorylate and inactivate tuberin. We demonstrate a novel mechanism of tuberin inactivation through ubiquitination by Pam, a putative RING finger-containing E3 ubiquitin (Ub) ligase in mammalian cells. We show that Pam associates with E2 ubiquitin-conjugating enzymes, and tuberin can be ubiquitinated by Pam through its RING finger domain. Tuberin ubiquitination is independent of its phosphorylation by Akt, RSK1, and ERK kinases. Pam is also self-ubiquitinated through its RING finger domain. Moreover, the TSC1 protein hamartin, which forms a heterodimer with tuberin, protects tuberin from ubiquitination by Pam. However, TSC1 fails to protect a disease-associated missense mutant of TSC2 from ubiquitination by Pam. Furthermore, Pam knockdown by RNA interference (RNAi) in rat primary neurons elevates the level of tuberin, and subsequently inhibits the mTOR pathway. Our results provide novel evidence that Pam can function as an E3 Ub ligase toward tuberin and regulate mTOR signaling, suggesting that Pam can in turn regulate cell growth and proliferation as well as neuronal function through the TSC/mTOR pathway in mammalian cells. FAU - Han, Sangyeul AU - Han S AD - Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA. FAU - Witt, Rochelle M AU - Witt RM FAU - Santos, Túlio M AU - Santos TM FAU - Polizzano, Carolyn AU - Polizzano C FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Ramesh, Vijaya AU - Ramesh V LA - eng GR - P30 NS045776/NS/NINDS NIH HHS/United States GR - NS45776/NS/NINDS NIH HHS/United States GR - R21 MH079213/MH/NIMH NIH HHS/United States GR - P01 NS024279-120008/NS/NINDS NIH HHS/United States GR - P01 NS024279/NS/NINDS NIH HHS/United States GR - NS24279/NS/NINDS NIH HHS/United States GR - R01 NS052707-03/NS/NINDS NIH HHS/United States GR - R01 NS052707/NS/NINDS NIH HHS/United States GR - R21 MH079213-01A1/MH/NIMH NIH HHS/United States GR - AS1862/AS/Autism Speaks/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20080201 PL - England TA - Cell Signal JT - Cellular signalling JID - 8904683 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (TSC2 protein, human) RN - 0 (Tsc2 protein, rat) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - 0 (Tumor Suppressor Proteins) RN - EC 1.- (Mixed Function Oxygenases) RN - EC 2.3.2.23 (Ubiquitin-Conjugating Enzymes) RN - EC 2.3.2.27 (MYCBP2 protein, human) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Adaptor Proteins, Signal Transducing/chemistry/*metabolism MH - Amino Acid Sequence MH - Animals MH - Cells, Cultured MH - Humans MH - Mixed Function Oxygenases/chemistry/*metabolism MH - Molecular Sequence Data MH - Mutation, Missense MH - Neurons/metabolism MH - Phosphorylation MH - Protein Kinases/*metabolism MH - Protein Structure, Tertiary MH - Rats MH - Signal Transduction MH - TOR Serine-Threonine Kinases MH - Tuberous Sclerosis/genetics MH - Tuberous Sclerosis Complex 2 Protein MH - Tumor Suppressor Proteins/*metabolism MH - Ubiquitin-Conjugating Enzymes/metabolism MH - Ubiquitin-Protein Ligases/chemistry/*metabolism MH - Ubiquitination PMC - PMC2435383 MID - NIHMS50682 EDAT- 2008/03/01 09:00 MHDA- 2008/09/30 09:00 CRDT- 2008/03/01 09:00 PHST- 2008/01/09 00:00 [received] PHST- 2008/01/21 00:00 [accepted] PHST- 2008/03/01 09:00 [pubmed] PHST- 2008/09/30 09:00 [medline] PHST- 2008/03/01 09:00 [entrez] AID - S0898-6568(08)00035-1 [pii] AID - 10.1016/j.cellsig.2008.01.020 [doi] PST - ppublish SO - Cell Signal. 2008 Jun;20(6):1084-91. doi: 10.1016/j.cellsig.2008.01.020. Epub 2008 Feb 1. PMID- 18202095 OWN - NLM STAT- MEDLINE DCOM- 20080423 LR - 20211020 IS - 1469-7793 (Electronic) IS - 0022-3751 (Print) IS - 0022-3751 (Linking) VI - 586 IP - 6 DP - 2008 Mar 15 TI - Developmental presence and disappearance of postsynaptically silent synapses on dendritic spines of rat layer 2/3 pyramidal neurons. PG - 1519-27 LID - 10.1113/jphysiol.2007.149336 [doi] AB - Silent synapses are synapses whose activation evokes NMDA-type glutamate receptor (NMDAR) but not AMPA-type glutamate receptor (AMPAR) mediated currents. Silent synapses are prominent early in postnatal development and are thought to play a role in the activity- and sensory-dependent refinement of neuronal circuits. The mechanisms that account for their silent nature have been controversial, and both presynaptic and postsynaptic mechanisms have been proposed. Here, we use two-photon laser uncaging of glutamate to directly activate glutamate receptors and measure AMPAR- and NMDAR-dependent currents on individual dendritic spines of rat somatosensory cortical layer 2/3 pyramidal neurons. We find that dendritic spines lacking functional surface AMPARs are commonly found before postnatal day 12 (P12) but are absent in older animals. Furthermore, AMPAR-lacking spines are contacted by release-competent presynaptic terminals. After P12, the AMPAR/NMDAR current ratio at individual spines continues to increase, consistent with continued addition of AMPARs to postsynaptic terminals. Our results confirm the existence of postsynaptically silent synapses and demonstrate that the morphology of the spine is not strongly predictive of its AMPAR content. FAU - Busetto, Giuseppe AU - Busetto G AD - Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. FAU - Higley, Michael J AU - Higley MJ FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R01 NS046579-05/NS/NINDS NIH HHS/United States GR - T32 NS007484/NS/NINDS NIH HHS/United States GR - 5T32 NS07484/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20080117 PL - England TA - J Physiol JT - The Journal of physiology JID - 0266262 SB - IM MH - Action Potentials/*physiology MH - Aging/*physiology MH - Animals MH - Cells, Cultured MH - Dendritic Spines/*physiology MH - Nerve Net/physiology MH - Neural Inhibition/*physiology MH - Neuronal Plasticity/*physiology MH - Pyramidal Cells/*physiology MH - Rats MH - Rats, Sprague-Dawley MH - Synapses/*physiology PMC - PMC2375692 EDAT- 2008/01/19 09:00 MHDA- 2008/04/24 09:00 CRDT- 2008/01/19 09:00 PHST- 2008/01/19 09:00 [pubmed] PHST- 2008/04/24 09:00 [medline] PHST- 2008/01/19 09:00 [entrez] AID - jphysiol.2007.149336 [pii] AID - 10.1113/jphysiol.2007.149336 [doi] PST - ppublish SO - J Physiol. 2008 Mar 15;586(6):1519-27. doi: 10.1113/jphysiol.2007.149336. Epub 2008 Jan 17. PMID- 18096597 OWN - NLM STAT- MEDLINE DCOM- 20080423 LR - 20211020 IS - 1469-7793 (Electronic) IS - 0022-3751 (Print) IS - 0022-3751 (Linking) VI - 586 IP - 6 DP - 2008 Mar 15 TI - Regulation of synaptic signalling by postsynaptic, non-glutamate receptor ion channels. PG - 1475-80 AB - Activation of glutamatergic synapses onto pyramidal neurons produces a synaptic depolarization as well as a buildup of intracellular calcium (Ca(2+)). The synaptic depolarization propagates through the dendritic arbor and can be detected at the soma with a recording electrode. Current influx through AMPA-type glutamate receptors (AMPARs) provides the depolarizing drive, and the amplitudes of synaptic potentials are generally thought to reflect the number and properties of these receptors at each synapse. In contrast, synaptically evoked Ca(2+) transients are limited to the spine containing the active synapse and result primarily from Ca(2+) influx through NMDA-type glutamate receptors (NMDARs). Here we review recent studies that reveal that both synaptic depolarizations and spine head Ca(2+) transients are strongly regulated by the activity of postsynaptic, non-glutamate receptor ion channels. In hippocampal pyramidal neurons, voltage- and Ca(2+)-gated ion channels located in dendritic spines open as downstream consequences of glutamate receptor activation and act within a complex signalling loop that feeds back to regulate synaptic signals. Dynamic regulation of these ion channels offers a powerful mechanism of synaptic plasticity that is independent of direct modulation of glutamate receptors. FAU - Bloodgood, Brenda L AU - Bloodgood BL AD - Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Review DEP - 20071220 PL - England TA - J Physiol JT - The Journal of physiology JID - 0266262 RN - 0 (Receptors, Glutamate) RN - 0 (Receptors, N-Methyl-D-Aspartate) SB - IM MH - Animals MH - Calcium Signaling/*physiology MH - Excitatory Postsynaptic Potentials/*physiology MH - Feedback/physiology MH - Ion Channel Gating/*physiology MH - Pyramidal Cells/*physiology MH - Receptors, Glutamate/*metabolism MH - Receptors, N-Methyl-D-Aspartate/*metabolism MH - Synaptic Transmission/*physiology PMC - PMC2375695 EDAT- 2007/12/22 09:00 MHDA- 2008/04/24 09:00 CRDT- 2007/12/22 09:00 PHST- 2007/12/22 09:00 [pubmed] PHST- 2008/04/24 09:00 [medline] PHST- 2007/12/22 09:00 [entrez] AID - jphysiol.2007.148353 [pii] AID - 10.1113/jphysiol.2007.148353 [doi] PST - ppublish SO - J Physiol. 2008 Mar 15;586(6):1475-80. doi: 10.1113/jphysiol.2007.148353. Epub 2007 Dec 20. PMID- 18097394 OWN - NLM STAT- MEDLINE DCOM- 20080129 LR - 20131121 IS - 1476-4687 (Electronic) IS - 0028-0836 (Linking) VI - 450 IP - 7173 DP - 2007 Dec 20 TI - Neuroscience: neighbourly synapses. PG - 1173-5 FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng PT - Comment PT - News PL - England TA - Nature JT - Nature JID - 0410462 RN - 3KX376GY7L (Glutamic Acid) SB - IM CON - Nature. 2007 Dec 20;450(7173):1195-200. PMID: 18097401 MH - Animals MH - Dendrites/*metabolism MH - Glutamic Acid/metabolism MH - Humans MH - Learning/*physiology MH - Long-Term Potentiation/*physiology MH - Mice MH - Models, Neurological MH - Pyramidal Cells/*metabolism MH - Synapses/*metabolism EDAT- 2007/12/22 09:00 MHDA- 2008/01/30 09:00 CRDT- 2007/12/22 09:00 PHST- 2007/12/22 09:00 [pubmed] PHST- 2008/01/30 09:00 [medline] PHST- 2007/12/22 09:00 [entrez] AID - 4501173a [pii] AID - 10.1038/4501173a [doi] PST - ppublish SO - Nature. 2007 Dec 20;450(7173):1173-5. doi: 10.1038/4501173a. PMID- 17629570 OWN - NLM STAT- MEDLINE DCOM- 20071012 LR - 20181113 IS - 0165-0270 (Print) IS - 0165-0270 (Linking) VI - 165 IP - 1 DP - 2007 Sep 15 TI - A novel computational approach for automatic dendrite spines detection in two-photon laser scan microscopy. PG - 122-34 AB - BACKGROUND: Recent research has shown that there is a strong correlation between the functional properties of a neuron and its morphologic structure. Current morphologic analyses typically involve a significant component of computer-assisted manual labor, which is very time-consuming and is susceptible to operator bias. The existing semi-automatic approaches largely reduce user efforts. However, some manual interventions, such as setting a global threshold for segmentation, are still needed during image processing. METHODS: We present an automated approach, which can greatly help neurobiologists obtain quantitative morphological information about a neuron and its spines. The automation includes an adaptive thresholding method, which can yield better segment results than the prevalent global thresholding method. It also introduces an efficient backbone extraction method, a SNR based, detached spine component detection method, and an attached spine component detection method based on the estimation of local dendrite morphology. RESULTS: The morphology information obtained both manually and automatically are compared in detail. Using the Kolmogov-Smirnov test, we find a 99.13% probability that the dendrite length distributions are the same for the automatic and manual processing methods. The spine detection results are also compared with other existing semi-automatic approaches. The comparison results show that our approach has 33% fewer false positives and 77% fewer false negatives on average. CONCLUSIONS: Because the proposed detection algorithm requires less user input and performs better than existing algorithms, our approach can quickly and accurately process neuron images without user intervention. FAU - Cheng, Jie AU - Cheng J AD - The Methodist Hospital Research Institute, Radiology Department, Houston, Texas 77030-2707, USA. FAU - Zhou, Xiaobo AU - Zhou X FAU - Miller, Eric AU - Miller E FAU - Witt, Rochelle M AU - Witt RM FAU - Zhu, Jinmin AU - Zhu J FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Wong, Steven T C AU - Wong ST LA - eng GR - R01 LM009161-01A1/LM/NLM NIH HHS/United States GR - R01 NS052707-02/NS/NINDS NIH HHS/United States GR - R01 LM008696/LM/NLM NIH HHS/United States GR - R01 NS052707/NS/NINDS NIH HHS/United States GR - R01 LM009161/LM/NLM NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20070524 PL - Netherlands TA - J Neurosci Methods JT - Journal of neuroscience methods JID - 7905558 SB - IM MH - Algorithms MH - Dendritic Spines/*ultrastructure MH - Image Processing, Computer-Assisted/*methods MH - Microscopy, Confocal MH - Photons PMC - PMC1989684 MID - NIHMS28209 EDAT- 2007/07/17 09:00 MHDA- 2007/10/13 09:00 CRDT- 2007/07/17 09:00 PHST- 2007/03/23 00:00 [received] PHST- 2007/05/17 00:00 [revised] PHST- 2007/05/17 00:00 [accepted] PHST- 2007/07/17 09:00 [pubmed] PHST- 2007/10/13 09:00 [medline] PHST- 2007/07/17 09:00 [entrez] AID - S0165-0270(07)00229-4 [pii] AID - 10.1016/j.jneumeth.2007.05.020 [doi] PST - ppublish SO - J Neurosci Methods. 2007 Sep 15;165(1):122-34. doi: 10.1016/j.jneumeth.2007.05.020. Epub 2007 May 24. PMID- 17699678 OWN - NLM STAT- MEDLINE DCOM- 20070914 LR - 20200225 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 27 IP - 33 DP - 2007 Aug 15 TI - Timing and location of synaptic inputs determine modes of subthreshold integration in striatal medium spiny neurons. PG - 8967-77 AB - Medium spiny neurons (MSNs) are the principal cells of the striatum and perform a central role in sensorimotor processing. MSNs must integrate many excitatory inputs located across their dendrites to fire action potentials and enable striatal function. However, the dependence of synaptic responses on the temporal and spatial distribution of these inputs remains unknown. Here, we use whole-cell recordings, two-photon microscopy, and two-photon glutamate uncaging to examine subthreshold synaptic integration in MSNs from acute rat brain slices. We find that synaptic responses can summate sublinearly, linearly, or supralinearly depending on the spatiotemporal pattern of activity. Repetitive activity at single inputs leads to sublinear summation, reflecting long-lived AMPA receptor desensitization. In contrast, asynchronous activity at multiple inputs generates linear summation, with synapses on neighboring spines functioning independently. Finally, synchronous activity at multiple inputs triggers supralinear summation at depolarized potentials, reflecting activation of NMDA receptors and L-type calcium channels. Thus, the properties of subthreshold integration in MSNs are determined by the distribution of synaptic inputs and the differential activation of multiple postsynaptic conductances. FAU - Carter, Adam G AU - Carter AG AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Soler-Llavina, Gilberto J AU - Soler-Llavina GJ FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - F31 NS049655-01/NS/NINDS NIH HHS/United States GR - R01 NS046579-01A/NS/NINDS NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - F31 NS049655/NS/NINDS NIH HHS/United States GR - R01 NS046579-06A1/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (Receptors, AMPA) RN - 3KX376GY7L (Glutamic Acid) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Animals, Newborn MH - Calcium/metabolism MH - Corpus Striatum/*cytology MH - Dendritic Spines/*physiology MH - Electric Stimulation/methods MH - Excitatory Amino Acid Antagonists/pharmacology MH - Excitatory Postsynaptic Potentials/physiology/radiation effects MH - Glutamic Acid/metabolism MH - In Vitro Techniques MH - Neurons/classification/*physiology MH - Nonlinear Dynamics MH - Patch-Clamp Techniques/methods MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, AMPA/physiology MH - Synapses/drug effects/*physiology/radiation effects PMC - PMC6672187 EDAT- 2007/08/19 09:00 MHDA- 2007/09/15 09:00 CRDT- 2007/08/19 09:00 PHST- 2007/08/19 09:00 [pubmed] PHST- 2007/09/15 09:00 [medline] PHST- 2007/08/19 09:00 [entrez] AID - 27/33/8967 [pii] AID - 3258166 [pii] AID - 10.1523/JNEUROSCI.2798-07.2007 [doi] PST - ppublish SO - J Neurosci. 2007 Aug 15;27(33):8967-77. doi: 10.1523/JNEUROSCI.2798-07.2007. PMID- 17626197 OWN - NLM STAT- MEDLINE DCOM- 20070807 LR - 20220309 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 27 IP - 28 DP - 2007 Jul 11 TI - Distinct structural and ionotropic roles of NMDA receptors in controlling spine and synapse stability. PG - 7365-76 AB - NMDA-type glutamate receptors (NMDARs) play a central role in the rapid regulation of synaptic transmission, but their contribution to the long-term stabilization of glutamatergic synapses is unknown. We find that, in hippocampal pyramidal neurons in rat organotypic slices, pharmacological blockade of NMDARs does not affect synapse formation and dendritic spine growth but does increase the motility of spines. Physical loss of synaptic NMDARs induced by RNA interference against the NR1 subunit of the receptor also increases the motility of spines. Furthermore, knock-down of NMDARs, but not their pharmacological block, destabilizes spine structure and over time leads to loss of spines and excitatory synapses. Maintenance of normal spine density requires the coexpression of two specific splice isoforms of the NR1 subunit that contain the C-terminal C2 cassette. Thus, although ionotropic properties of NMDARs induce synaptic plasticity, it is the physical interactions of the C-tail of the receptor that mediate the long-term stabilization of synapses and spines. FAU - Alvarez, Veronica A AU - Alvarez VA AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Ridenour, Dennis A AU - Ridenour DA FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - T32 NS007484/NS/NINDS NIH HHS/United States GR - 5T32 NS07484/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Disks Large Homolog 4 Protein) RN - 0 (Dlg4 protein, rat) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Membrane Proteins) RN - 0 (NR1 NMDA receptor) RN - 0 (Receptors, AMPA) RN - 0 (Receptors, N-Methyl-D-Aspartate) SB - IM MH - Animals MH - Dendritic Spines/*physiology/ultrastructure MH - Disks Large Homolog 4 Protein MH - Electric Conductivity MH - Excitatory Postsynaptic Potentials MH - Hippocampus/cytology/*physiology/ultrastructure MH - In Vitro Techniques MH - Intracellular Signaling Peptides and Proteins/metabolism MH - Membrane Proteins/metabolism MH - Neuronal Plasticity/physiology MH - Pyramidal Cells/metabolism/*physiology/ultrastructure MH - RNA Interference MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, AMPA/metabolism MH - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/genetics/*physiology MH - Signal Transduction/physiology MH - Synapses/metabolism/*physiology PMC - PMC6672602 EDAT- 2007/07/13 09:00 MHDA- 2007/08/08 09:00 CRDT- 2007/07/13 09:00 PHST- 2007/07/13 09:00 [pubmed] PHST- 2007/08/08 09:00 [medline] PHST- 2007/07/13 09:00 [entrez] AID - 27/28/7365 [pii] AID - 3241649 [pii] AID - 10.1523/JNEUROSCI.0956-07.2007 [doi] PST - ppublish SO - J Neurosci. 2007 Jul 11;27(28):7365-76. doi: 10.1523/JNEUROSCI.0956-07.2007. PMID- 17451936 OWN - NLM STAT- MEDLINE DCOM- 20071002 LR - 20161025 IS - 0959-4388 (Print) IS - 0959-4388 (Linking) VI - 17 IP - 3 DP - 2007 Jun TI - Ca(2+) signaling in dendritic spines. PG - 345-51 AB - Recent studies have revealed that Ca(2+) signals evoked by action potentials or by synaptic activity within individual dendritic spines are regulated at multiple levels. Ca(2+) influx through glutamate receptors and voltage-sensitive Ca(2+) channels located on spines depends on the channel subunit composition, the activity of kinases and phosphatases, the local membrane potential and past patterns of activity. Furthermore, sources of spine Ca(2+) interact nonlinearly such that activation of one Ca(2+) channel can enhance or depress the activity of others. These studies have revealed that each spine is a complex and partitioned Ca(2+) signaling domain capable of autonomously regulating the electrical and biochemical consequences of synaptic activity. FAU - Bloodgood, Brenda L AU - Bloodgood BL AD - Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Review DEP - 20070423 PL - England TA - Curr Opin Neurobiol JT - Current opinion in neurobiology JID - 9111376 RN - 0 (Calcium Channels) RN - 0 (Receptors, Glutamate) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Calcium/metabolism MH - Calcium Channels/physiology MH - Calcium Signaling/*physiology MH - Dendritic Spines/*physiology MH - Models, Biological MH - Neurons/cytology MH - Receptors, Glutamate/metabolism RF - 75 EDAT- 2007/04/25 09:00 MHDA- 2007/10/03 09:00 CRDT- 2007/04/25 09:00 PHST- 2007/02/20 00:00 [received] PHST- 2007/04/11 00:00 [accepted] PHST- 2007/04/25 09:00 [pubmed] PHST- 2007/10/03 09:00 [medline] PHST- 2007/04/25 09:00 [entrez] AID - S0959-4388(07)00057-8 [pii] AID - 10.1016/j.conb.2007.04.003 [doi] PST - ppublish SO - Curr Opin Neurobiol. 2007 Jun;17(3):345-51. doi: 10.1016/j.conb.2007.04.003. Epub 2007 Apr 23. PMID- 17448688 OWN - NLM STAT- MEDLINE DCOM- 20070718 LR - 20191210 IS - 1053-8119 (Print) IS - 1053-8119 (Linking) VI - 36 IP - 2 DP - 2007 Jun TI - Dendritic spine detection using curvilinear structure detector and LDA classifier. PG - 346-60 AB - Dendritic spines are small, bulbous cellular compartments that carry synapses. Biologists have been studying the biochemical pathways by examining the morphological and statistical changes of the dendritic spines at the intracellular level. In this paper a novel approach is presented for automated detection of dendritic spines in neuron images. The dendritic spines are recognized as small objects of variable shape attached or detached to multiple dendritic backbones in the 2D projection of the image stack along the optical direction. We extend the curvilinear structure detector to extract the boundaries as well as the centerlines for the dendritic backbones and spines. We further build a classifier using Linear Discriminate Analysis (LDA) to classify the attached spines into valid and invalid types to improve the accuracy of the spine detection. We evaluate the proposed approach by comparing with the manual results in terms of backbone length, spine number, spine length, and spine density. FAU - Zhang, Yong AU - Zhang Y AD - Center for Bioinformatics, Harvard Center for Neurodegeneration and Repair, Harvard Medical School, Boston, MA 02215, USA. FAU - Zhou, Xiaobo AU - Zhou X FAU - Witt, Rochelle M AU - Witt RM FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Adjeroh, Donald AU - Adjeroh D FAU - Wong, Stephen T C AU - Wong ST LA - eng GR - R01 NS052707/NS/NINDS NIH HHS/United States GR - R01 NS052707-01A2/NS/NINDS NIH HHS/United States GR - R01 LM0008696/LM/NLM NIH HHS/United States PT - Evaluation Study PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20070313 PL - United States TA - Neuroimage JT - NeuroImage JID - 9215515 SB - IM MH - *Algorithms MH - *Artificial Intelligence MH - Computer Graphics MH - Dendrites/*diagnostic imaging MH - Discriminant Analysis MH - Image Enhancement/*methods MH - Image Interpretation, Computer-Assisted/*methods MH - Imaging, Three-Dimensional/*methods MH - Numerical Analysis, Computer-Assisted MH - Pattern Recognition, Automated/*methods MH - Reproducibility of Results MH - Sensitivity and Specificity MH - Ultrasonography EDAT- 2007/04/24 09:00 MHDA- 2007/07/19 09:00 CRDT- 2007/04/24 09:00 PHST- 2006/10/25 00:00 [received] PHST- 2007/02/24 00:00 [revised] PHST- 2007/02/27 00:00 [accepted] PHST- 2007/04/24 09:00 [pubmed] PHST- 2007/07/19 09:00 [medline] PHST- 2007/04/24 09:00 [entrez] AID - S1053-8119(07)00170-X [pii] AID - 10.1016/j.neuroimage.2007.02.044 [doi] PST - ppublish SO - Neuroimage. 2007 Jun;36(2):346-60. doi: 10.1016/j.neuroimage.2007.02.044. Epub 2007 Mar 13. PMID- 17360908 OWN - NLM STAT- MEDLINE DCOM- 20070405 LR - 20220331 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 27 IP - 11 DP - 2007 Mar 14 TI - Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. PG - 2866-75 AB - Alzheimer's disease (AD) is characterized by decreased synapse density in hippocampus and neocortex, and synapse loss is the strongest anatomical correlate of the degree of clinical impairment. Although considerable evidence supports a causal role for the amyloid-beta protein (Abeta) in AD, a direct link between a specific form of Abeta and synapse loss has not been established. We demonstrate that physiological concentrations of naturally secreted Abeta dimers and trimers, but not monomers, induce progressive loss of hippocampal synapses. Pyramidal neurons in rat organotypic slices had markedly decreased density of dendritic spines and numbers of electrophysiologically active synapses after exposure to picomolar levels of soluble oligomers. Spine loss was reversible and was prevented by Abeta-specific antibodies or a small-molecule modulator of Abeta aggregation. Mechanistically, Abeta-mediated spine loss required activity of NMDA-type glutamate receptors (NMDARs) and occurred through a pathway involving cofilin and calcineurin. Furthermore, NMDAR-mediated calcium influx into active spines was reduced by Abeta oligomers. Partial blockade of NMDARs by pharmacological antagonists was sufficient to trigger spine loss. We conclude that soluble, low-n oligomers of human Abeta trigger synapse loss that can be reversed by therapeutic agents. Our approach provides a quantitative cellular model for elucidating the molecular basis of Abeta-induced neuronal dysfunction. FAU - Shankar, Ganesh M AU - Shankar GM AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Bloodgood, Brenda L AU - Bloodgood BL FAU - Townsend, Matthew AU - Townsend M FAU - Walsh, Dominic M AU - Walsh DM FAU - Selkoe, Dennis J AU - Selkoe DJ FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 AG027443/AG/NIA NIH HHS/United States GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R01 NS046579-05/NS/NINDS NIH HHS/United States GR - 1R01AG027443/AG/NIA NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Amyloid beta-Peptides) RN - 0 (Receptors, N-Methyl-D-Aspartate) SB - IM MH - Alzheimer Disease/metabolism/pathology MH - Amyloid beta-Peptides/*physiology MH - Animals MH - CHO Cells MH - Cells, Cultured MH - Cricetinae MH - Cricetulus MH - Excitatory Postsynaptic Potentials/physiology MH - Humans MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/*physiology MH - Signal Transduction/*physiology MH - Synapses/*pathology/*physiology PMC - PMC6672572 EDAT- 2007/03/16 09:00 MHDA- 2007/04/06 09:00 CRDT- 2007/03/16 09:00 PHST- 2007/03/16 09:00 [pubmed] PHST- 2007/04/06 09:00 [medline] PHST- 2007/03/16 09:00 [entrez] AID - 27/11/2866 [pii] AID - 3200276 [pii] AID - 10.1523/JNEUROSCI.4970-06.2007 [doi] PST - ppublish SO - J Neurosci. 2007 Mar 14;27(11):2866-75. doi: 10.1523/JNEUROSCI.4970-06.2007. PMID- 17224406 OWN - NLM STAT- MEDLINE DCOM- 20070227 LR - 20220408 IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 53 IP - 2 DP - 2007 Jan 18 TI - Nonlinear regulation of unitary synaptic signals by CaV(2.3) voltage-sensitive calcium channels located in dendritic spines. PG - 249-60 AB - The roles of voltage-sensitive sodium (Na) and calcium (Ca) channels located on dendrites and spines in regulating synaptic signals are largely unknown. Here we use 2-photon glutamate uncaging to stimulate individual spines while monitoring uncaging-evoked excitatory postsynaptic potentials (uEPSPs) and Ca transients. We find that, in CA1 pyramidal neurons in acute mouse hippocampal slices, CaV(2.3) voltage-sensitive Ca channels (VSCCs) are found selectively on spines and act locally to dampen uncaging-evoked Ca transients and somatic potentials. These effects are mediated by a regulatory loop that requires opening of CaV(2.3) channels, voltage-gated Na channels, small conductance Ca-activated potassium (SK) channels, and NMDA receptors. Ca influx through CaV(2.3) VSCCs selectively activates SK channels, revealing the presence of functional Ca microdomains within the spine. Our results suggest that synaptic strength can be modulated by mechanisms that regulate voltage-gated conductances within the spine but do not alter the properties or numbers of synaptic glutamate receptors. FAU - Bloodgood, Brenda L AU - Bloodgood BL AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - R01 NS046579-01A/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Cacna1e protein, mouse) RN - 0 (Calcium Channels, R-Type) RN - 0 (Cation Transport Proteins) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (Small-Conductance Calcium-Activated Potassium Channels) RN - 0 (Sodium Channels) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Calcium/metabolism MH - Calcium Channels, R-Type/chemistry/*physiology MH - Cation Transport Proteins/chemistry/*physiology MH - Dendritic Spines/*metabolism MH - Electrophysiology MH - Excitatory Postsynaptic Potentials MH - Hippocampus/metabolism/*physiology MH - In Vitro Techniques MH - Ion Channel Gating MH - Mice MH - Mice, Inbred C57BL MH - Protein Structure, Tertiary MH - Pyramidal Cells/metabolism/*physiology MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Small-Conductance Calcium-Activated Potassium Channels/metabolism MH - Sodium Channels/metabolism MH - Synapses/*physiology MH - Temperature EDAT- 2007/01/17 09:00 MHDA- 2007/02/28 09:00 CRDT- 2007/01/17 09:00 PHST- 2006/06/26 00:00 [received] PHST- 2006/11/10 00:00 [revised] PHST- 2006/12/14 00:00 [accepted] PHST- 2007/01/17 09:00 [pubmed] PHST- 2007/02/28 09:00 [medline] PHST- 2007/01/17 09:00 [entrez] AID - S0896-6273(06)01022-1 [pii] AID - 10.1016/j.neuron.2006.12.017 [doi] PST - ppublish SO - Neuron. 2007 Jan 18;53(2):249-60. doi: 10.1016/j.neuron.2006.12.017. PMID- 17280523 OWN - NLM STAT- MEDLINE DCOM- 20070921 LR - 20220330 IS - 0147-006X (Print) IS - 0147-006X (Linking) VI - 30 DP - 2007 TI - Anatomical and physiological plasticity of dendritic spines. PG - 79-97 AB - In excitatory neurons, most glutamatergic synapses are made on the heads of dendritic spines, each of which houses the postsynaptic terminal of a single glutamatergic synapse. We review recent studies demonstrating in vivo that spines are motile and plastic structures whose morphology and lifespan are influenced, even in adult animals, by changes in sensory input. However, most spines that appear in adult animals are transient, and the addition of stable spines and synapses is rare. In vitro studies have shown that patterns of neuronal activity known to induce synaptic plasticity can also trigger changes in spine morphology. Therefore, it is tempting to speculate that the plastic changes of spine morphology reflect the dynamic state of its associated synapse and are responsible to some extent for neuronal circuitry remodeling. Nevertheless, morphological changes are not required for all forms of synaptic plasticity, and whether changes in the spine shape and size significantly impact synaptic signals is unclear. FAU - Alvarez, Veronica A AU - Alvarez VA AD - Harvard Medical School, Department of Neurobiology, Boston, Massachusetts 02115, USA. valvarez@hms.harvard.edu FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States PT - Journal Article PT - Review PL - United States TA - Annu Rev Neurosci JT - Annual review of neuroscience JID - 7804039 SB - IM MH - Aging/physiology MH - Animals MH - Brain/*physiology/ultrastructure MH - Dendritic Spines/*physiology/ultrastructure MH - Humans MH - Membrane Potentials/physiology MH - Neural Pathways/physiology/ultrastructure MH - Neuronal Plasticity/*physiology MH - Sensation/physiology MH - Synapses/*physiology/ultrastructure MH - Synaptic Transmission/*physiology RF - 84 EDAT- 2007/02/07 09:00 MHDA- 2007/09/22 09:00 CRDT- 2007/02/07 09:00 PHST- 2007/02/07 09:00 [pubmed] PHST- 2007/09/22 09:00 [medline] PHST- 2007/02/07 09:00 [entrez] AID - 10.1146/annurev.neuro.30.051606.094222 [doi] PST - ppublish SO - Annu Rev Neurosci. 2007;30:79-97. doi: 10.1146/annurev.neuro.30.051606.094222. PMID- 16870727 OWN - NLM STAT- MEDLINE DCOM- 20060814 LR - 20220309 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 26 IP - 30 DP - 2006 Jul 26 TI - Retraction of synapses and dendritic spines induced by off-target effects of RNA interference. PG - 7820-5 AB - RNA interference (RNAi), which allows selective gene silencing, has been proposed for functional genomic analysis and for the treatment of human disease. However, induction of RNAi in mammalian cells by expression of double-stranded RNA can activate innate antiviral response pathways that perturb off-target gene expression. The activation and functional consequences of these effects in neurons are unknown. We find that expression of subsets of short hairpin RNAs (shRNAs) in rat hippocampal pyramidal neurons can have off-target effects that reduce the complexity of dendritic arbors and trigger the loss of dendritic spines. Morphological changes are accompanied by electrophysiological perturbations in passive membrane properties and a decrease in the number and strength of excitatory and inhibitory synapses. These perturbations depend on the shRNA sequence and are independent of the identity of the targeted protein. Our results indicate that off-target effects of RNAi severely perturb neuronal structure and function and may lead to the functional withdrawal of affected cells from the brain circuitry. FAU - Alvarez, Veronica A AU - Alvarez VA AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Ridenour, Dennis A AU - Ridenour DA FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - 5T32 NS07484/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Nerve Tissue Proteins) SB - IM MH - Adaptation, Physiological/genetics MH - Animals MH - Cells, Cultured MH - Dendritic Spines/*physiology/*ultrastructure MH - Hippocampus/physiology/ultrastructure MH - Nerve Tissue Proteins/*genetics/*metabolism MH - RNA Interference/*physiology MH - Rats MH - Rats, Sprague-Dawley MH - Synapses/*physiology/*ultrastructure PMC - PMC6674211 EDAT- 2006/07/28 09:00 MHDA- 2006/08/15 09:00 CRDT- 2006/07/28 09:00 PHST- 2006/07/28 09:00 [pubmed] PHST- 2006/08/15 09:00 [medline] PHST- 2006/07/28 09:00 [entrez] AID - 26/30/7820 [pii] AID - 10.1523/JNEUROSCI.1957-06.2006 [doi] PST - ppublish SO - J Neurosci. 2006 Jul 26;26(30):7820-5. doi: 10.1523/JNEUROSCI.1957-06.2006. PMID- 16680164 OWN - NLM STAT- MEDLINE DCOM- 20060811 LR - 20220309 IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 9 IP - 6 DP - 2006 Jun TI - Synapse-specific plasticity and compartmentalized signaling in cerebellar stellate cells. PG - 798-806 AB - Here we demonstrate that cerebellar stellate cells diffusionally isolate synaptically evoked signals in dendrites and are capable of input-specific synaptic plasticity. Sustained activity of parallel fibers induces a form of long-term depression that requires opening of calcium (Ca(2+))-permeable AMPA-type glutamate receptors (CP-AMPARs) and signaling through class 1 metabotropic glutamate receptors (mGluR1) and CB1 receptors. This depression is induced by postsynaptic increases in Ca(2+) concentration ([Ca(2+)]) and is limited to activated synapses. To understand how synapse-specific plasticity is induced by diffusible second messengers in aspiny dendrites, we examined diffusion of Ca(2+) and small molecules within stellate cell dendrites. Activation of a single parallel fiber opened CP-AMPARs, generating long-lived Ca(2+) transients that were confined to submicron dendritic stretches. The diffusion of Ca(2+) was severely retarded due to interactions with parvalbumin and a general restriction of small molecule mobility. Thus stellate cell dendrites spatially restrict signaling cascades that lead from CP-AMPAR activation to endocannabinoid production and trigger the selective regulation of active synapses. FAU - Soler-Llavina, Gilberto J AU - Soler-Llavina GJ AD - Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579/NS/NINDS NIH HHS/United States GR - 1 F31 NS049655-01/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20060507 PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 0 (Calcium Channels) RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (Parvalbumins) RN - 0 (Receptor, Cannabinoid, CB1) RN - 0 (Receptors, AMPA) RN - 0 (Receptors, Metabotropic Glutamate) RN - 0 (metabotropic glutamate receptor type 1) RN - SY7Q814VUP (Calcium) SB - IM CIN - Nat Neurosci. 2006 Jun;9(6):719-20. PMID: 16732199 MH - Animals MH - Calcium/metabolism MH - Calcium Channels/drug effects/metabolism MH - Calcium Signaling/drug effects/physiology MH - Cell Compartmentation/physiology MH - Cerebellar Cortex/cytology/drug effects/*physiology MH - Dendrites/drug effects/*physiology MH - Electric Stimulation MH - Excitatory Amino Acid Antagonists/pharmacology MH - Interneurons/drug effects/*physiology MH - Long-Term Synaptic Depression/drug effects/physiology MH - Neuronal Plasticity/*physiology MH - Organ Culture Techniques MH - Parvalbumins/metabolism MH - Patch-Clamp Techniques MH - Rats MH - Receptor, Cannabinoid, CB1/drug effects/metabolism MH - Receptors, AMPA/drug effects/metabolism MH - Receptors, Metabotropic Glutamate/drug effects/metabolism MH - Signal Transduction/drug effects/physiology MH - Synapses/drug effects/*physiology MH - Synaptic Membranes/drug effects/metabolism MH - Synaptic Transmission/*physiology EDAT- 2006/05/09 09:00 MHDA- 2006/08/12 09:00 CRDT- 2006/05/09 09:00 PHST- 2006/03/21 00:00 [received] PHST- 2006/04/17 00:00 [accepted] PHST- 2006/05/09 09:00 [pubmed] PHST- 2006/08/12 09:00 [medline] PHST- 2006/05/09 09:00 [entrez] AID - nn1698 [pii] AID - 10.1038/nn1698 [doi] PST - ppublish SO - Nat Neurosci. 2006 Jun;9(6):798-806. doi: 10.1038/nn1698. Epub 2006 May 7. PMID- 16595860 OWN - NLM STAT- MEDLINE DCOM- 20060522 LR - 20181201 IS - 1539-2791 (Print) IS - 1539-2791 (Linking) VI - 4 IP - 1 DP - 2006 Winter TI - Mutual information-based feature selection in studying perturbation of dendritic structure caused by TSC2 inactivation. PG - 81-94 AB - In this study, the effect of protein Tuberous sclerosis 2 (TSC2) on the dendritic spine density and length was demonstrated by using TSC2-RNAinactivation. In addition, the role of rapamycin, an antagonist of the molecular target of rapamycin, in the morphological changes of spine caused by TSC2 silencing was investigated. The features were extracted from highresolution three-dimensional image stacks collected by two-photon laser scanning microscopy of green fluorescing pyramidal cells expressing TSC2-RNA interference (RNAi), or TSC2-RNAi and rapamycin treatment in rat hippocampal slice cultures. We proposed to apply the lognormal distribution method for feature extraction. The extracted features of three cases under investigation, namely, (1) green-fluorescent protein GFP vs TSC2-RNAi, (2) GFP vs TSC2-RNAi and rapamycin, and (3) TSC2-RNAi vs TSC2-RNAi and rapamycin, were analyzed by mutual information-based feature selection and evaluated by three classifiers, K-nearest neighbor, Perceptron, and two-layer neural networks. The results showed that both the spine density and length have significant morphological changes after TSC2-RNAi treatment. However, rapamycin treatment could reverse the effect of TSC2-RNAi on spine length but not on spine density. These results are consistent with the results reported in the scientific literature. Finally, we explored the application of pattern recognition method in a small sample with richer feature properties, namely bootstrap mutual information estimation and a mutual information- based feature selection method. FAU - Zhou, Xiaobo AU - Zhou X AD - HCNR -- Center for Bioinformatics, Harvard Medical School, Boston, Massachusetts 02215, USA. FAU - Zhu, Jinmin AU - Zhu J FAU - Liu, Kuang-Yu AU - Liu KY FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Wong, Stephen T C AU - Wong ST LA - eng GR - R01 NS052707/NS/NINDS NIH HHS/United States GR - R01 NS052707-01A2/NS/NINDS NIH HHS/United States PT - Journal Article PL - United States TA - Neuroinformatics JT - Neuroinformatics JID - 101142069 RN - 0 (Dyt1 protein, mouse) RN - 0 (Molecular Chaperones) RN - 0 (Tsc2 protein, mouse) RN - 0 (Tsc2 protein, rat) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - 0 (Tumor Suppressor Proteins) RN - 147336-22-9 (Green Fluorescent Proteins) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Algorithms MH - Animals MH - Cell Differentiation/*genetics MH - Cell Shape/drug effects/physiology MH - Cerebral Cortex/abnormalities/*pathology/physiopathology MH - Dendritic Spines/metabolism/*pathology MH - Gene Silencing MH - Green Fluorescent Proteins MH - Image Cytometry/*methods/trends MH - Microscopy, Confocal/methods/trends MH - Molecular Chaperones/metabolism MH - Organ Culture Techniques MH - Pyramidal Cells/metabolism/pathology MH - RNA Interference MH - Rats MH - Sirolimus/pharmacology MH - Software MH - Tuberous Sclerosis/genetics/*pathology/physiopathology MH - Tuberous Sclerosis Complex 2 Protein MH - Tumor Suppressor Proteins/*genetics EDAT- 2006/04/06 09:00 MHDA- 2006/05/23 09:00 CRDT- 2006/04/06 09:00 PHST- 1999/11/30 00:00 [received] PHST- 1999/11/30 00:00 [revised] PHST- 1999/11/30 00:00 [accepted] PHST- 2006/04/06 09:00 [pubmed] PHST- 2006/05/23 09:00 [medline] PHST- 2006/04/06 09:00 [entrez] AID - NI:4:1:81 [pii] AID - 10.1385/NI:4:1:81 [doi] PST - ppublish SO - Neuroinformatics. 2006 Winter;4(1):81-94. doi: 10.1385/NI:4:1:81. PMID- 16286931 OWN - NLM STAT- MEDLINE DCOM- 20060124 LR - 20231120 IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 8 IP - 12 DP - 2005 Dec TI - Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. PG - 1727-34 AB - Mutations in the TSC1 or TSC2 tumor suppressor genes lead to tuberous sclerosis complex (TSC), a dominant hamartomatous disorder that often presents with mental retardation, epilepsy and autism. The etiology of these neurological symptoms is unclear and the function of the TSC pathway in neurons is unknown. We found that in post-mitotic, hippocampal pyramidal neurons of mice and rats, loss of Tsc1 or Tsc2 triggered enlargement of somas and dendritic spines and altered the properties of glutamatergic synapses. Furthermore, loss of a single copy of the Tsc1 gene was sufficient to perturb dendritic spine structure. Morphological changes required regulation of the actin-depolymerization factor cofilin at a conserved LIM-kinase phosphorylation site, the phosphorylation of which was increased by loss of Tsc2. Thus, the TSC pathway regulates growth and synapse function in neurons, and perturbations of neuronal structure and function are likely to contribute to the pathogenesis of the neurological symptoms of TSC. FAU - Tavazoie, Sohail F AU - Tavazoie SF AD - Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. FAU - Alvarez, Veronica A AU - Alvarez VA FAU - Ridenour, Dennis A AU - Ridenour DA FAU - Kwiatkowski, David J AU - Kwiatkowski DJ FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - 5T32 NS07484/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20051106 PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 0 (Cofilin 1) RN - 0 (TSC1 protein, human) RN - 0 (TSC2 protein, human) RN - 0 (Tsc1 protein, mouse) RN - 0 (Tsc1 protein, rat) RN - 0 (Tsc2 protein, mouse) RN - 0 (Tsc2 protein, rat) RN - 0 (Tuberous Sclerosis Complex 1 Protein) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - 0 (Tumor Suppressor Proteins) SB - IM MH - Animals MH - Brain/cytology/*growth & development/*metabolism MH - Cell Differentiation/*genetics MH - Cell Line MH - Cell Shape/genetics MH - Cofilin 1/metabolism MH - Dendritic Spines/metabolism/ultrastructure MH - Gene Expression Regulation, Developmental/genetics MH - Hippocampus/cytology/growth & development/metabolism MH - Humans MH - Mice MH - Mice, Knockout MH - Mice, Transgenic MH - Neurons/cytology/*metabolism MH - Phosphorylation MH - Pyramidal Cells/cytology/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Tuberous Sclerosis/genetics/metabolism/physiopathology MH - Tuberous Sclerosis Complex 1 Protein MH - Tuberous Sclerosis Complex 2 Protein MH - Tumor Suppressor Proteins/*genetics EDAT- 2005/11/16 09:00 MHDA- 2006/01/25 09:00 CRDT- 2005/11/16 09:00 PHST- 2005/06/28 00:00 [received] PHST- 2005/09/15 00:00 [accepted] PHST- 2005/11/16 09:00 [pubmed] PHST- 2006/01/25 09:00 [medline] PHST- 2005/11/16 09:00 [entrez] AID - nn1566 [pii] AID - 10.1038/nn1566 [doi] PST - ppublish SO - Nat Neurosci. 2005 Dec;8(12):1727-34. doi: 10.1038/nn1566. Epub 2005 Nov 6. PMID- 16272125 OWN - NLM STAT- MEDLINE DCOM- 20051123 LR - 20131121 IS - 1095-9203 (Electronic) IS - 0036-8075 (Linking) VI - 310 IP - 5749 DP - 2005 Nov 4 TI - Neuronal activity regulates diffusion across the neck of dendritic spines. PG - 866-9 AB - In mammalian excitatory neurons, dendritic spines are separated from dendrites by thin necks. Diffusion across the neck limits the chemical and electrical isolation of each spine. We found that spine/dendrite diffusional coupling is heterogeneous and uncovered a class of diffusionally isolated spines. The barrier to diffusion posed by the neck and the number of diffusionally isolated spines is bidirectionally regulated by neuronal activity. Furthermore, coincident synaptic activation and postsynaptic action potentials rapidly restrict diffusion across the neck. The regulation of diffusional coupling provides a possible mechanism for determining the amplitude of postsynaptic potentials and the accumulation of plasticity-inducing molecules within the spine head. FAU - Bloodgood, Brenda L AU - Bloodgood BL AD - Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Science JT - Science (New York, N.Y.) JID - 0404511 RN - 0 (GABA-A Receptor Antagonists) RN - 0 (Receptors, AMPA) RN - 0 (Receptors, GABA-A) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 3KX376GY7L (Glutamic Acid) SB - IM MH - Action Potentials MH - Animals MH - Cytoplasm/physiology MH - Dendrites/*physiology MH - Dendritic Spines/*physiology MH - Diffusion MH - Excitatory Postsynaptic Potentials MH - Fluorescence MH - GABA-A Receptor Antagonists MH - Glutamic Acid/metabolism MH - Green Fluorescent Proteins/metabolism MH - Hippocampus/physiology MH - Neurons/*physiology MH - Organ Culture Techniques MH - Patch-Clamp Techniques MH - Pyramidal Cells/physiology MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, AMPA/antagonists & inhibitors/metabolism MH - Receptors, GABA-A/metabolism MH - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism MH - Synapses/*physiology MH - Synaptic Transmission MH - Transfection MH - Viscosity EDAT- 2005/11/08 09:00 MHDA- 2005/12/13 09:00 CRDT- 2005/11/08 09:00 PHST- 2005/11/08 09:00 [pubmed] PHST- 2005/12/13 09:00 [medline] PHST- 2005/11/08 09:00 [entrez] AID - 310/5749/866 [pii] AID - 10.1126/science.1114816 [doi] PST - ppublish SO - Science. 2005 Nov 4;310(5749):866-9. doi: 10.1126/science.1114816. PMID- 15852011 OWN - NLM STAT- MEDLINE DCOM- 20050708 LR - 20220408 IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 8 IP - 5 DP - 2005 May TI - SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines. PG - 642-9 AB - Small-conductance Ca(2+)-activated K(+) channels (SK channels) influence the induction of synaptic plasticity at hippocampal CA3-CA1 synapses. We find that in mice, SK channels are localized to dendritic spines, and their activity reduces the amplitude of evoked synaptic potentials in an NMDA receptor (NMDAR)-dependent manner. Using combined two-photon laser scanning microscopy and two-photon laser uncaging of glutamate, we show that SK channels regulate NMDAR-dependent Ca(2+) influx within individual spines. SK channels are tightly coupled to synaptically activated Ca(2+) sources, and their activity reduces the amplitude of NMDAR-dependent Ca(2+) transients. These effects are mediated by a feedback loop within the spine head; during an excitatory postsynaptic potential (EPSP), Ca(2+) influx opens SK channels that provide a local shunting current to reduce the EPSP and promote rapid Mg(2+) block of the NMDAR. Thus, blocking SK channels facilitates the induction of long-term potentiation by enhancing NMDAR-dependent Ca(2+) signals within dendritic spines. FAU - Ngo-Anh, Thu Jennifer AU - Ngo-Anh TJ AD - Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. FAU - Bloodgood, Brenda L AU - Bloodgood BL FAU - Lin, Michael AU - Lin M FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Maylie, James AU - Maylie J FAU - Adelman, John P AU - Adelman JP LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. DEP - 20050424 PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 0 (Potassium Channel Blockers) RN - 0 (Potassium Channels, Calcium-Activated) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (Small-Conductance Calcium-Activated Potassium Channels) RN - 24345-16-2 (Apamin) RN - I38ZP9992A (Magnesium) RN - SY7Q814VUP (Calcium) SB - IM CIN - Nat Neurosci. 2005 May;8(5):550. PMID: 15856059 MH - Animals MH - Animals, Newborn MH - Apamin/pharmacology MH - Calcium/metabolism MH - Calcium Signaling/drug effects/*physiology MH - Cells, Cultured MH - Dendritic Spines/drug effects/*metabolism/ultrastructure MH - Excitatory Postsynaptic Potentials/drug effects/physiology MH - Feedback, Physiological/drug effects/*physiology MH - Hippocampus/cytology/*physiology MH - Immunohistochemistry MH - Magnesium/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Neuronal Plasticity/drug effects/physiology MH - Organ Culture Techniques MH - Potassium Channel Blockers/pharmacology MH - Potassium Channels, Calcium-Activated/drug effects/*metabolism MH - Receptors, N-Methyl-D-Aspartate/drug effects/*metabolism MH - Small-Conductance Calcium-Activated Potassium Channels MH - Synaptic Transmission/drug effects/physiology EDAT- 2005/04/27 09:00 MHDA- 2005/07/09 09:00 CRDT- 2005/04/27 09:00 PHST- 2005/03/11 00:00 [received] PHST- 2005/03/29 00:00 [accepted] PHST- 2005/04/27 09:00 [pubmed] PHST- 2005/07/09 09:00 [medline] PHST- 2005/04/27 09:00 [entrez] AID - nn1449 [pii] AID - 10.1038/nn1449 [doi] PST - ppublish SO - Nat Neurosci. 2005 May;8(5):642-9. doi: 10.1038/nn1449. Epub 2005 Apr 24. PMID- 15504328 OWN - NLM STAT- MEDLINE DCOM- 20050118 LR - 20141120 IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 44 IP - 3 DP - 2004 Oct 28 TI - State-dependent calcium signaling in dendritic spines of striatal medium spiny neurons. PG - 483-93 AB - Striatal medium spiny neurons (MSNs) in vivo undergo large membrane depolarizations known as state transitions. Calcium (Ca) entry into MSNs triggers diverse downstream cellular processes. However, little is known about Ca signals in MSN dendrites and spines and how state transitions influence these signals. Here, we develop a novel approach, combining 2-photon Ca imaging and 2-photon glutamate uncaging, to examine how voltage-sensitive Ca channels (VSCCs) and ionotropic glutamate receptors contribute to Ca signals in MSNs. We find that upstate transitions switch the VSCCs available in dendrites and spines, decreasing T-type while enhancing L-type channels. Moreover, these transitions change the dominant synaptic Ca source from Ca-permeable AMPA receptors to NMDA receptors. Finally, pairing bAPs with synaptic inputs generates additional synaptic Ca signals due to enhanced Ca influx through NMDA receptors. By altering the sources, amplitude, and kinetics of spine Ca signals, state transitions may gate synaptic plasticity and gene expression in MSNs. FAU - Carter, Adam G AU - Carter AG AD - Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL LA - eng GR - R01 NS046579-01A/NS/NINDS NIH HHS/United States GR - T32 NS07484/NS/NINDS NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Calcium Channel Blockers) RN - 0 (Drug Combinations) RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (Glutamates) RN - 0 (alpha-(4,5-dimethoxy-2-nitrobenzyl) glutamate) RN - 4368-28-9 (Tetrodotoxin) RN - I38ZP9992A (Magnesium) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Calcium/*metabolism MH - Calcium Channel Blockers MH - Calcium Signaling/*physiology MH - Corpus Striatum/*cytology MH - Dendritic Spines/*physiology MH - Dose-Response Relationship, Radiation MH - Drug Combinations MH - Electric Stimulation/methods MH - Excitatory Amino Acid Antagonists/pharmacology MH - Excitatory Postsynaptic Potentials/physiology MH - Glutamates/pharmacology MH - In Vitro Techniques MH - Magnesium/pharmacology MH - Membrane Potentials/drug effects/physiology MH - Microscopy, Confocal/methods MH - Neurons/classification/*physiology MH - Patch-Clamp Techniques/methods MH - Rats MH - Synapses/drug effects/physiology MH - Tetrodotoxin/pharmacology EDAT- 2004/10/27 09:00 MHDA- 2005/01/19 09:00 CRDT- 2004/10/27 09:00 PHST- 2004/07/09 00:00 [received] PHST- 2004/09/07 00:00 [revised] PHST- 2004/09/24 00:00 [accepted] PHST- 2004/10/27 09:00 [pubmed] PHST- 2005/01/19 09:00 [medline] PHST- 2004/10/27 09:00 [entrez] AID - S0896627304006725 [pii] AID - 10.1016/j.neuron.2004.10.013 [doi] PST - ppublish SO - Neuron. 2004 Oct 28;44(3):483-93. doi: 10.1016/j.neuron.2004.10.013. PMID- 14872098 OWN - NLM STAT- MEDLINE DCOM- 20040826 LR - 20061115 IS - 1525-8882 (Electronic) IS - 1525-8882 (Linking) VI - 2004 IP - 219 DP - 2004 Feb 3 TI - Imaging calcium concentration dynamics in small neuronal compartments. PG - pl5 AB - Calcium and its regulation play central roles diverse physiologic processes. Quantification of calcium concentrations ([Ca2+]) in small neuronal compartments is crucial to understanding Ca2+-dependent signaling. Here, we describe techniques that are optimized for 2-photon imaging of [Ca2+] dynamics in small compartments such as dendrites and dendritic spines. FAU - Yasuda, Ryohei AU - Yasuda R AD - Howard Hughes Medical Institute, The Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA. FAU - Nimchinsky, Esther A AU - Nimchinsky EA FAU - Scheuss, Volker AU - Scheuss V FAU - Pologruto, Thomas A AU - Pologruto TA FAU - Oertner, Thomas G AU - Oertner TG FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Svoboda, Karel AU - Svoboda K LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. DEP - 20040203 PL - United States TA - Sci STKE JT - Science's STKE : signal transduction knowledge environment JID - 100964423 SB - IM MH - Animals MH - Calcium Signaling/*physiology MH - Cell Compartmentation/physiology MH - Dendrites/chemistry/physiology MH - Hippocampus/cytology MH - Image Processing, Computer-Assisted/instrumentation/methods MH - Lasers MH - Microscopy, Fluorescence, Multiphoton/instrumentation/methods MH - Neurons/*chemistry/physiology MH - Patch-Clamp Techniques/instrumentation/methods MH - Rats EDAT- 2004/02/12 05:00 MHDA- 2004/08/27 05:00 CRDT- 2004/02/12 05:00 PHST- 2004/02/12 05:00 [pubmed] PHST- 2004/08/27 05:00 [medline] PHST- 2004/02/12 05:00 [entrez] AID - stke.2192004pl5 [pii] AID - 10.1126/stke.2192004pl5 [doi] PST - epublish SO - Sci STKE. 2004 Feb 3;2004(219):pl5. doi: 10.1126/stke.2192004pl5. PMID- 12937422 OWN - NLM STAT- MEDLINE DCOM- 20031028 LR - 20141120 IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 6 IP - 9 DP - 2003 Sep TI - Plasticity of calcium channels in dendritic spines. PG - 948-55 AB - Voltage-sensitive Ca2+ channels (VSCCs) constitute a major source of calcium ions in dendritic spines, but their function is unknown. Here we show that R-type VSCCs in spines of rat CA1 pyramidal neurons are depressed for at least 30 min after brief trains of back-propagating action potentials. Populations of channels in single spines are depressed stochastically and synchronously, independent of channels in the parent dendrite and other spines, implying that depression is the result of signaling restricted to individual spines. Induction of VSCC depression blocks theta-burst-induced long-term potentiation (LTP), indicating that postsynaptic action potentials can modulate synaptic plasticity by tuning VSCCs. Induction of depression requires [Ca2+] elevations and activation of L-type VSCCs, which activate Ca2+/calmodulin-dependent kinase II (CaMKII) and a cyclic adenosine monophosphate (cAMP)-dependent pathway. Given that L-type VSCCs do not contribute measurably to Ca2+ influx in spines, they must activate downstream effectors either directly through voltage-dependent conformational changes or via [Ca2+] microdomains. FAU - Yasuda, Ryohei AU - Yasuda R AD - Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road Cold Spring Harbor, New York 11724, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Svoboda, Karel AU - Svoboda K LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 0 (Calcium Channels, R-Type) RN - SY7Q814VUP (Calcium) SB - IM MH - Action Potentials/drug effects/*physiology MH - Animals MH - Calcium/pharmacology/physiology MH - Calcium Channels, R-Type/*physiology MH - Dendrites/drug effects/*physiology MH - Hippocampus/cytology/drug effects/physiology MH - In Vitro Techniques MH - Neuronal Plasticity/drug effects/*physiology MH - Rats EDAT- 2003/08/26 05:00 MHDA- 2003/10/29 05:00 CRDT- 2003/08/26 05:00 PHST- 2003/05/09 00:00 [received] PHST- 2003/06/13 00:00 [accepted] PHST- 2003/08/26 05:00 [pubmed] PHST- 2003/10/29 05:00 [medline] PHST- 2003/08/26 05:00 [entrez] AID - nn1112 [pii] AID - 10.1038/nn1112 [doi] PST - ppublish SO - Nat Neurosci. 2003 Sep;6(9):948-55. doi: 10.1038/nn1112. PMID- 12801419 OWN - NLM STAT- MEDLINE DCOM- 20040810 LR - 20220309 IS - 1475-925X (Electronic) IS - 1475-925X (Linking) VI - 2 DP - 2003 May 17 TI - ScanImage: flexible software for operating laser scanning microscopes. PG - 13 AB - BACKGROUND: Laser scanning microscopy is a powerful tool for analyzing the structure and function of biological specimens. Although numerous commercial laser scanning microscopes exist, some of the more interesting and challenging applications demand custom design. A major impediment to custom design is the difficulty of building custom data acquisition hardware and writing the complex software required to run the laser scanning microscope. RESULTS: We describe a simple, software-based approach to operating a laser scanning microscope without the need for custom data acquisition hardware. Data acquisition and control of laser scanning are achieved through standard data acquisition boards. The entire burden of signal integration and image processing is placed on the CPU of the computer. We quantitate the effectiveness of our data acquisition and signal conditioning algorithm under a variety of conditions. We implement our approach in an open source software package (ScanImage) and describe its functionality. CONCLUSIONS: We present ScanImage, software to run a flexible laser scanning microscope that allows easy custom design. FAU - Pologruto, Thomas A AU - Pologruto TA AD - Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. pologrut@cshl.org; FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Svoboda, Karel AU - Svoboda K LA - eng GR - R01 EB001464/EB/NIBIB NIH HHS/United States GR - R01 EB01464-01/EB/NIBIB NIH HHS/United States PT - Evaluation Study PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. DEP - 20030517 PL - England TA - Biomed Eng Online JT - Biomedical engineering online JID - 101147518 SB - IM MH - Equipment Design MH - Image Enhancement/methods MH - Microscopy, Confocal/*instrumentation MH - Signal Processing, Computer-Assisted MH - *Software MH - Software Design MH - User-Computer Interface PMC - PMC161784 EDAT- 2003/06/13 05:00 MHDA- 2004/08/11 05:00 CRDT- 2003/06/13 05:00 PHST- 2003/02/09 00:00 [received] PHST- 2003/05/17 00:00 [accepted] PHST- 2003/06/13 05:00 [pubmed] PHST- 2004/08/11 05:00 [medline] PHST- 2003/06/13 05:00 [entrez] AID - 1475-925X-2-13 [pii] AID - 10.1186/1475-925X-2-13 [doi] PST - epublish SO - Biomed Eng Online. 2003 May 17;2:13. doi: 10.1186/1475-925X-2-13. PMID- 12055631 OWN - NLM STAT- MEDLINE DCOM- 20020712 LR - 20181130 IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 5 IP - 7 DP - 2002 Jul TI - Facilitation at single synapses probed with optical quantal analysis. PG - 657-64 AB - Many synapses can change their strength rapidly in a use-dependent manner, but the mechanisms of such short-term plasticity remain unknown. To understand these mechanisms, measurements of neurotransmitter release at single synapses are required. We probed transmitter release by imaging transient increases in [Ca(2+)] mediated by synaptic N-methyl-D-aspartate receptors (NMDARs) in individual dendritic spines of CA1 pyramidal neurons in rat brain slices, enabling quantal analysis at single synapses. We found that changes in release probability, produced by paired-pulse facilitation (PPF) or by manipulation of presynaptic adenosine receptors, were associated with changes in glutamate concentration in the synaptic cleft, indicating that single synapses can release a variable amount of glutamate per action potential. The relationship between release probability and response size is consistent with a binomial model of vesicle release with several (>5) independent release sites per active zone, suggesting that multivesicular release contributes to facilitation at these synapses. FAU - Oertner, Thomas G AU - Oertner TG AD - Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA. FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Nimchinsky, Esther A AU - Nimchinsky EA FAU - Svoboda, Karel AU - Svoboda K LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 0 (Neurotransmitter Agents) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (Receptors, Purinergic P1) RN - 146-77-0 (2-Chloroadenosine) RN - 3KX376GY7L (Glutamic Acid) RN - SY7Q814VUP (Calcium) SB - IM MH - 2-Chloroadenosine/pharmacology MH - Action Potentials/physiology MH - Animals MH - Calcium/analysis/metabolism MH - Calcium Signaling/drug effects/physiology MH - Electric Stimulation MH - Excitatory Postsynaptic Potentials/physiology MH - Glutamic Acid/metabolism MH - In Vitro Techniques MH - Neuronal Plasticity/physiology MH - Neurotransmitter Agents/*metabolism MH - Presynaptic Terminals/metabolism MH - Pyramidal Cells/drug effects/*physiology/ultrastructure MH - Rats MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Receptors, Purinergic P1/metabolism MH - Sensory Thresholds/physiology MH - Synapses/drug effects/metabolism/*physiology EDAT- 2002/06/11 10:00 MHDA- 2002/07/13 10:01 CRDT- 2002/06/11 10:00 PHST- 2002/06/11 10:00 [pubmed] PHST- 2002/07/13 10:01 [medline] PHST- 2002/06/11 10:00 [entrez] AID - nn867 [pii] AID - 10.1038/nn867 [doi] PST - ppublish SO - Nat Neurosci. 2002 Jul;5(7):657-64. doi: 10.1038/nn867. PMID- 11832230 OWN - NLM STAT- MEDLINE DCOM- 20020305 LR - 20220318 IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 33 IP - 3 DP - 2002 Jan 31 TI - The life cycle of Ca(2+) ions in dendritic spines. PG - 439-52 AB - Spine Ca(2+) is critical for the induction of synaptic plasticity, but the factors that control Ca(2+) handling in dendritic spines under physiological conditions are largely unknown. We studied [Ca(2+)] signaling in dendritic spines of CA1 pyramidal neurons and find that spines are specialized structures with low endogenous Ca(2+) buffer capacity that allows large and extremely rapid [Ca(2+)] changes. Under physiological conditions, Ca(2+) diffusion across the spine neck is negligible, and the spine head functions as a separate compartment on long time scales, allowing localized Ca(2+) buildup during trains of synaptic stimuli. Furthermore, the kinetics of Ca(2+) sources governs the time course of [Ca(2+)] signals and may explain the selective activation of long-term synaptic potentiation (LTP) and long-term depression (LTD) by NMDA-R-mediated synaptic Ca(2+). FAU - Sabatini, Bernardo L AU - Sabatini BL AD - Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA. FAU - Oertner, Thomas G AU - Oertner TG FAU - Svoboda, Karel AU - Svoboda K LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Buffers) RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (Fluorescent Dyes) RN - 0 (GABA Antagonists) RN - 0 (Quinoxalines) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 118876-58-7 (2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline) RN - SY7Q814VUP (Calcium) RN - Y37615DVKC (Bicuculline) SB - IM MH - Action Potentials/physiology MH - Animals MH - Bicuculline/pharmacology MH - Buffers MH - Calcium/*metabolism MH - Cells, Cultured MH - Dendrites/*metabolism MH - Excitatory Amino Acid Antagonists/pharmacology MH - Fluorescent Dyes/metabolism MH - GABA Antagonists/pharmacology MH - Hippocampus/cytology/*metabolism MH - In Vitro Techniques MH - Mathematics MH - Microscopy, Confocal MH - Models, Neurological MH - Neurons/cytology/drug effects/*metabolism MH - Quinoxalines/pharmacology MH - Rats MH - Receptors, N-Methyl-D-Aspartate/metabolism EDAT- 2002/02/08 10:00 MHDA- 2002/03/07 10:01 CRDT- 2002/02/08 10:00 PHST- 2002/02/08 10:00 [pubmed] PHST- 2002/03/07 10:01 [medline] PHST- 2002/02/08 10:00 [entrez] AID - S0896627302005731 [pii] AID - 10.1016/s0896-6273(02)00573-1 [doi] PST - ppublish SO - Neuron. 2002 Jan 31;33(3):439-52. doi: 10.1016/s0896-6273(02)00573-1. PMID- 11826272 OWN - NLM STAT- MEDLINE DCOM- 20020509 LR - 20220309 IS - 0066-4278 (Print) IS - 0066-4278 (Linking) VI - 64 DP - 2002 TI - Structure and function of dendritic spines. PG - 313-53 AB - Spines are neuronal protrusions, each of which receives input typically from one excitatory synapse. They contain neurotransmitter receptors, organelles, and signaling systems essential for synaptic function and plasticity. Numerous brain disorders are associated with abnormal dendritic spines. Spine formation, plasticity, and maintenance depend on synaptic activity and can be modulated by sensory experience. Studies of compartmentalization have shown that spines serve primarily as biochemical, rather than electrical, compartments. In particular, recent work has highlighted that spines are highly specialized compartments for rapid large-amplitude Ca(2+) signals underlying the induction of synaptic plasticity. FAU - Nimchinsky, Esther A AU - Nimchinsky EA AD - Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. nimchins@cshl.org FAU - Sabatini, Bernardo L AU - Sabatini BL FAU - Svoboda, Karel AU - Svoboda K LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PL - United States TA - Annu Rev Physiol JT - Annual review of physiology JID - 0370600 RN - 0 (Calcium Channels) RN - 0 (Receptors, N-Methyl-D-Aspartate) SB - IM MH - Animals MH - Calcium Channels/physiology MH - Dendrites/*physiology/*ultrastructure MH - Receptors, N-Methyl-D-Aspartate/physiology RF - 229 EDAT- 2002/02/05 10:00 MHDA- 2002/05/10 10:01 CRDT- 2002/02/05 10:00 PHST- 2002/02/05 10:00 [pubmed] PHST- 2002/05/10 10:01 [medline] PHST- 2002/02/05 10:00 [entrez] AID - 64/1/313 [pii] AID - 10.1146/annurev.physiol.64.081501.160008 [doi] PST - ppublish SO - Annu Rev Physiol. 2002;64:313-53. doi: 10.1146/annurev.physiol.64.081501.160008. PMID- 11399434 OWN - NLM STAT- MEDLINE DCOM- 20010809 LR - 20190921 IS - 0959-4388 (Print) IS - 0959-4388 (Linking) VI - 11 IP - 3 DP - 2001 Jun TI - Ca(2+) signaling in dendritic spines. PG - 349-56 AB - Dendritic spines are cellular microcompartments that are isolated from their parent dendrites and neighboring spines. Recently, imaging studies of spine Ca(2+) dynamics have revealed that Ca(2+) can enter spines through voltage-sensitive and ligand-activated channels, as well as through Ca(2+) release from intracellular stores. Relationships between spine Ca(2+) signals and induction of various forms of synaptic plasticity are beginning to be elucidated. Measurements of spine Ca(2+) concentration are also being used to probe the properties of single synapses and even individual calcium channels in their native environment. FAU - Sabatini, B L AU - Sabatini BL AD - Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11743, USA. FAU - Maravall, M AU - Maravall M FAU - Svoboda, K AU - Svoboda K LA - eng PT - Journal Article PT - Review PL - England TA - Curr Opin Neurobiol JT - Current opinion in neurobiology JID - 9111376 RN - 0 (Calcium Channels) RN - 0 (Nerve Tissue Proteins) RN - 0 (Receptors, N-Methyl-D-Aspartate) SB - IM MH - Action Potentials/physiology MH - Animals MH - Calcium Channels/physiology MH - Calcium Signaling/*physiology MH - Cell Compartmentation MH - Dendrites/*physiology/ultrastructure MH - Humans MH - Ion Channel Gating MH - Ion Transport MH - Mice MH - Mice, Knockout MH - Nerve Tissue Proteins/physiology MH - Neuronal Plasticity/physiology MH - Purkinje Cells/cytology/physiology MH - Pyramidal Cells/cytology/physiology MH - Rats MH - Rats, Mutant Strains MH - Receptors, N-Methyl-D-Aspartate/physiology MH - Signal Transduction/*physiology MH - Synaptic Transmission/*physiology RF - 68 EDAT- 2001/06/12 10:00 MHDA- 2001/08/10 10:01 CRDT- 2001/06/12 10:00 PHST- 2001/06/12 10:00 [pubmed] PHST- 2001/08/10 10:01 [medline] PHST- 2001/06/12 10:00 [entrez] AID - S0959-4388(00)00218-X [pii] AID - 10.1016/s0959-4388(00)00218-x [doi] PST - ppublish SO - Curr Opin Neurobiol. 2001 Jun;11(3):349-56. doi: 10.1016/s0959-4388(00)00218-x. PMID- 11117746 OWN - NLM STAT- MEDLINE DCOM- 20001222 LR - 20141120 IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 408 IP - 6812 DP - 2000 Nov 30 TI - Analysis of calcium channels in single spines using optical fluctuation analysis. PG - 589-93 AB - Most synapses form on small, specialized postsynaptic structures known as dendritic spines. The influx of Ca2+ ions into such spines--through synaptic receptors and voltage-sensitive Ca2+ channels (VSCCs)--triggers diverse processes that underlie synaptic plasticity. Using two-photon laser scanning microscopy, we imaged action-potential-induced transient changes in Ca2+ concentration in spines and dendrites of CA1 pyramidal neurons in rat hippocampal slices. Through analysis of the large trial-to-trial fluctuations in these transients, we have determined the number and properties of VSCCs in single spines. Here we report that each spine contains 1-20 VSCCs, and that this number increases with spine volume. We are able to detect the opening of a single VSCC on a spine. In spines located on the proximal dendritic tree, VSCCs normally open with high probability (approximately 0.5) following dendritic action potentials. Activation of GABA(B) receptors reduced this probability in apical spines to approximately 0.3 but had no effect on VSCCs in dendrites or basal spines. Our studies show that the spatial distribution of VSCC subtypes and their modulatory potential is regulated with submicrometre precision. FAU - Sabatini, B L AU - Sabatini BL AD - Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, New York 11724, USA. FAU - Svoboda, K AU - Svoboda K LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Calcium Channels) RN - 0 (Receptors, GABA-B) SB - IM MH - Action Potentials MH - Animals MH - Calcium Channels/*metabolism MH - Dendrites/metabolism MH - In Vitro Techniques MH - Membrane Potentials MH - Microscopy, Confocal MH - Pyramidal Cells/*metabolism MH - Rats MH - Receptors, GABA-B/metabolism MH - Synaptic Membranes/metabolism EDAT- 2000/12/16 11:00 MHDA- 2001/02/28 10:01 CRDT- 2000/12/16 11:00 PHST- 2000/12/16 11:00 [pubmed] PHST- 2001/02/28 10:01 [medline] PHST- 2000/12/16 11:00 [entrez] AID - 10.1038/35046076 [doi] PST - ppublish SO - Nature. 2000 Nov 30;408(6812):589-93. doi: 10.1038/35046076. PMID- 10777761 OWN - NLM STAT- MEDLINE DCOM- 20000626 LR - 20220414 IS - 0006-3495 (Print) IS - 1542-0086 (Electronic) IS - 0006-3495 (Linking) VI - 78 IP - 5 DP - 2000 May TI - Estimating intracellular calcium concentrations and buffering without wavelength ratioing. PG - 2655-67 AB - We describe a method for determining intracellular free calcium concentration ([Ca(2+)]) from single-wavelength fluorescence signals. In contrast to previous single-wavelength calibration methods, the proposed method does not require independent estimates of resting [Ca(2+)] but relies on the measurement of fluorescence close to indicator saturation during an experiment. Consequently, it is well suited to [Ca(2+)] indicators for which saturation can be achieved under physiological conditions. In addition, the method requires that the indicators have large dynamic ranges. Popular indicators such as Calcium Green-1 or Fluo-3 fulfill these conditions. As a test of the method, we measured [Ca(2+)] in CA1 pyramidal neurons in rat hippocampal slices using Oregon Green BAPTA-1 and 2-photon laser scanning microscopy (BAPTA: 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid). Resting [Ca(2+)] was 32-59 nM in the proximal apical dendrite. Monitoring action potential-evoked [Ca(2+)] transients as a function of indicator loading yielded estimates of endogenous buffering capacity (44-80) and peak [Ca(2+)] changes at zero added buffer (178-312 nM). In young animals (postnatal days 14-17) our results were comparable to previous estimates obtained by ratiometric methods (, Biophys. J. 70:1069-1081), and no significant differences were seen in older animals (P24-28). We expect our method to be widely applicable to measurements of [Ca(2+)] and [Ca(2+)]-dependent processes in small neuronal compartments, particularly in the many situations that do not permit wavelength ratio imaging. FAU - Maravall, M AU - Maravall M AD - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 USA. FAU - Mainen, Z F AU - Mainen ZF FAU - Sabatini, B L AU - Sabatini BL FAU - Svoboda, K AU - Svoboda K LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Biophys J JT - Biophysical journal JID - 0370626 RN - 0 (Buffers) RN - SY7Q814VUP (Calcium) SB - IM MH - Action Potentials MH - Animals MH - Biophysical Phenomena MH - Biophysics MH - Buffers MH - Calcium/*analysis/metabolism MH - Calcium Signaling MH - In Vitro Techniques MH - Intracellular Fluid/*chemistry/metabolism MH - Models, Biological MH - Pyramidal Cells/metabolism MH - Rats PMC - PMC1300854 EDAT- 2000/04/25 09:00 MHDA- 2000/07/06 11:00 CRDT- 2000/04/25 09:00 PHST- 2000/04/25 09:00 [pubmed] PHST- 2000/07/06 11:00 [medline] PHST- 2000/04/25 09:00 [entrez] AID - S0006-3495(00)76809-3 [pii] AID - 10.1016/S0006-3495(00)76809-3 [doi] PST - ppublish SO - Biophys J. 2000 May;78(5):2655-67. doi: 10.1016/S0006-3495(00)76809-3. PMID- 10099700 OWN - NLM STAT- MEDLINE DCOM- 19990526 LR - 20220309 IS - 0066-4278 (Print) IS - 0066-4278 (Linking) VI - 61 DP - 1999 TI - Timing of synaptic transmission. PG - 521-42 AB - Many behaviors require rapid and precisely timed synaptic transmission. These include the determination of a sound's direction by detecting small interaural time differences and visual processing, which relies on synchronous activation of large populations of neurons. In addition, throughout the brain, concerted firing is required by Hebbian learning mechanisms, and local circuits are recruited rapidly by fast synaptic transmission. To achieve speed and precision, synapses must optimize the many steps between the firing of a presynaptic cell and the response of its postsynaptic targets. Until recently, the behavior of mammalian synapses at physiological temperatures was primarily extrapolated from studies at room temperature or from the properties of invertebrate synapses. Recent studies have revealed some of the specializations that make synapses fast and precise in the mammalian central nervous system at physiological temperatures. FAU - Sabatini, B L AU - Sabatini BL AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Regehr, W G AU - Regehr WG LA - eng GR - R01-NS32405-01/NS/NINDS NIH HHS/United States GR - T32EY07110-06/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PT - Review PL - United States TA - Annu Rev Physiol JT - Annual review of physiology JID - 0370600 RN - SY7Q814VUP (Calcium) SB - IM MH - Action Potentials/physiology MH - Animals MH - Calcium/metabolism MH - Neural Conduction/physiology MH - Presynaptic Terminals/metabolism MH - Reaction Time/physiology MH - Synapses/physiology MH - Synaptic Transmission/*physiology MH - Time Factors RF - 117 EDAT- 1999/04/01 00:00 MHDA- 1999/04/01 00:01 CRDT- 1999/04/01 00:00 PHST- 1999/04/01 00:00 [pubmed] PHST- 1999/04/01 00:01 [medline] PHST- 1999/04/01 00:00 [entrez] AID - 10.1146/annurev.physiol.61.1.521 [doi] PST - ppublish SO - Annu Rev Physiol. 1999;61:521-42. doi: 10.1146/annurev.physiol.61.1.521. PMID- 9512051 OWN - NLM STAT- MEDLINE DCOM- 19980512 LR - 20181113 IS - 0006-3495 (Print) IS - 1542-0086 (Electronic) IS - 0006-3495 (Linking) VI - 74 IP - 3 DP - 1998 Mar TI - Optical measurement of presynaptic calcium currents. PG - 1549-63 AB - Measurements of presynaptic calcium currents are vital to understanding the control of transmitter release. However, most presynaptic boutons in the vertebrate central nervous system are too small to allow electrical recordings of presynaptic calcium currents (I(Ca)pre). We therefore tested the possibility of measuring I(Ca)pre optically in boutons loaded with calcium-sensitive fluorophores. From a theoretical treatment of a system containing an endogenous buffer and an indicator, we determined the conditions necessary for the derivative of the stimulus-evoked change in indicator fluorescence to report I(Ca)pre accurately. Matching the calcium dissociation rates of the endogenous buffer and indicator allows the most precise optical measurements of I(Ca)pre. We tested our ability to measure I(Ca)pre in granule cells in rat cerebellar slices. The derivatives of stimulus-evoked fluorescence transients from slices loaded with the low-affinity calcium indicators magnesium green and mag-fura-5 had the same time courses and were unaffected by changes in calcium influx or indicator concentration. Thus both of these indicators were well suited to measuring I(Ca)pre. In contrast, the high-affinity indicator fura-2 distorted I(Ca)pre. The optically determined I(Ca)pre was well approximated by a Gaussian with a half-width of 650 micros at 24 degrees C and 340 micros at 34 degrees C. FAU - Sabatini, B L AU - Sabatini BL AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Regehr, W G AU - Regehr WG LA - eng GR - R01-NS32405-01/NS/NINDS NIH HHS/United States GR - T32EY07110-06/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Biophys J JT - Biophysical journal JID - 0370626 RN - 0 (Calcium Channels) RN - 0 (Fluorescent Dyes) RN - SY7Q814VUP (Calcium) RN - TSN3DL106G (Fura-2) SB - IM MH - Action Potentials/physiology MH - Animals MH - Calcium/*metabolism MH - Calcium Channels/*physiology MH - Cerebellum/*physiology MH - Electric Stimulation MH - Evoked Potentials/physiology MH - Fluorescent Dyes MH - Fura-2 MH - In Vitro Techniques MH - Kinetics MH - Models, Chemical MH - Nerve Fibers/physiology MH - Presynaptic Terminals/*physiology MH - Rats MH - Rats, Sprague-Dawley MH - Spectrometry, Fluorescence MH - Temperature PMC - PMC1299501 EDAT- 1998/03/25 00:00 MHDA- 1998/03/25 00:01 CRDT- 1998/03/25 00:00 PHST- 1998/03/25 00:00 [pubmed] PHST- 1998/03/25 00:01 [medline] PHST- 1998/03/25 00:00 [entrez] AID - S0006-3495(98)77867-1 [pii] AID - 10.1016/S0006-3495(98)77867-1 [doi] PST - ppublish SO - Biophys J. 1998 Mar;74(3):1549-63. doi: 10.1016/S0006-3495(98)77867-1. PMID- 9133368 OWN - NLM STAT- MEDLINE DCOM- 19970602 LR - 20220309 IS - 0270-6474 (Print) IS - 1529-2401 (Electronic) IS - 0270-6474 (Linking) VI - 17 IP - 10 DP - 1997 May 15 TI - Control of neurotransmitter release by presynaptic waveform at the granule cell to Purkinje cell synapse. PG - 3425-35 AB - The effect of changes in the shape of the presynaptic action potential on neurotransmission was examined at synapses between granule and Purkinje cells in slices from the rat cerebellum. Low concentrations of tetraethylammonium were used to broaden the presynaptic action potential. The presynaptic waveform was monitored with voltage-sensitive dyes, the time course and amplitude of presynaptic calcium entry were determined with fluorescent calcium indicators, and EPSCs were measured with a whole-cell voltage clamp. Spike broadening increased calcium influx primarily by prolonging calcium entry without greatly affecting peak presynaptic calcium currents, indicating that the majority of calcium channels reach maximal probability of opening in response to a single action potential and that spike broadening increases the open time of these channels. EPSCs were exquisitely sensitive to elevations of calcium influx produced by spike broadening; there was a high power relationship between calcium influx and release such that a 23% increase in spike width led to a 25% increase in total calcium influx, which in turn doubled synaptic strength. The finding that even small changes in spike width influence neurotransmitter release suggests that altering the presynaptic waveform may be an important means of modifying the strength of this synapse. Waveform changes do not, however, contribute significantly to presynaptic modulation via activation of adenosine A1 or GABAB receptors. Furthermore, greatly reducing presynaptic calcium influx did not alter the presynaptic waveform, indicating that calcium channels and calcium-activated channels do not participate in shaping the presynaptic waveform. FAU - Sabatini, B L AU - Sabatini BL AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Regehr, W G AU - Regehr WG LA - eng GR - R01-NS32405-01/NS/NINDS NIH HHS/United States GR - T32EY07110-06/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (1-(3-sulfonatopropyl)-4-(beta-(2-(di-n-octylamino)-6-naphthyl)vinyl)pyridinium betaine) RN - 0 (Calcium Channels) RN - 0 (Fluorescent Dyes) RN - 0 (Neurotransmitter Agents) RN - 0 (Potassium Channel Blockers) RN - 0 (Pyridinium Compounds) RN - 0 (Tetraethylammonium Compounds) RN - 3KX376GY7L (Glutamic Acid) RN - 66-40-0 (Tetraethylammonium) RN - SY7Q814VUP (Calcium) SB - IM MH - Action Potentials/physiology MH - Animals MH - Calcium/pharmacokinetics MH - Calcium Channels/physiology MH - Fluorescent Dyes MH - Glutamic Acid/pharmacology MH - Ion Channel Gating/drug effects/physiology MH - Neurotransmitter Agents/*metabolism MH - Patch-Clamp Techniques MH - Potassium Channel Blockers MH - Presynaptic Terminals/chemistry/*physiology MH - Purkinje Cells/chemistry/drug effects/*physiology MH - Pyridinium Compounds MH - Rats MH - Rats, Sprague-Dawley MH - Sensitivity and Specificity MH - Synapses/chemistry/metabolism MH - Synaptic Transmission/drug effects/*physiology MH - Tetraethylammonium MH - Tetraethylammonium Compounds/pharmacology PMC - PMC6573699 EDAT- 1997/05/15 00:00 MHDA- 1997/05/15 00:01 CRDT- 1997/05/15 00:00 PHST- 1997/05/15 00:00 [pubmed] PHST- 1997/05/15 00:01 [medline] PHST- 1997/05/15 00:00 [entrez] AID - 10.1523/JNEUROSCI.17-10-03425.1997 [doi] PST - ppublish SO - J Neurosci. 1997 May 15;17(10):3425-35. doi: 10.1523/JNEUROSCI.17-10-03425.1997. PMID- 8906792 OWN - NLM STAT- MEDLINE DCOM- 19961210 LR - 20220309 IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 384 IP - 6605 DP - 1996 Nov 14 TI - Timing of neurotransmission at fast synapses in the mammalian brain. PG - 170-2 AB - Understanding the factors controlling synaptic delays has broad implications. On a systems level, the speed of synaptic transmission limits the communication rate between neurons and strongly influences local circuit dynamics. On a molecular level, the delay from presynaptic calcium entry to postsynaptic responses constrains the molecular mechanism of vesicle fusion. Previously it has not been possible to elucidate the determinants of synaptic delays in the mammalian central nervous system, where presynaptic terminals are small and difficult to study. We have developed a new approach to study timing at rat cerebellar synapses: we used optical techniques to measure voltage and calcium current simultaneously from presynaptic boutons while monitoring postsynaptic currents electrically. Here we report that the classic view that vesicle release is driven by calcium entry during action-potential repolarization holds for these synapses at room temperature, but not at physiological temperatures, where postsynaptic responses commence just 150 micros after the start of the presynaptic action potential. This brisk communication is a consequence of rapid calcium-channel kinetics, which allow significant calcium entry during the upstroke of the presynaptic action potential, and extremely fast calcium-driven vesicle fusion, which lags behind calcium influx by 60 micros. FAU - Sabatini, B L AU - Sabatini BL AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Regehr, W G AU - Regehr WG LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - England TA - Nature JT - Nature JID - 0410462 RN - SY7Q814VUP (Calcium) SB - IM MH - Action Potentials MH - Animals MH - Calcium/metabolism MH - Cerebellum/cytology/*physiology MH - In Vitro Techniques MH - Models, Neurological MH - Rats MH - Reaction Time MH - Synapses/*physiology MH - Synaptic Transmission/*physiology MH - Temperature EDAT- 1996/11/14 00:00 MHDA- 1996/11/14 00:01 CRDT- 1996/11/14 00:00 PHST- 1996/11/14 00:00 [pubmed] PHST- 1996/11/14 00:01 [medline] PHST- 1996/11/14 00:00 [entrez] AID - 10.1038/384170a0 [doi] PST - ppublish SO - Nature. 1996 Nov 14;384(6605):170-2. doi: 10.1038/384170a0. PMID- 8606793 OWN - NLM STAT- MEDLINE DCOM- 19960520 LR - 20190726 IS - 0028-3908 (Print) IS - 0028-3908 (Linking) VI - 34 IP - 11 DP - 1995 Nov TI - Detecting changes in calcium influx which contribute to synaptic modulation in mammalian brain slice. PG - 1453-67 AB - The control of neurotransmitter release by modulation of presynaptic calcium influx was investigated at the granule cell to Purkinje cell synapse in rat cerebellar slices. Excitatory post-synaptic currents were measured using whole cell voltage clamp, and changes in presynaptic Ca influx were determined with the Ca-sensitive dye mag-fura-5. Single stimuli of the parallel fibers evoked rapid changes in mag-fura-5 fluorescence which increased from 10 to 90% in 1.4 msec, and then decayed within hundreds of milliseconds to prestimulus levels. These fluorescence changes were unaffected by disruption of internal stores with ryanodine or thapsigargin, and were reduced by 79% by the calcium channel toxin omega-conotoxin-MVIIC. We conclude that these signals result from calcium entry into presynaptic terminals through voltage gated calcium channels opened by action potentials. These fluorescence signals allow us to quantitate changes in calcium influx. We used this approach to study the enhancement of stimulus-evoked synaptic currents by 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor and antagonist of adenosine receptors. Both enhancement of calcium influx into presynaptic terminals, and reduction in the firing threshold of the parallel fibers, were found to contribute to IBMX-mediated synaptic enhancement. Changes in presynaptic calcium influx were also quantified with a novel method, which is unaffected by changes in fiber threshold. These studies illustrate some of the difficulties encountered when determining the factors responsible for synaptic enhancement and demonstrate how measurements of presynaptic calcium influx can contribute to our understanding of synaptic modulation. The approach described here promises to be widely useful in elucidating the role of calcium influx in the modulation of synapses in brain slice. FAU - Sabatini, B L AU - Sabatini BL AD - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. FAU - Regehr, W G AU - Regehr WG LA - eng GR - NS32405/NS/NINDS NIH HHS/United States GR - T32EY07110-06/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Calcium Channels) RN - 0 (Fluorescent Dyes) RN - 0 (Phosphodiesterase Inhibitors) RN - 0 (Purinergic P1 Receptor Antagonists) RN - SY7Q814VUP (Calcium) RN - TBT296U68M (1-Methyl-3-isobutylxanthine) SB - IM MH - 1-Methyl-3-isobutylxanthine/pharmacology MH - Animals MH - Calcium/analysis/*metabolism MH - Calcium Channels/physiology MH - Cerebellum/*physiology MH - Electrophysiology MH - Fluorescent Dyes MH - In Vitro Techniques MH - Phosphodiesterase Inhibitors/pharmacology MH - Presynaptic Terminals/*metabolism MH - Purinergic P1 Receptor Antagonists MH - Rats MH - Spectrometry, Fluorescence MH - Synaptic Transmission/*physiology EDAT- 1995/11/01 00:00 MHDA- 1995/11/01 00:01 CRDT- 1995/11/01 00:00 PHST- 1995/11/01 00:00 [pubmed] PHST- 1995/11/01 00:01 [medline] PHST- 1995/11/01 00:00 [entrez] AID - 002839089500129T [pii] AID - 10.1016/0028-3908(95)00129-t [doi] PST - ppublish SO - Neuropharmacology. 1995 Nov;34(11):1453-67. doi: 10.1016/0028-3908(95)00129-t. PMID- 7546746 OWN - NLM STAT- MEDLINE DCOM- 19951025 LR - 20220309 IS - 0896-6273 (Print) IS - 0896-6273 (Linking) VI - 15 IP - 3 DP - 1995 Sep TI - Calcium control of transmitter release at a cerebellar synapse. PG - 675-88 AB - The manner in which presynaptic Ca2+ influx controls the release of neurotransmitter was investigated at the granule cell to Purkinje cell synapse in rat cerebellar slices. Excitatory postsynaptic currents were measured using whole-cell voltage clamp, and changes in presynaptic Ca2+ influx were determined with the Ca(2+)-sensitive dye furaptra. We manipulated presynaptic Ca2+ entry by altering external Ca2+ levels and by blocking Ca2+ channels with Cd2+ or with the toxins omega-conotoxin GVIA and omega-Aga-IVA. For all of the manipulations, other than the application of omega-Aga-IVA, the relationship between Ca2+ influx and release was well approximated by a power law, n approximately 2.5. When omega-Aga-IVA was applied, release appeared to be more steeply dependent on Ca2+ (n approximately 4), suggesting that omega-Aga-IVA-sensitive channels are more effective at triggering release. Based on interactive effects of toxins on synaptic currents, we conclude that multiple types of Ca2+ channels synergistically control individual release sites. FAU - Mintz, I M AU - Mintz IM AD - Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Sabatini, B L AU - Sabatini BL FAU - Regehr, W G AU - Regehr WG LA - eng GR - R01-NS32405/NS/NINDS NIH HHS/United States GR - T32EY07110-06/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Neuron JT - Neuron JID - 8809320 RN - 0 (Benzofurans) RN - 0 (Calcium Channel Blockers) RN - 0 (Calcium Channels) RN - 0 (Fluorescent Dyes) RN - 0 (Neurotransmitter Agents) RN - 0 (Oxazoles) RN - 0 (Peptides) RN - 0 (Spider Venoms) RN - 0 (omega-Agatoxin IVA) RN - 00BH33GNGH (Cadmium) RN - 120551-15-7 (2-(2-(5-carboxy)oxazole)-5-hydroxy-6-aminobenzofuran-N,N,O-triacetic acid) RN - 92078-76-7 (omega-Conotoxin GVIA) RN - SY7Q814VUP (Calcium) RN - TSN3DL106G (Fura-2) SB - IM MH - Animals MH - Benzofurans MH - Cadmium/pharmacology MH - Calcium/*metabolism/pharmacology MH - Calcium Channel Blockers/pharmacology MH - Calcium Channels/*physiology MH - Cerebellum/*physiology MH - Electric Conductivity MH - Fluorescent Dyes MH - *Fura-2/*analogs & derivatives MH - Neurotransmitter Agents/*metabolism MH - Oxazoles MH - Peptides/pharmacology MH - Purkinje Cells/physiology MH - Rats MH - Spider Venoms/pharmacology MH - Synapses/*physiology MH - omega-Agatoxin IVA MH - omega-Conotoxin GVIA EDAT- 1995/09/01 00:00 MHDA- 1995/09/01 00:01 CRDT- 1995/09/01 00:00 PHST- 1995/09/01 00:00 [pubmed] PHST- 1995/09/01 00:01 [medline] PHST- 1995/09/01 00:00 [entrez] AID - 0896-6273(95)90155-8 [pii] AID - 10.1016/0896-6273(95)90155-8 [doi] PST - ppublish SO - Neuron. 1995 Sep;15(3):675-88. doi: 10.1016/0896-6273(95)90155-8.