@article {1787201,
	title = {Cortical reactivations predict future sensory responses},
	journal = {Nature},
	volume = {625},
	number = {7993},
	year = {2024},
	month = {2024 Jan},
	pages = {110-118},
	abstract = {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 pattern1,2. However, sensory-evoked patterns are not stable but, instead, drift across repeated experiences3-6. 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 discrimination7.},
	issn = {1476-4687},
	doi = {10.1038/s41586-023-06810-1},
	author = {Nguyen, Nghia D and Lutas, Andrew and Amsalem, Oren and Fernando, Jesseba and Ahn, Andy Young-Eon and Hakim, Richard and Vergara, Josselyn and McMahon, Justin and Dimidschstein, Jordane and Sabatini, Bernardo L and Andermann, Mark L}
}
@article {1789636,
	title = {Neuronal-Activity Dependent Mechanisms of Small Cell Lung Cancer Progression},
	journal = {bioRxiv},
	year = {2023},
	month = {2023 Jan 20},
	abstract = {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.},
	doi = {10.1101/2023.01.19.524430},
	author = {Savchuk, Solomiia and Gentry, Kaylee and Wengang Wang and Carleton, Elana and Yal{\c c}{\i}n, Belgin and Liu, Yin and Pavarino, Elisa C and LaBelle, Jenna and Toland, Angus M and Woo, Pamelyn J and Qu, Fangfei and Filbin, Mariella G and Krasnow, Mark A and Sabatini, Bernardo L and Sage, Julien and Monje, Michelle and Venkatesh, Humsa S}
}
@article {1787211,
	title = {A Cre-dependent reporter mouse for quantitative real-time imaging of Protein Kinase A activity dynamics},
	journal = {bioRxiv},
	year = {2023},
	month = {2023 Nov 02},
	abstract = {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 Gαs and Gαq-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.},
	doi = {10.1101/2023.10.31.565028},
	author = {Tilden, Elizabeth I and Maduskar, Aditi and Oldenborg, Anna and Sabatini, Bernardo L and Chen, Yao}
}
@article {1787231,
	title = {Developmental regulation of GABAergic gene expression in forebrain cholinergic neurons},
	journal = {Front Neural Circuits},
	volume = {17},
	year = {2023},
	month = {2023},
	pages = {1125071},
	abstract = {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.},
	keywords = {Acetylcholine, Animals, Cerebral Cortex, Choline O-Acetyltransferase, Cholinergic Neurons, gamma-Aminobutyric Acid, Gene Expression, In Situ Hybridization, Fluorescence, Mice},
	issn = {1662-5110},
	doi = {10.3389/fncir.2023.1125071},
	author = {Granger, Adam J and Mao, Karen and Saulnier, Jessica L and Hines, Morgan E and Sabatini, Bernardo L}
}
@article {1787221,
	title = {Dopamine and glutamate regulate striatal acetylcholine in decision-making},
	journal = {Nature},
	volume = {621},
	number = {7979},
	year = {2023},
	month = {2023 Sep},
	pages = {577-585},
	abstract = {Striatal dopamine and acetylcholine are essential for the selection and reinforcement of motor actions and decision-making1. 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.},
	keywords = {Acetylcholine, Animals, Cholinergic Neurons, Corpus Striatum, Decision making, Dopamine, Glutamic Acid, Mice, Neostriatum, Neural Pathways, Receptors, Dopamine D2, Reward},
	issn = {1476-4687},
	doi = {10.1038/s41586-023-06492-9},
	author = {Chantranupong, Lynne and Beron, Celia C and Zimmer, Joshua A and Wen, Michelle J and Wengang Wang and Sabatini, Bernardo L}
}
@article {1787241,
	title = {A NPAS4-NuA4 complex couples synaptic activity to DNA repair},
	journal = {Nature},
	volume = {614},
	number = {7949},
	year = {2023},
	month = {2023 Feb},
	pages = {732-741},
	abstract = {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 neurons1-5. 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.},
	keywords = {Aging, Basic Helix-Loop-Helix Transcription Factors, Brain, DNA Breaks, Double-Stranded, DNA Repair, Gene Expression Regulation, Genome, Longevity, Lysine Acetyltransferase 5, Multiprotein Complexes, Mutation, Neurodegenerative Diseases, Neurons, Synapses},
	issn = {1476-4687},
	doi = {10.1038/s41586-023-05711-7},
	author = {Pollina, Elizabeth A and Gilliam, Daniel T and Landau, Andrew T and Lin, Cindy and Pajarillo, Naomi and Davis, Christopher P and Harmin, David A and Ee-Lynn Yap and Vogel, Ian R and Griffith, Eric C and Nagy, M Aurel and Ling, Emi and Duffy, Erin E and Sabatini, Bernardo L and Weitz, Charles J and Greenberg, Michael E}
}
@article {1787246,
	title = {Spontaneous behaviour is structured by reinforcement without explicit reward},
	journal = {Nature},
	volume = {614},
	number = {7946},
	year = {2023},
	month = {2023 Feb},
	pages = {108-117},
	abstract = {Spontaneous animal behaviour is built from action modules that are concatenated by the brain into sequences1,2. 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.},
	keywords = {Animals, Behavior, Animal, Corpus Striatum, Cues, Dopamine, Mice, Optogenetics, Photometry, Reinforcement, Psychology, Reward},
	issn = {1476-4687},
	doi = {10.1038/s41586-022-05611-2},
	author = {Markowitz, Jeffrey E and Gillis, Winthrop F and Maya Jay and Jeffrey Wood and Ryley W Harris and Robert Cieszkowski and Scott, Rebecca and Brann, David and Koveal, Dorothy and Tomasz Kula and Caleb Weinreb and Mohammed Abdal Monium Osman and Sandra Romero Pinto and Uchida, Naoshige and Linderman, Scott W and Sabatini, Bernardo L and Datta, Sandeep Robert}
}
@article {1787206,
	title = {Striatum supports fast learning but not memory recall},
	journal = {bioRxiv},
	year = {2023},
	month = {2023 Nov 09},
	abstract = {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.},
	doi = {10.1101/2023.11.08.566333},
	author = {Reinhold, Kimberly and Iadarola, Marci and Tang, Shi and Kuwamoto, Whitney and Sun, Senmiao and Hakim, Richard and Zimmer, Joshua and Wengang Wang and Sabatini, Bernardo L}
}
@article {1787236,
	title = {Sub-clinical triiodothyronine levels predict health, demographic, and socioeconomic outcomes},
	journal = {bioRxiv},
	year = {2023},
	month = {2023 Mar 13},
	abstract = {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.},
	doi = {10.1101/2023.03.09.531775},
	author = {Lawton, Ralph I and Sabatini, Bernardo L and Hochbaum, Daniel R}
}
@article {1787216,
	title = {Synaptic and circuit functions of multitransmitter neurons in the mammalian brain},
	journal = {Neuron},
	volume = {111},
	number = {19},
	year = {2023},
	month = {2023 Oct 04},
	pages = {2969-2983},
	abstract = {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.},
	keywords = {Animals, Brain, Central Nervous System, Glutamic Acid, Mammals, Neurons, Neurotransmitter Agents, Synaptic Transmission},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2023.06.003},
	author = {Wallace, Michael L and Sabatini, Bernardo L}
}
@article {1787226,
	title = {Thyroid hormone rewires cortical circuits to coordinate body-wide metabolism and exploratory drive},
	journal = {bioRxiv},
	year = {2023},
	month = {2023 Aug 10},
	abstract = {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.},
	doi = {10.1101/2023.08.10.552874},
	author = {Hochbaum, Daniel R and Dubinsky, Alexandra C and Farnsworth, Hannah C and Hulshof, Lauren and Kleinberg, Giona and Urke, Amanda and Wengang Wang and Hakim, Richard and Robertson, Keira and Park, Canaria and Solberg, Alyssa and Yang, Yechan and Baynard, Caroline and Nadaf, Naeem M and Beron, Celia C and Girasole, Allison E and Chantranupong, Lynne and Cortopassi, Marissa and Prouty, Shannon and Geistlinger, Ludwig and Banks, Alexander and Scanlan, Thomas and Greenberg, Michael E and Boulting, Gabriella L and Macosko, Evan Z and Sabatini, Bernardo L}
}
@article {1789701,
	title = {Analysis of Thermogenesis Experiments with CalR},
	journal = {Methods Mol Biol},
	volume = {2448},
	year = {2022},
	month = {2022},
	pages = {43-72},
	abstract = {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{\textquoteright} CLAMS, Sable Systems{\textquoteright} Promethion, and TSE Systems{\textquoteright} 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.},
	keywords = {Animals, Body Weight, Calorimetry, Indirect, Energy Metabolism, Mice, Obesity, Thermogenesis},
	issn = {1940-6029},
	doi = {10.1007/978-1-0716-2087-8_3},
	author = {Cortopassi, Marissa D and Ramachandran, Deepti and Rubio, William B and Hochbaum, Daniel and Sabatini, Bernardo L and Banks, Alexander S}
}
@article {1789641,
	title = {Analytical approaches to examine gamma-aminobutyric acid and glutamate vesicular co-packaging},
	journal = {Front Synaptic Neurosci},
	volume = {14},
	year = {2022},
	month = {2022},
	pages = {1076616},
	abstract = {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.},
	issn = {1663-3563},
	doi = {10.3389/fnsyn.2022.1076616},
	author = {Kim, Seulah and Sabatini, Bernardo L}
}
@article {1789646,
	title = {Ascertaining cells{\textquoteright} synaptic connections and RNA expression simultaneously with barcoded rabies virus libraries},
	journal = {Nat Commun},
	volume = {13},
	number = {1},
	year = {2022},
	month = {2022 Nov 16},
	pages = {6993},
	abstract = {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{\textquoteright}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.},
	keywords = {Animals, Mice, Neurons, Rabies, Rabies virus, RNA, Synapses},
	issn = {2041-1723},
	doi = {10.1038/s41467-022-34334-1},
	author = {Saunders, Arpiar and Huang, Kee Wui and Vondrak, Cassandra and Hughes, Christina and Smolyar, Karina and Sen, Harsha and Philson, Adrienne C and James Nemesh and Wysoker, Alec and Kashin, Seva and Sabatini, Bernardo L and McCarroll, Steven A}
}
@article {1789686,
	title = {Astrocyte-neuron crosstalk through Hedgehog signaling mediates cortical synapse development},
	journal = {Cell Rep},
	volume = {38},
	number = {8},
	year = {2022},
	month = {2022 Feb 22},
	pages = {110416},
	abstract = {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.},
	keywords = {Astrocytes, Hedgehog Proteins, neurogenesis, Neurons, Synapses},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2022.110416},
	author = {Yajun Xie and Aaron T Kuan and Wengang Wang and Herbert, Zachary T and Olivia Mosto and Olukoya, Olubusola and Manal Adam and Steve Vu and Minsu Kim and Tran, Diana and G{\'o}mez, Nicol{\'a}s and Claire Charpentier and Ingie Sorour and Lacey, Tiara E and Tolstorukov, Michael Y and Sabatini, Bernardo L and Lee, Wei-Chung Allen and Harwell, Corey C}
}
@article {1789671,
	title = {Co-packaging of opposing neurotransmitters in individual synaptic vesicles in the central nervous system},
	journal = {Neuron},
	volume = {110},
	number = {8},
	year = {2022},
	month = {2022 Apr 20},
	pages = {1371-1384.e7},
	abstract = {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.},
	keywords = {Animals, gamma-Aminobutyric Acid, Glutamic Acid, Habenula, Mammals, Mice, Neurotransmitter Agents, Synaptic Vesicles},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2022.01.007},
	author = {Kim, Seulah and Wallace, Michael L and El-Rifai, Mahmoud and Knudsen, Alexa R and Sabatini, Bernardo L}
}
@article {1789681,
	title = {Dendritic branch structure compartmentalizes voltage-dependent calcium influx in cortical layer 2/3 pyramidal cells},
	journal = {Elife},
	volume = {11},
	year = {2022},
	month = {2022 Mar 23},
	abstract = {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.},
	keywords = {Action Potentials, Animals, Calcium, Calcium Channels, Dendrites, Mice, Pyramidal Cells},
	issn = {2050-084X},
	doi = {10.7554/eLife.76993},
	author = {Landau, Andrew T and Park, Pojeong and Wong-Campos, J David and Tian, He and Adam E. Cohen and Sabatini, Bernardo L}
}
@article {1789676,
	title = {Mice exhibit stochastic and efficient action switching during probabilistic decision making},
	journal = {Proc Natl Acad Sci U S A},
	volume = {119},
	number = {15},
	year = {2022},
	month = {2022 Apr 12},
	pages = {e2113961119},
	abstract = {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{\textendash}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.},
	keywords = {Animals, Choice Behavior, Decision making, Mice, Reward, Uncertainty},
	issn = {1091-6490},
	doi = {10.1073/pnas.2113961119},
	author = {Beron, Celia C and Neufeld, Shay Q and Linderman, Scott W and Sabatini, Bernardo L}
}
@article {1789696,
	title = {Neurophotonic tools for microscopic measurements and manipulation: status report},
	journal = {Neurophotonics},
	volume = {9},
	number = {Suppl 1},
	year = {2022},
	month = {2022 Jan},
	pages = {013001},
	abstract = {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{\textquoteright} 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.},
	issn = {2329-423X},
	doi = {10.1117/1.NPh.9.S1.013001},
	author = {Abdelfattah, Ahmed S and Ahuja, Sapna and Akkin, Taner and Allu, Srinivasa Rao and Brake, Joshua and Boas, David A and Buckley, Erin M and Campbell, Robert E and Chen, Anderson I and Cheng, Xiaojun and {\v C}i{\v z}m{\'a}r, Tom{\'a}{\v s} and Costantini, Irene and Massimo De Vittorio and Devor, Anna and Doran, Patrick R and El Khatib, Mirna and Emiliani, Valentina and Fomin-Thunemann, Natalie and Fainman, Yeshaiahu and Fernandez-Alfonso, Tomas and Ferri, Christopher G L and Gilad, Ariel and Han, Xue and Andrew Harris and Hillman, Elizabeth M C and Hochgeschwender, Ute and Holt, Matthew G and Ji, Na and K{\i}l{\i}{\c c}, K{\i}v{\i}lc{\i}m and Lake, Evelyn M R and Li, Lei and Li, Tianqi and M{\"a}chler, Philipp and Miller, Evan W and Mesquita, Rickson C and Nadella, K M Naga Srinivas and N{\"a}gerl, U Valentin and Nasu, Yusuke and Nimmerjahn, Axel and Ondr{\'a}{\v c}kov{\'a}, Petra and Pavone, Francesco S and Perez Campos, Citlali and Peterka, Darcy S and Filippo Pisano and Ferruccio Pisanello and Puppo, Francesca and Sabatini, Bernardo L and Sadegh, Sanaz and Sakadzic, Sava and Shoham, Shy and Shroff, Sanaya N and Silver, R Angus and Sims, Ruth R and Smith, Spencer L and Srinivasan, Vivek J and Thunemann, Martin and Tian, Lei and Tian, Lin and Troxler, Thomas and Valera, Antoine and Vaziri, Alipasha and Vinogradov, Sergei A and Vitale, Flavia and Wang, Lihong V and Uhl{\'\i}{\v r}ov{\'a}, Hana and Xu, Chris and Yang, Changhuei and Yang, Mu-Han and Yellen, Gary and Yizhar, Ofer and Yongxin Zhao}
}
@article {1789691,
	title = {Orthogonalization of far-field detection in tapered optical fibers for depth-selective fiber photometry in brain tissue},
	journal = {APL Photonics},
	volume = {7},
	number = {2},
	year = {2022},
	month = {2022 Feb 01},
	pages = {026106},
	abstract = {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.},
	issn = {2378-0967},
	doi = {10.1063/5.0073594},
	author = {Marco Bianco and Marco Pisanello and Antonio Balena and Montinaro, Cinzia and Filippo Pisano and Barbara Spagnolo and Sabatini, Bernardo L and Massimo De Vittorio and Ferruccio Pisanello}
}
@article {1789661,
	title = {Publisher Correction: Viral manipulation of functionally distinct interneurons in mice, non-human primates and humans},
	journal = {Nat Neurosci},
	volume = {25},
	number = {9},
	year = {2022},
	month = {2022 Sep},
	pages = {1247},
	issn = {1546-1726},
	doi = {10.1038/s41593-022-01155-w},
	author = {Vormstein-Schneider, Douglas and Lin, Jessica D and Pelkey, Kenneth A and Chittajallu, Ramesh and Guo, Baolin and Arias-Garcia, Mario A and Allaway, Kathryn and Sakopoulos, Sofia and Schneider, Gates and Stevenson, Olivia and Vergara, Josselyn and Sharma, Jitendra and Zhang, Qiangge and Franken, Tom P and Jared Smith and Ibrahim, Leena A and Mastro, Kevin J and Sabri, Ehsan and Huang, Shuhan and Favuzzi, Emilia and Burbridge, Timothy and Xu, Qing and Guo, Lihua and Vogel, Ian and Vanessa Sanchez and Saldi, Giuseppe A and Gorissen, Bram L and Yuan, Xiaoqing and Zaghloul, Kareem A and Devinsky, Orrin and Sabatini, Bernardo L and Batista-Brito, Renata and Reynolds, John and Feng, Guoping and Zhanyan Fu and McBain, Chris J and Fishell, Gord and Dimidschstein, Jordane}
}
@article {1789651,
	title = {A single-cell atlas of the cycling murine ovary},
	journal = {Elife},
	volume = {11},
	year = {2022},
	month = {2022 Oct 07},
	abstract = {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 \&gt;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.},
	keywords = {Animals, Estrous Cycle, Female, Mice, Ovarian Follicle, Ovary, Ovulation, Pelvis},
	issn = {2050-084X},
	doi = {10.7554/eLife.77239},
	author = {Morris, Mary E and Meinsohn, Marie-Charlotte and Chauvin, Maeva and Saatcioglu, Hatice D and Kashiwagi, Aki and Sicher, Natalie A and Nguyen, Ngoc and Yuan, Selena and Stavely, Rhian and Hyun, Minsuk and Donahoe, Patricia K and Sabatini, Bernardo L and P{\'e}pin, David}
}
@article {1789666,
	title = {Tapered fibertrodes for optoelectrical neural interfacing in small brain volumes with reduced artefacts},
	journal = {Nat Mater},
	volume = {21},
	number = {7},
	year = {2022},
	month = {2022 Jul},
	pages = {826-835},
	abstract = {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 {\textquoteright}fibertrodes{\textquoteright} 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.},
	keywords = {Artifacts, Brain, Electrodes, Neurons, Optogenetics},
	issn = {1476-4660},
	doi = {10.1038/s41563-022-01272-8},
	author = {Barbara Spagnolo and Antonio Balena and Peixoto, Rui T and Marco Pisanello and Leonardo Sileo and Marco Bianco and Rizzo, Alessandro and Filippo Pisano and Qualtieri, Antonio and Lofrumento, Dario Domenico and De Nuccio, Francesco and Assad, John A and Sabatini, Bernardo L and Massimo De Vittorio and Ferruccio Pisanello}
}
@article {1789656,
	title = {Wireless multi-lateral optofluidic microsystems for real-time programmable optogenetics and photopharmacology},
	journal = {Nat Commun},
	volume = {13},
	number = {1},
	year = {2022},
	month = {2022 Sep 22},
	pages = {5571},
	abstract = {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.},
	keywords = {Animals, Brain, Glutamates, Mice, Neurosciences, Optogenetics, Wireless Technology},
	issn = {2041-1723},
	doi = {10.1038/s41467-022-32947-0},
	author = {Wu, Yixin and Wu, Mingzheng and V{\'a}zquez-Guardado, Abraham and Kim, Joohee and Zhang, Xin and Avila, Raudel and Kim, Jin-Tae and Deng, Yujun and Yu, Yongjoon and Melzer, Sarah and Bai, Yun and Yoon, Hyoseo and Meng, Lingzi and Zhang, Yi and Guo, Hexia and Hong, Liu and Kanatzidis, Evangelos E and Haney, Chad R and Waters, Emily A and Banks, Anthony R and Hu, Ziying and Lie, Ferrona and Chamorro, Leonardo P and Sabatini, Bernardo L and Huang, Yonggang and Kozorovitskiy, Yevgenia and Rogers, John A}
}
@article {Cortopassi2022-wy,
	title = {Analysis of thermogenesis experiments with CalR},
	journal = {Methods Mol. Biol.},
	volume = {2448},
	year = {2022},
	pages = {43{\textendash}72},
	abstract = {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{\textquoteright} CLAMS, Sable Systems{\textquoteright} Promethion, and TSE Systems{\textquoteright} 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.},
	keywords = {Adrenergic agonist, Body Weight, Cold exposure, Energy expenditure, Hyperthyroid, Indirect calorimetry, Metabolic rate, Thermogenesis, Weight Gain, Weight Loss},
	author = {Cortopassi, Marissa D and Ramachandran, Deepti and Rubio, William B and Hochbaum, Daniel and Sabatini, Bernardo L and Banks, Alexander S}
}
@article {Xie2022-jg,
	title = {Astrocyte-neuron crosstalk through Hedgehog signaling mediates cortical synapse development},
	journal = {Cell Rep.},
	volume = {38},
	number = {8},
	year = {2022},
	pages = {110416},
	publisher = {Elsevier BV},
	abstract = {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.},
	keywords = {Astrocytes, cortical circuits, Lrig1, neuron-glia interaction, Sonic hedgehog, Sparc, synapse formation},
	author = {Yajun Xie and Aaron T Kuan and Wengang Wang and Herbert, Zachary T and Olivia Mosto and Olukoya, Olubusola and Manal Adam and Steve Vu and Minsu Kim and Tran, Diana and G{\'o}mez, Nicol{\'a}s and Claire Charpentier and Ingie Sorour and Lacey, Tiara E and Tolstorukov, Michael Y and Sabatini, Bernardo L and Lee, Wei-Chung Allen and Harwell, Corey C}
}
@article {Kim2022-qn,
	title = {Co-packaging of opposing neurotransmitters in individual synaptic vesicles in the central nervous system},
	journal = {Neuron},
	year = {2022},
	abstract = {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.},
	keywords = {Basal Ganglia, Computational modeling, digital micromirror device, entopeduncular nucleus, GABA, glutamate, lateral habenula, neurotransmitter co-release},
	author = {Kim, Seulah and Wallace, Michael L and El-Rifai, Mahmoud and Knudsen, Alexa R and Sabatini, Bernardo L}
}
@article {Beron2022-pl,
	title = {Mice exhibit stochastic and efficient action switching during probabilistic decision making},
	journal = {Proc. Natl. Acad. Sci. U. S. A.},
	volume = {119},
	number = {15},
	year = {2022},
	pages = {e2113961119},
	publisher = {Proceedings of the National Academy of Sciences},
	abstract = {SignificanceTo obtain rewards in changing and uncertain environments, animals must adapt their behavior. We found that mouse choice and trial-to-trial switching behavior in a dynamic and probabilistic two-choice task could be modeled by equivalent theoretical, algorithmic, and descriptive models. These models capture components of evidence accumulation, choice history bias, and stochasticity in mouse behavior. Furthermore, they reveal that mice adapt their behavior in different environmental contexts by modulating their level of stickiness to their previous choice. Despite deviating from the behavior of a theoretically ideal observer, the empirical models achieve comparable levels of near-maximal reward. These results make predictions to guide interrogation of the neural mechanisms underlying flexible decision-making strategies.},
	keywords = {Bayesian inference, Decision making, explore-exploit, perseveration, stochastic choice},
	author = {Beron, Celia C and Neufeld, Shay Q and Linderman, Scott W and Sabatini, Bernardo L}
}
@article {Bianco2022-mr,
	title = {Orthogonalization of far-field detection in tapered optical fibers for depth-selective fiber photometry in brain tissue},
	journal = {APL Photonics},
	volume = {7},
	number = {2},
	year = {2022},
	month = {feb},
	pages = {026106},
	publisher = {AIP Publishing},
	abstract = {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.},
	author = {Marco Bianco and Marco Pisanello and Antonio Balena and Montinaro, Cinzia and Filippo Pisano and Barbara Spagnolo and Sabatini, Bernardo L and Massimo De Vittorio and Ferruccio Pisanello}
}
@article {1789711,
	title = {Bombesin-like peptide recruits disinhibitory cortical circuits and enhances fear memories},
	journal = {Cell},
	volume = {184},
	number = {22},
	year = {2021},
	month = {2021 Oct 28},
	pages = {5622-5634.e25},
	abstract = {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.},
	keywords = {Amino Acid Sequence, Animals, Auditory Cortex, Bombesin, Calcium, Calcium Signaling, Conditioning, Classical, Fear, Gastrin-Releasing Peptide, Gene Expression Regulation, Genes, Immediate-Early, HEK293 Cells, Humans, Intracellular Space, Male, Memory, Mice, Inbred C57BL, Nerve Net, Receptors, Bombesin, Sound, Vasoactive Intestinal Peptide},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2021.09.013},
	author = {Melzer, Sarah and Newmark, Elena R and Mizuno, Grace Or and Hyun, Minsuk and Philson, Adrienne C and Quiroli, Eleonora and Righetti, Beatrice and Gregory, Malika R and Huang, Kee Wui and Levasseur, James and Tian, Lin and Sabatini, Bernardo L}
}
@article {1789726,
	title = {Cell-type-specific asynchronous modulation of PKA by dopamine in learning},
	journal = {Nature},
	volume = {590},
	number = {7846},
	year = {2021},
	month = {2021 Feb},
	pages = {451-456},
	abstract = {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 release1. Dopamine is thought to guide learning via dynamic and differential modulation of protein kinase~A (PKA) in each class of spiny projection neuron2. 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.},
	keywords = {Animals, Cyclic AMP-Dependent Protein Kinases, Dopamine, Dopaminergic Neurons, Female, Fluorescence, GABAergic Neurons, Learning, Male, Mice, Neuronal Plasticity, Nucleus Accumbens, Photometry, Receptors, Dopamine},
	issn = {1476-4687},
	doi = {10.1038/s41586-020-03050-5},
	author = {Lee, Suk Joon and Lodder, Bart and Chen, Yao and Patriarchi, Tommaso and Tian, Lin and Sabatini, Bernardo L}
}
@article {1789721,
	title = {Comparative study of autofluorescence in flat and tapered optical fibers towards application in depth-resolved fluorescence lifetime photometry in brain tissue},
	journal = {Biomed Opt Express},
	volume = {12},
	number = {2},
	year = {2021},
	month = {2021 Feb 01},
	pages = {993-1010},
	abstract = {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.},
	issn = {2156-7085},
	doi = {10.1364/BOE.410244},
	author = {Marco Bianco and Antonio Balena and Marco Pisanello and Filippo Pisano and Leonardo Sileo and Barbara Spagnolo and Montinaro, Cinzia and Sabatini, Bernardo L and Massimo De Vittorio and Ferruccio Pisanello}
}
@article {1789731,
	title = {The Kinase Specificity of Protein Kinase Inhibitor Peptide},
	journal = {Front Pharmacol},
	volume = {12},
	year = {2021},
	month = {2021},
	pages = {632815},
	abstract = {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.},
	issn = {1663-9812},
	doi = {10.3389/fphar.2021.632815},
	author = {Chen, Yao and Sabatini, Bernardo L}
}
@article {1789716,
	title = {Real-Time, In Vivo Measurement of Protein Kinase A Activity in Deep Brain Structures Using Fluorescence Lifetime Photometry (FLiP)},
	journal = {Curr Protoc},
	volume = {1},
	number = {10},
	year = {2021},
	month = {2021 Oct},
	pages = {e265},
	abstract = {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. {\textcopyright} 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.},
	keywords = {Animals, Brain, Cyclic AMP-Dependent Protein Kinases, Mice, Neurons, Phosphorylation, Photometry},
	issn = {2691-1299},
	doi = {10.1002/cpz1.265},
	author = {Lodder, Bart and Lee, Suk Joon and Sabatini, Bernardo L}
}
@article {1789736,
	title = {Social isolation uncovers a circuit underlying context-dependent territory-covering micturition},
	journal = {Proc Natl Acad Sci U S A},
	volume = {118},
	number = {1},
	year = {2021},
	month = {2021 Jan 05},
	abstract = {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.},
	keywords = {Animals, Brain, Communication, Hypothalamus, Male, Mice, Mice, 129 Strain, Mice, Inbred BALB C, Mice, Inbred C57BL, Pons, Reflex, Social Isolation, Spinal Cord, Urinary Bladder, Urination},
	issn = {1091-6490},
	doi = {10.1073/pnas.2018078118},
	author = {Hyun, Minsuk and Taranda, Julian and Radeljic, Gianna and Miner, Lauren and Wengang Wang and Ochandarena, Nicole and Huang, Kee Wui and Osten, Pavel and Sabatini, Bernardo L}
}
@article {1789706,
	title = {Striatal indirect pathway mediates exploration via collicular competition},
	journal = {Nature},
	volume = {599},
	number = {7886},
	year = {2021},
	month = {2021 Nov},
	pages = {645-649},
	abstract = {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 processes1-5, 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.},
	keywords = {Animals, Basal Ganglia, Behavior, Animal, Corpus Striatum, Decision making, Exploratory Behavior, Female, Male, Mice, Neural Inhibition, Neural Pathways, Neurons, Optogenetics, Reward, Superior Colliculi},
	issn = {1476-4687},
	doi = {10.1038/s41586-021-04055-4},
	author = {Lee, Jaeeon and Sabatini, Bernardo L}
}
@article {Melzer2021-xj,
	title = {Bombesin-like peptide recruits disinhibitory cortical circuits and enhances fear memories},
	journal = {Cell},
	volume = {184},
	number = {22},
	year = {2021},
	pages = {5622{\textendash}5634.e25},
	publisher = {Elsevier BV},
	abstract = {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.},
	keywords = {cortex, CRISPR-Cas9, disinhibition, fear memory, Gastrin-Releasing Peptide, neuropeptide, VIP cells},
	author = {Melzer, Sarah and Newmark, Elena R and Mizuno, Grace Or and Hyun, Minsuk and Philson, Adrienne C and Quiroli, Eleonora and Righetti, Beatrice and Gregory, Malika R and Huang, Kee Wui and Levasseur, James and Tian, Lin and Sabatini, Bernardo L}
}
@article {Lodder2021-oc,
	title = {Real-time, in vivo measurement of protein kinase A activity in deep brain structures using fluorescence lifetime photometry (FLiP)},
	journal = {Curr Protoc},
	volume = {1},
	number = {10},
	year = {2021},
	month = {oct},
	pages = {e265},
	publisher = {Wiley},
	abstract = {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. \copyright 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.},
	keywords = {FLiP, Fluorescence, lifetime, Photometry, PKA},
	author = {Lodder, Bart and Lee, Suk Joon and Sabatini, Bernardo L}
}
@article {Lee2021-se,
	title = {Striatal indirect pathway mediates exploration via collicular competition},
	journal = {Nature},
	volume = {599},
	number = {7886},
	year = {2021},
	pages = {645{\textendash}649},
	publisher = {Springer Science and Business Media LLC},
	abstract = {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 processes1-5, 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.},
	author = {Lee, Jaeeon and Sabatini, Bernardo L}
}
@article {bianco_comparative_2021,
	title = {Comparative study of autofluorescence in flat and tapered optical fibers towards application in depth-resolved fluorescence lifetime photometry in brain tissue.},
	journal = {Biomedical optics express},
	volume = {12},
	number = {2},
	year = {2021},
	pages = {993{\textendash}1010},
	abstract = {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.},
	issn = {2156-7085},
	doi = {10.1364/BOE.410244},
	author = {Marco Bianco and Antonio Balena and Marco Pisanello and Filippo Pisano and Leonardo Sileo and Barbara Spagnolo and Montinaro, Cinzia and Bernardo L. Sabatini and Massimo De Vittorio and Ferruccio Pisanello}
}
@article {chen_kinase_2021,
	title = {The Kinase Specificity of Protein Kinase Inhibitor Peptide.},
	journal = {Frontiers in pharmacology},
	volume = {12},
	year = {2021},
	pages = {632815},
	abstract = {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.},
	keywords = {endogenous, facilitation, inhibition, kinase screen, protein kinase A, Protein Kinase C, protein kinase inhibitor peptide, specificity},
	issn = {1663-9812},
	doi = {10.3389/fphar.2021.632815},
	author = {Chen, Yao and Bernardo L. Sabatini}
}
@article {hyun_social_2021,
	title = {Social isolation uncovers a circuit underlying context-dependent territory-covering micturition.},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {118},
	number = {1},
	year = {2021},
	abstract = {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.},
	keywords = {*hypothamaus, *micturition, *pons, *social hierarchy, 129 Strain, Animals, Brain/physiology, Communication, Hypothalamus/*physiology, Inbred BALB C, Inbred C57BL, Male, Mice, Pons/physiology, Reflex/physiology, Social Isolation/*psychology, Spinal Cord/physiology, Urinary Bladder/physiology, Urination/genetics/*physiology},
	issn = {1091-6490 0027-8424},
	doi = {10.1073/pnas.2018078118},
	author = {Hyun, Minsuk and Taranda, Julian and Radeljic, Gianna and Miner, Lauren and Wengang Wang and Ochandarena, Nicole and Huang, Kee Wui and Osten, Pavel and Bernardo L. Sabatini}
}
@article {lee_cell-type-specific_2021,
	title = {Cell-type-specific asynchronous modulation of PKA by dopamine in learning.},
	journal = {Nature},
	volume = {590},
	number = {7846},
	year = {2021},
	pages = {451{\textendash}456},
	abstract = {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\&nbsp;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.},
	keywords = {*Learning/drug effects, Animals, Cyclic AMP-Dependent Protein Kinases/antagonists \& inhibitors/*metabolism, Dopamine/*metabolism, Dopamine/classification/metabolism, Dopaminergic Neurons/drug effects/enzymology/metabolism, Female, Fluorescence, GABAergic Neurons/drug effects/enzymology/metabolism, Male, Mice, Neuronal Plasticity/drug effects, Nucleus Accumbens/cytology, Photometry, Receptors},
	issn = {1476-4687 0028-0836},
	doi = {10.1038/s41586-020-03050-5},
	author = {Lee, Suk Joon and Lodder, Bart and Chen, Yao and Patriarchi, Tommaso and Tian, Lin and Bernardo L. Sabatini}
}
@article {1789786,
	title = {Anatomical and single-cell transcriptional profiling of the murine habenular complex},
	journal = {Elife},
	volume = {9},
	year = {2020},
	month = {2020 Feb 11},
	abstract = {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.},
	keywords = {Animals, Brain Mapping, Dopaminergic Neurons, GABAergic Neurons, Gene Expression Profiling, Habenula, Mice, Single-Cell Analysis, Transcriptome, Ventral Tegmental Area},
	issn = {2050-084X},
	doi = {10.7554/eLife.51271},
	author = {Wallace, Michael L and Huang, Kee Wui and Hochbaum, Daniel and Hyun, Minsuk and Radeljic, Gianna and Sabatini, Bernardo L}
}
@article {1789746,
	title = {Anatomically segregated basal ganglia pathways allow parallel behavioral modulation},
	journal = {Nat Neurosci},
	volume = {23},
	number = {11},
	year = {2020},
	month = {2020 Nov},
	pages = {1388-1398},
	abstract = {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.},
	keywords = {Animals, Basal Ganglia, Behavior, Animal, Cerebral Cortex, Female, Intralaminar Thalamic Nuclei, Male, Mice, Inbred C57BL, Neural Pathways, Neuroanatomical Tract-Tracing Techniques, Neurons, Pars Reticulata, Superior Colliculi, Ventral Thalamic Nuclei},
	issn = {1546-1726},
	doi = {10.1038/s41593-020-00712-5},
	author = {Lee, Jaeeon and Wengang Wang and Sabatini, Bernardo L}
}
@article {1789781,
	title = {Caveolae in CNS arterioles mediate neurovascular coupling},
	journal = {Nature},
	volume = {579},
	number = {7797},
	year = {2020},
	month = {2020 Mar},
	pages = {106-110},
	abstract = {Proper brain function depends on neurovascular coupling: neural activity rapidly increases local blood flow to meet moment-to-moment changes in regional brain energy demand1. Neurovascular coupling is the basis for functional brain imaging2, and impaired neurovascular coupling is implicated in neurodegeneration1. 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 flow1. 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.},
	keywords = {Animals, Arterioles, Caveolae, Central Nervous System, Cerebral Cortex, Endothelial Cells, Female, Male, Mice, Microscopy, Fluorescence, Multiphoton, Neurovascular Coupling, Nitric Oxide Synthase Type III, Vasodilation, Vibrissae},
	issn = {1476-4687},
	doi = {10.1038/s41586-020-2026-1},
	author = {Chow, Brian W and Nu{\~n}ez, Vicente and Kaplan, Luke and Granger, Adam J and Bistrong, Karina and Zucker, Hannah L and Kumar, Payal and Sabatini, Bernardo L and Gu, Chenghua}
}
@article {1789771,
	title = {Cortical ChAT neurons co-transmit acetylcholine and GABA in a target- and brain-region-specific manner},
	journal = {Elife},
	volume = {9},
	year = {2020},
	month = {2020 Jul 02},
	abstract = {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.},
	keywords = {Acetylcholine, Animals, Brain, Cerebral Cortex, Choline O-Acetyltransferase, gamma-Aminobutyric Acid, Heterozygote, Interneurons, Mice, Neurons, Prefrontal Cortex, Presynaptic Terminals},
	issn = {2050-084X},
	doi = {10.7554/eLife.57749},
	author = {Granger, Adam J and Wengang Wang and Robertson, Keiramarie and El-Rifai, Mahmoud and Zanello, Andrea F and Bistrong, Karina and Saunders, Arpiar and Chow, Brian W and Nu{\~n}ez, Vicente and Garc{\'\i}a, Miguel Turrero and Harwell, Corey C and Gu, Chenghua and Sabatini, Bernardo L}
}
@article {1789751,
	title = {Imaging Neurotransmitter and Neuromodulator Dynamics In~Vivo with Genetically Encoded Indicators},
	journal = {Neuron},
	volume = {108},
	number = {1},
	year = {2020},
	month = {2020 Oct 14},
	pages = {17-32},
	abstract = {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{\textquoteright}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.},
	keywords = {Animals, Biosensing Techniques, Brain, Humans, Neurons, Neurotransmitter Agents, Optical Imaging, Optogenetics, Periplasmic Binding Proteins, Protein Engineering, Receptors, G-Protein-Coupled},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2020.09.036},
	author = {Sabatini, Bernardo L and Tian, Lin}
}
@article {1789756,
	title = {Rapid purification and metabolomic profiling of synaptic vesicles from mammalian brain},
	journal = {Elife},
	volume = {9},
	year = {2020},
	month = {2020 Oct 12},
	abstract = {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.},
	keywords = {Animals, Brain, Female, Glutamic Acid, Male, Mass Spectrometry, Metabolome, Metabolomics, Mice, Synaptic Vesicles},
	issn = {2050-084X},
	doi = {10.7554/eLife.59699},
	author = {Chantranupong, Lynne and Saulnier, Jessica L and Wengang Wang and Jones, Drew R and Pacold, Michael E and Sabatini, Bernardo L}
}
@article {1789766,
	title = {Ray tracing models for estimating light collection properties of microstructured tapered optical fibers for optical neural interfaces},
	journal = {Opt Lett},
	volume = {45},
	number = {14},
	year = {2020},
	month = {2020 Jul 15},
	pages = {3856-3859},
	abstract = {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.},
	issn = {1539-4794},
	doi = {10.1364/OL.397022},
	author = {Emanuela Maglie and Marco Pisanello and Filippo Pisano and Antonio Balena and Marco Bianco and Barbara Spagnolo and Leonardo Sileo and Sabatini, Bernardo L and Massimo De Vittorio and Ferruccio Pisanello}
}
@article {1789776,
	title = {Single-Cell Analysis of Neuroinflammatory Responses Following Intracranial Injection of G-Deleted Rabies Viruses},
	journal = {Front Cell Neurosci},
	volume = {14},
	year = {2020},
	month = {2020},
	pages = {65},
	abstract = {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.},
	issn = {1662-5102},
	doi = {10.3389/fncel.2020.00065},
	author = {Huang, Kee Wui and Sabatini, Bernardo L}
}
@article {1789761,
	title = {Two-photon fluorescence-assisted laser ablation of non-planar metal surfaces: fabrication of optical apertures on tapered fibers for optical neural interfaces},
	journal = {Opt Express},
	volume = {28},
	number = {15},
	year = {2020},
	month = {2020 Jul 20},
	pages = {21368-21381},
	abstract = {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.},
	issn = {1094-4087},
	doi = {10.1364/OE.395187},
	author = {Antonio Balena and Marco Bianco and Filippo Pisano and Marco Pisanello and Leonardo Sileo and Sabatini, Bernardo L and Massimo De Vittorio and Ferruccio Pisanello}
}
@article {1789741,
	title = {Viral manipulation of functionally distinct interneurons in mice, non-human primates and humans},
	journal = {Nat Neurosci},
	volume = {23},
	number = {12},
	year = {2020},
	month = {2020 Dec},
	pages = {1629-1636},
	abstract = {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.},
	keywords = {Animals, Callithrix, Cerebral Cortex, Dependovirus, Female, Genetic Vectors, Humans, Interneurons, Macaca mulatta, Mice, Mice, Inbred C57BL, NAV1.1 Voltage-Gated Sodium Channel, Neurons, Parvalbumins, Rats, Rats, Sprague-Dawley, Species Specificity, Vasoactive Intestinal Peptide},
	issn = {1546-1726},
	doi = {10.1038/s41593-020-0692-9},
	author = {Vormstein-Schneider, Douglas and Lin, Jessica D and Pelkey, Kenneth A and Chittajallu, Ramesh and Guo, Baolin and Arias-Garcia, Mario A and Allaway, Kathryn and Sakopoulos, Sofia and Schneider, Gates and Stevenson, Olivia and Vergara, Josselyn and Sharma, Jitendra and Zhang, Qiangge and Franken, Tom P and Jared Smith and Ibrahim, Leena A and Mastro, Kevin J and Sabri, Ehsan and Huang, Shuhan and Favuzzi, Emilia and Burbridge, Timothy and Xu, Qing and Guo, Lihua and Vogel, Ian and Vanessa Sanchez and Saldi, Giuseppe A and Gorissen, Bram L and Yuan, Xiaoqing and Zaghloul, Kareem A and Devinsky, Orrin and Sabatini, Bernardo L and Batista-Brito, Renata and Reynolds, John and Feng, Guoping and Zhanyan Fu and McBain, Chris J and Fishell, Gord and Dimidschstein, Jordane}
}
@article {balena_two-photon_2020,
	title = {Two-photon fluorescence-assisted laser ablation of non-planar metal surfaces: fabrication of optical apertures on tapered fibers for optical neural interfaces.},
	journal = {Optics express},
	volume = {28},
	number = {15},
	year = {2020},
	pages = {21368{\textendash}21381},
	abstract = {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.},
	issn = {1094-4087},
	doi = {10.1364/OE.395187},
	author = {Antonio Balena and Marco Bianco and Filippo Pisano and Marco Pisanello and Leonardo Sileo and Bernardo L. Sabatini and Massimo De Vittorio and Ferruccio Pisanello}
}
@article {lee_anatomically_2020,
	title = {Anatomically segregated basal ganglia pathways allow parallel behavioral modulation.},
	journal = {Nature neuroscience},
	volume = {23},
	number = {11},
	year = {2020},
	pages = {1388{\textendash}1398},
	abstract = {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.},
	keywords = {Animal/*physiology, Animals, Basal Ganglia/*cytology/*physiology, Behavior, Cerebral Cortex/physiology, Female, Inbred C57BL, Intralaminar Thalamic Nuclei/cytology/physiology, Male, Mice, Neural Pathways/cytology/physiology, Neuroanatomical Tract-Tracing Techniques, Neurons/*physiology, Pars Reticulata/cytology/physiology, Superior Colliculi/cytology/physiology, Ventral Thalamic Nuclei/cytology/physiology},
	issn = {1546-1726 1097-6256},
	doi = {10.1038/s41593-020-00712-5},
	author = {Lee, Jaeeon and Wengang Wang and Bernardo L. Sabatini}
}
@article {chow_caveolae_2020,
	title = {Caveolae in CNS arterioles mediate neurovascular coupling.},
	journal = {Nature},
	volume = {579},
	number = {7797},
	year = {2020},
	pages = {106{\textendash}110},
	abstract = {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.},
	keywords = {*Neurovascular Coupling, Animals, Arterioles/*cytology/*metabolism, Caveolae/*metabolism, Central Nervous System/*cytology, Cerebral Cortex/cytology, Endothelial Cells/metabolism, Female, Fluorescence, Male, Mice, Microscopy, Multiphoton, Nitric Oxide Synthase Type III/deficiency/metabolism, Vasodilation, Vibrissae/physiology},
	issn = {1476-4687 0028-0836},
	doi = {10.1038/s41586-020-2026-1},
	author = {Chow, Brian W. and Nu{\~n}ez, Vicente and Kaplan, Luke and Granger, Adam J. and Bistrong, Karina and Zucker, Hannah L. and Kumar, Payal and Bernardo L. Sabatini and Gu, Chenghua}
}
@article {granger_cortical_2020,
	title = {Cortical ChAT(+) neurons co-transmit acetylcholine and GABA in a target- and brain-region-specific manner.},
	journal = {eLife},
	volume = {9},
	year = {2020},
	abstract = {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.},
	keywords = {*Acetylcholine, *cortical interneurons, *GABA, *mouse, *neuromodulation, *neuroscience, *neurotransmitter co-release, *VIP, Acetylcholine/*metabolism, Animals, Brain/*metabolism, Cerebral Cortex/metabolism, Choline O-Acetyltransferase/*metabolism, gamma-Aminobutyric Acid/*metabolism, Heterozygote, Interneurons/metabolism, Mice, Neurons/*metabolism, Prefrontal Cortex/metabolism, Presynaptic Terminals/metabolism},
	issn = {2050-084X},
	doi = {10.7554/eLife.57749},
	author = {Granger, Adam J. and Wengang Wang and Robertson, Keiramarie and El-Rifai, Mahmoud and Zanello, Andrea F. and Bistrong, Karina and Saunders, Arpiar and Chow, Brian W. and Nu{\~n}ez, Vicente and Garc{\'\i}a, Miguel Turrero and Harwell, Corey C. and Gu, Chenghua and Bernardo L. Sabatini}
}
@article {sabatini_imaging_2020,
	title = {Imaging Neurotransmitter and Neuromodulator Dynamics In Vivo with Genetically Encoded Indicators.},
	journal = {Neuron},
	volume = {108},
	number = {1},
	year = {2020},
	note = {Place: United States},
	pages = {17{\textendash}32},
	abstract = {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{\textquoteright}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\&nbsp;vivo studies.},
	keywords = {*Biosensing Techniques, *Optical Imaging, *Optogenetics, Animals, Brain/diagnostic imaging/*metabolism, G-Protein-Coupled/genetics, Humans, Neurons/*metabolism, Neurotransmitter Agents/*metabolism, Periplasmic Binding Proteins/genetics, Protein Engineering, Receptors},
	issn = {1097-4199 0896-6273},
	doi = {10.1016/j.neuron.2020.09.036},
	author = {Bernardo L. Sabatini and Tian, Lin}
}
@article {chantranupong_rapid_2020,
	title = {Rapid purification and metabolomic profiling of synaptic vesicles from mammalian brain.},
	journal = {eLife},
	volume = {9},
	year = {2020},
	month = {oct},
	abstract = {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.},
	keywords = {*Metabolome, *Metabolomics, *mouse, *neuroscience, *neurotransmitters, *synaptic vesicle, Animals, Brain/*metabolism, Female, Glutamic Acid/metabolism, Male, Mass Spectrometry/*methods, Metabolomics/*methods, Mice, Synaptic Vesicles/*metabolism},
	issn = {2050-084X},
	doi = {10.7554/eLife.59699},
	author = {Chantranupong, Lynne and Jessica L. Saulnier and Wengang Wang and Jones, Drew R. and Pacold, Michael E. and Bernardo L. Sabatini}
}
@article {huang_single-cell_2020,
	title = {Single-Cell Analysis of Neuroinflammatory Responses Following Intracranial Injection of G-Deleted Rabies Viruses.},
	journal = {Frontiers in cellular neuroscience},
	volume = {14},
	year = {2020},
	pages = {65},
	abstract = {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.},
	keywords = {brain infiltration, G-deleted rabies virus, Microglia, neuroinflammation, scRNA-seq},
	issn = {1662-5102},
	doi = {10.3389/fncel.2020.00065},
	author = {Huang, Kee Wui and Bernardo L. Sabatini}
}
@article {vormstein-schneider_viral_2020,
	title = {Viral manipulation of functionally distinct interneurons in mice, non-human primates and humans.},
	journal = {Nature neuroscience},
	volume = {23},
	number = {12},
	year = {2020},
	pages = {1629{\textendash}1636},
	abstract = {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.},
	keywords = {Animals, Callithrix, Cerebral Cortex/cytology, Dependovirus/*genetics, Female, Genetic Vectors/*genetics, Humans, Inbred C57BL, Interneurons/*physiology, Macaca mulatta, Mice, NAV1.1 Voltage-Gated Sodium Channel/genetics, Neurons, Parvalbumins/physiology, Rats, Species Specificity, Sprague-Dawley, Vasoactive Intestinal Peptide/physiology},
	issn = {1546-1726 1097-6256},
	doi = {10.1038/s41593-020-0692-9},
	author = {Vormstein-Schneider, Douglas and Lin, Jessica D. and Pelkey, Kenneth A. and Chittajallu, Ramesh and Guo, Baolin and Arias-Garcia, Mario A. and Allaway, Kathryn and Sakopoulos, Sofia and Schneider, Gates and Stevenson, Olivia and Vergara, Josselyn and Sharma, Jitendra and Zhang, Qiangge and Franken, Tom P. and Jared Smith and Ibrahim, Leena A. and M Astro, Kevin J. and Sabri, Ehsan and Huang, Shuhan and Favuzzi, Emilia and Burbridge, Timothy and Xu, Qing and Guo, Lihua and Vogel, Ian and Vanessa Sanchez and Saldi, Giuseppe A. and Gorissen, Bram L. and Yuan, Xiaoqing and Zaghloul, Kareem A. and Devinsky, Orrin and Bernardo L. Sabatini and Batista-Brito, Renata and Reynolds, John and Feng, Guoping and Zhanyan Fu and McBain, Chris J. and Fishell, Gord and Dimidschstein, Jordane}
}
@article {1603082,
	title = {Ray tracing models for estimating light collection properties of microstructured tapered optical fibers for optical neural interfaces},
	journal = {Optics Letters},
	volume = {45},
	number = {14},
	year = {2020},
	pages = {3856-3859 },
	author = {Emanuela Maglie and Marco Pisanello and Filippo Pisano and Antonio Balena and Marco Bianco and Barbara Spagnolo and Leonardo Sileo and Sabatini, Bernardo L and Massimo De Vittorio and Ferruccio Pisanello}
}
@article {1489672,
	title = {Anatomical and single-cell transcriptional profiling of the murine habenular complex},
	journal = {Elife},
	volume = {11},
	number = {9},
	year = {2020},
	author = {ML Wallace and KW Huang and D Hochbaum and M Hyun and G Radeljic and BL Sabatini}
}
@article {1789791,
	title = {Abnormal Striatal Development Underlies the Early Onset of Behavioral Deficits in Shank3B Mice},
	journal = {Cell Rep},
	volume = {29},
	number = {7},
	year = {2019},
	month = {2019 Nov 12},
	pages = {2016-2027.e4},
	abstract = {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.},
	keywords = {Animals, Autism Spectrum Disorder, Behavior, Animal, Corpus Striatum, Cyclic AMP-Dependent Protein Kinases, Disease Models, Animal, Mice, Mice, Knockout, Microfilament Proteins, Nerve Tissue Proteins, Neurons},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2019.10.021},
	author = {Peixoto, Rui Tiago and Chantranupong, Lynne and Hakim, Richard and Levasseur, James and Wengang Wang and Merchant, Tasha and Gorman, Kelly and Budnik, Bogdan and Sabatini, Bernardo Luis}
}
@article {1789796,
	title = {Depth-resolved fiber photometry with a single tapered optical fiber implant},
	journal = {Nat Methods},
	volume = {16},
	number = {11},
	year = {2019},
	month = {2019 Nov},
	pages = {1185-1192},
	abstract = {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.},
	keywords = {Animals, Corpus Striatum, Dopamine, Fluorescence, Male, Mice, Mice, Inbred C57BL, Optical Fibers, Photometry},
	issn = {1548-7105},
	doi = {10.1038/s41592-019-0581-x},
	author = {Filippo Pisano and Marco Pisanello and Lee, Suk Joon and Lee, Jaeeon and Emanuela Maglie and Antonio Balena and Leonardo Sileo and Barbara Spagnolo and Marco Bianco and Hyun, Minsuk and Massimo De Vittorio and Sabatini, Bernardo L and Ferruccio Pisanello}
}
@article {1789826,
	title = {Distinct Cortical-Thalamic-Striatal Circuits through the Parafascicular Nucleus},
	journal = {Neuron},
	volume = {102},
	number = {3},
	year = {2019},
	month = {2019 May 08},
	pages = {636-652.e7},
	abstract = {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.},
	keywords = {Animals, Cerebral Cortex, Corpus Striatum, Gene Expression Profiling, Intralaminar Thalamic Nuclei, Mice, Neural Pathways, Neuroanatomical Tract-Tracing Techniques, Neurons, Patch-Clamp Techniques, Single-Cell Analysis, Thalamus},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2019.02.035},
	author = {Mandelbaum, Gil and Taranda, Julian and Haynes, Trevor M and Hochbaum, Daniel R and Huang, Kee Wui and Hyun, Minsuk and Venkataraju, Kannan Umadevi and Christoph Straub and Wengang Wang and Robertson, Keiramarie and Osten, Pavel and Sabatini, Bernardo L}
}
@article {1789821,
	title = {Focused ion beam nanomachining of tapered optical fibers for patterned light delivery},
	journal = {Microelectron Eng},
	volume = {195},
	year = {2019},
	month = {2019 May 29},
	pages = {41-49},
	abstract = {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{\textdegree}, 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{\textdegree} symmetry. The result is a versatile technology enabling reconfigurable light-delivery that can be tailored to specific experimental needs.},
	issn = {0167-9317},
	doi = {10.1016/j.mee.2018.03.023},
	author = {Filippo Pisano and Marco Pisanello and Leonardo Sileo and Qualtieri, Antonio and Sabatini, Bernardo L and Massimo De Vittorio and Ferruccio Pisanello}
}
@article {1789816,
	title = {In vivo nuclear capture and molecular profiling identifies Gmeb1 as a transcriptional regulator essential for dopamine neuron function},
	journal = {Nat Commun},
	volume = {10},
	number = {1},
	year = {2019},
	month = {2019 Jun 07},
	pages = {2508},
	abstract = {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.},
	keywords = {Animals, Dopamine Plasma Membrane Transport Proteins, Dopaminergic Neurons, Gene Expression Profiling, Gene Expression Regulation, Gene Knockdown Techniques, Mesencephalon, Mice, Pars Compacta, Transcription Factors, Tyrosine 3-Monooxygenase},
	issn = {2041-1723},
	doi = {10.1038/s41467-019-10267-0},
	author = {Tuesta, Luis M and Djekidel, Mohamed N and Chen, Renchao and Lu, Falong and Wengang Wang and Sabatini, Bernardo L and Zhang, Yi}
}
@article {1789806,
	title = {Molecular and anatomical organization of the dorsal raphe nucleus},
	journal = {Elife},
	volume = {8},
	year = {2019},
	month = {2019 Aug 14},
	abstract = {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.},
	keywords = {Animals, Dorsal Raphe Nucleus, Gene Expression Profiling, Genotype, In Situ Hybridization, Mice, Neuroanatomical Tract-Tracing Techniques, Neurons, Phenotype, Sequence Analysis, RNA, Spatial Analysis},
	issn = {2050-084X},
	doi = {10.7554/eLife.46464},
	author = {Huang, Kee Wui and Ochandarena, Nicole E and Philson, Adrienne C and Hyun, Minsuk and Birnbaum, Jaclyn E and Cicconet, Marcelo and Sabatini, Bernardo L}
}
@article {1789811,
	title = {Monitoring Behaviorally Induced Biochemical Changes Using Fluorescence Lifetime Photometry},
	journal = {Front Neurosci},
	volume = {13},
	year = {2019},
	month = {2019},
	pages = {766},
	abstract = {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{\textquoteright} 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.},
	issn = {1662-4548},
	doi = {10.3389/fnins.2019.00766},
	author = {Lee, Suk Joon and Chen, Yao and Lodder, Bart and Sabatini, Bernardo L}
}
@article {1789801,
	title = {Population imaging of neural activity in awake behaving mice},
	journal = {Nature},
	volume = {574},
	number = {7778},
	year = {2019},
	month = {2019 Oct},
	pages = {413-417},
	abstract = {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 reagents1-8. 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 techniques9-11, 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.},
	keywords = {Action Potentials, Animals, Environmental Biomarkers, hippocampus, Mice, Neurons, Optical Imaging, Optogenetics, Wakefulness},
	issn = {1476-4687},
	doi = {10.1038/s41586-019-1641-1},
	author = {Piatkevich, Kiryl D and Bensussen, Seth and Tseng, Hua-An and Shroff, Sanaya N and Lopez-Huerta, Violeta Gisselle and Park, Demian and Jung, Erica E and Shemesh, Or A and Christoph Straub and Gritton, Howard J and Romano, Michael F and Costa, Emma and Sabatini, Bernardo L and Zhanyan Fu and Edward S Boyden and Han, Xue}
}
@article {1789831,
	title = {The Three-Dimensional Signal Collection Field for Fiber Photometry in Brain Tissue},
	journal = {Front Neurosci},
	volume = {13},
	year = {2019},
	month = {2019},
	pages = {82},
	abstract = {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 105 to 106 μm3 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.},
	issn = {1662-4548},
	doi = {10.3389/fnins.2019.00082},
	author = {Marco Pisanello and Filippo Pisano and Hyun, Minsuk and Emanuela Maglie and Antonio Balena and Massimo De Vittorio and Sabatini, Bernardo L and Ferruccio Pisanello}
}
@article {1489671,
	title = {Abnormal Striatal Development Underlies the Early Onset of Behavioral Deficits in Shank3B-/- Mice},
	journal = {Cell Reports},
	volume = {12},
	number = {29},
	year = {2019},
	author = {RT Peixoto and L Chantranupong and R Hakim and J Levasseur and Wang, W. and T Merchant and K Gorman and B Budnik and BL Sabatini}
}
@article {1489669,
	title = {Population imaging of neural activity in awake behaving mice},
	journal = {Nature},
	volume = {574},
	year = {2019},
	author = {KD Piatkevich and S Bensussen and HA Tseng and SN Shroff and VG Lopez-Huerta and Park, D and EE Jung and OA Shemesh and C Straub and HJ Gritton and MF Romano and E Costa and BL Sabatini and Z Fu and ES Boyden and Han, X}
}
@article {1489666,
	title = {Depth-resolved fiber photometry with a single tapered optical fiber implant},
	journal = {Nature Methods},
	volume = {16},
	number = {11},
	year = {2019},
	author = {F Pisano and M Pisanello and Lee, S. J. and J. Lee and E Maglie and A Balena and L Sileo and B Spagnolo and M Bianco and M Hyun and M De Vittorio and BL Sabatini and F Pisanello}
}
@article {1489664,
	title = {Monitoring Behaviorally Induced Biochemical Changes Using Fluorescence Lifetime Photometry},
	journal = {Frontiers in Neuroscience},
	volume = {13},
	year = {2019},
	author = {Lee, S. J. and Chen, Y. and B Lodder and Sabatini BL}
}
@article {1489663,
	title = {Molecular and anatomical organization of the dorsal raphe nucleus},
	journal = {Elife},
	volume = {14},
	number = {8},
	year = {2019},
	author = {KW Huang and NE Ochandarena and AC Philson and M Hyun and JE Birnbaum and M Cicconet and BL Sabatini}
}
@article {1489662,
	title = {Focused ion beam nanomachining of tapered optical fibers for patterned light delivery},
	journal = {Microelectronic Engineering},
	volume = {195},
	year = {2019},
	author = {F Pisano and M Pisanello and L Sileo and A Qualtieri and BL Sabatini and M De Vittorio and F Pisanello}
}
@article {1489660,
	title = {In vivo nuclear capture and molecular profiling identifies Gmeb1 as a transcriptional regulator essential for dopamine neuron function.},
	journal = {Nature Communications},
	volume = {10},
	number = {1},
	year = {2019},
	author = {LM Tuesta and MN Djekidel and Chen, R and F Lu and Wang, W. and BL Sabatini and Zhang, Y.}
}
@article {1433815,
	title = {Distinct Cortical-Thalamic-Striatal Circuits through the Parafascicular Nucleus.},
	journal = {Neuron},
	volume = {102},
	year = {2019},
	author = {G Mandelbaum and J Taranda and TM Haynes and DR Hochbaum and KW Huang and M Hyun and K Umadevi Venkataraju and C Straub and Wang, W. and K Robertson and P Osten and BL Sabatini}
}
@article {1433814,
	title = {The Three-Dimensional Signal Collection Field for Fiber Photometry in Brain Tissue},
	journal = {Frontiers in Neuroscience},
	volume = {13},
	number = {82},
	year = {2019},
	author = {M Pisanello and F Pisano and M Hyun and E Maglie and A Balena and M De Vittorio and BL Sabatini and F Pisanello}
}
@article {1789861,
	title = {A Caged Enkephalin Optimized for Simultaneously Probing Mu and Delta Opioid Receptors},
	journal = {ACS Chem Neurosci},
	volume = {9},
	number = {4},
	year = {2018},
	month = {2018 Apr 18},
	pages = {684-690},
	abstract = {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 [Leu5]-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.},
	keywords = {Animals, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-, Enkephalins, hippocampus, Neurons, Potassium Channels, Rats, Sprague-Dawley, Receptors, Opioid, delta, Receptors, Opioid, mu, Synaptic Transmission},
	issn = {1948-7193},
	doi = {10.1021/acschemneuro.7b00485},
	author = {Banghart, Matthew R and He, Xinyi J and Sabatini, Bernardo L}
}
@article {1789881,
	title = {Efficient and accurate extraction of in vivo calcium signals from microendoscopic video data},
	journal = {Elife},
	volume = {7},
	year = {2018},
	month = {2018 Feb 22},
	abstract = {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.},
	keywords = {Animals, Brain, Calcium Signaling, Endoscopy, Image Processing, Computer-Assisted, Mice, Neurons, Video Recording},
	issn = {2050-084X},
	doi = {10.7554/eLife.28728},
	author = {Zhou, Pengcheng and Resendez, Shanna L and Rodriguez-Romaguera, Jose and Jimenez, Jessica C and Neufeld, Shay Q and Andrea Giovannucci and Friedrich, Johannes and Pnevmatikakis, Eftychios A and Stuber, Garret D and Hen, Rene and Kheirbek, Mazen A and Sabatini, Bernardo L and Kass, Robert E and Paninski, Liam}
}
@article {1789836,
	title = {Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships},
	journal = {Cell},
	volume = {174},
	number = {6},
	year = {2018},
	month = {2018 Sep 06},
	pages = {1450-1464.e23},
	abstract = {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{\textquoteright}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.},
	keywords = {Amino Acid Sequence, Animals, Calcium-Binding Proteins, Cell Adhesion Molecules, Neuronal, Drosophila, Drosophila Proteins, Female, Glycopeptides, Heparitin Sulfate, Humans, Membrane Proteins, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins, Neural Cell Adhesion Molecules, Neurons, Protein Binding, Rats, RNA Interference, RNA, Small Interfering, Sequence Alignment, Synapses},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2018.07.002},
	author = {Zhang, Peng and Lu, Hong and Peixoto, Rui T and Pines, Mary K and Ge, Yuan and Oku, Shinichiro and Siddiqui, Tabrez J and Xie, Yicheng and Wu, Wenlan and Archer-Hartmann, Stephanie and Yoshida, Keitaro and Tanaka, Kenji F and Aricescu, A Radu and Azadi, Parastoo and Gordon, Michael D and Sabatini, Bernardo L and Wong, Rachel O L and Craig, Ann Marie}
}
@article {1789841,
	title = {Publisher Correction: A robotic multidimensional directed evolution approach applied to fluorescent voltage reporters},
	journal = {Nat Chem Biol},
	volume = {14},
	number = {9},
	year = {2018},
	month = {2018 Sep},
	pages = {901},
	abstract = {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.},
	issn = {1552-4469},
	doi = {10.1038/s41589-018-0023-6},
	author = {Piatkevich, Kiryl D and Jung, Erica E and Christoph Straub and Linghu, Changyang and Park, Demian and Suk, Ho-Jun and Hochbaum, Daniel R and Goodwin, Daniel and Pnevmatikakis, Eftychios and Pak, Nikita and Kawashima, Takashi and Chao-Tsung Yang and Rhoades, Jeffrey L and Shemesh, Or and Shoh Asano and Yoon, Young-Gyu and Freifeld, Limor and Saulnier, Jessica L and Clemens Riegler and Engert, Florian and Hughes, Thom and Drobizhev, Mikhail and Szabo, Balint and Ahrens, Misha B and Flavell, Steven W and Sabatini, Bernardo L and Edward S Boyden}
}
@article {1789846,
	title = {Publisher Correction: Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex},
	journal = {Nat Neurosci},
	volume = {21},
	number = {7},
	year = {2018},
	month = {2018 Jul},
	pages = {1017},
	abstract = {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.},
	issn = {1546-1726},
	doi = {10.1038/s41593-018-0112-6},
	author = {Hrvatin, Sinisa and Hochbaum, Daniel R and Nagy, M Aurel and Cicconet, Marcelo and Robertson, Keiramarie and Cheadle, Lucas and Zilionis, Rapolas and Ratner, Alex and Borges-Monroy, Rebeca and Klein, Allon M and Sabatini, Bernardo L and Greenberg, Michael E}
}
@article {1789866,
	title = {A robotic multidimensional directed evolution approach applied to fluorescent voltage reporters},
	journal = {Nat Chem Biol},
	volume = {14},
	number = {4},
	year = {2018},
	month = {2018 Apr},
	pages = {352-360},
	abstract = {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.},
	keywords = {Animals, Brain, Caenorhabditis elegans, Cell Separation, Directed Molecular Evolution, Female, Flow Cytometry, Fluorescence, Gene Library, Genes, Reporter, HEK293 Cells, hippocampus, Humans, Luminescent Proteins, Male, Mice, Microscopy, Fluorescence, Neurons, Optogenetics, Protein Engineering, Robotics, Zebrafish},
	issn = {1552-4469},
	doi = {10.1038/s41589-018-0004-9},
	author = {Piatkevich, Kiryl D and Jung, Erica E and Christoph Straub and Linghu, Changyang and Park, Demian and Suk, Ho-Jun and Hochbaum, Daniel R and Goodwin, Daniel and Pnevmatikakis, Eftychios and Pak, Nikita and Kawashima, Takashi and Chao-Tsung Yang and Rhoades, Jeffrey L and Shemesh, Or and Shoh Asano and Yoon, Young-Gyu and Freifeld, Limor and Saulnier, Jessica L and Clemens Riegler and Engert, Florian and Hughes, Thom and Drobizhev, Mikhail and Szabo, Balint and Ahrens, Misha B and Flavell, Steven W and Sabatini, Bernardo L and Edward S Boyden}
}
@article {1789871,
	title = {Silk Fibroin Films Facilitate Single-Step Targeted Expression of Optogenetic Proteins},
	journal = {Cell Rep},
	volume = {22},
	number = {12},
	year = {2018},
	month = {2018 Mar 20},
	pages = {3351-3361},
	abstract = {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.},
	keywords = {Fibroins, Humans, Optogenetics},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2018.02.081},
	author = {Jackman, Skyler L and Chen, Christopher H and Selmaan N Chettih and Neufeld, Shay Q and Drew, Iain R and Agba, Chimuanya K and Flaquer, Isabella and Stefano, Alexis N and Kennedy, Thomas J and Belinsky, Justine E and Roberston, Keiramarie and Beron, Celia C and Sabatini, Bernardo L and Christopher D Harvey and Regehr, Wade G}
}
@article {1789886,
	title = {Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex},
	journal = {Nat Neurosci},
	volume = {21},
	number = {1},
	year = {2018},
	month = {2018 Jan},
	pages = {120-129},
	abstract = {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.},
	keywords = {Animals, Basic Helix-Loop-Helix Transcription Factors, Gene Expression Regulation, Gene Ontology, Light, Male, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins, Neural Inhibition, Neuroglia, Neurons, Neurovascular Coupling, Photic Stimulation, Proto-Oncogene Proteins c-fos, Signal Transduction, Single-Cell Analysis, Statistics, Nonparametric, Transcription, Genetic, Transcriptome, Visual Cortex, Visual Pathways},
	issn = {1546-1726},
	doi = {10.1038/s41593-017-0029-5},
	author = {Hrvatin, Sinisa and Hochbaum, Daniel R and Nagy, M Aurel and Cicconet, Marcelo and Robertson, Keiramarie and Cheadle, Lucas and Zilionis, Rapolas and Ratner, Alex and Borges-Monroy, Rebeca and Klein, Allon M and Sabatini, Bernardo L and Greenberg, Michael E}
}
@article {1789851,
	title = {The Striatum Organizes 3D Behavior via Moment-to-Moment Action Selection},
	journal = {Cell},
	volume = {174},
	number = {1},
	year = {2018},
	month = {2018 Jun 28},
	pages = {44-58.e17},
	abstract = {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.},
	keywords = {Animals, Behavior, Animal, Calcium, Corpus Striatum, Electrodes, Implanted, Female, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, N-Methylaspartate, Neurons, Photometry, Receptors, Dopamine D1},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2018.04.019},
	author = {Markowitz, Jeffrey E and Gillis, Winthrop F and Beron, Celia C and Neufeld, Shay Q and Robertson, Keiramarie and Bhagat, Neha D and Peterson, Ralph E and Peterson, Emalee and Hyun, Minsuk and Linderman, Scott W and Sabatini, Bernardo L and Datta, Sandeep Robert}
}
@article {1789856,
	title = {Sunlight Brightens Learning and Memory},
	journal = {Cell},
	volume = {173},
	number = {7},
	year = {2018},
	month = {2018 Jun 14},
	pages = {1570-1572},
	abstract = {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.},
	keywords = {Animals, Biosynthetic Pathways, Brain, Glutamic Acid, Learning, Memory, Mice, Sunlight},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2018.05.044},
	author = {Chantranupong, Lynne and Sabatini, Bernardo L}
}
@article {1789876,
	title = {Tailoring light delivery for optogenetics by modal demultiplexing in tapered optical fibers},
	journal = {Sci Rep},
	volume = {8},
	number = {1},
	year = {2018},
	month = {2018 Mar 13},
	pages = {4467},
	abstract = {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 (θin) and the output position along the taper, finding that for θin \&gt; 10{\textdegree} 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.},
	keywords = {Animals, Humans, Male, Optical Fibers, Optogenetics, Photic Stimulation, Visual Cortex},
	issn = {2045-2322},
	doi = {10.1038/s41598-018-22790-z},
	author = {Marco Pisanello and Filippo Pisano and Leonardo Sileo and Emanuela Maglie and Bellistri, Elisa and Barbara Spagnolo and Mandelbaum, Gil and Sabatini, Bernardo L and Massimo De Vittorio and Ferruccio Pisanello}
}
@article {1331248,
	title = {The Striatum Organizes 3D Behavior via Moment-to-Moment Action Selection.},
	journal = {Cell},
	volume = {174},
	number = {1},
	year = {2018},
	pages = {44-58},
	author = {JE Markowitz and WF Gillis and CC Beron and SQ Neufeld and K Robertson and ND Bhagat and RE Peterson and E Peterson and M Hyun and SW Linderman and BL Sabatini and SR Datta}
}
@article {1331245,
	title = {Silk Fibroin Films Facilitate Single-Step Targeted Expression of Optogenetic Proteins.},
	journal = {Cell Reports},
	volume = {22},
	number = {12},
	year = {2018},
	pages = {3351-3361},
	author = {SL Jackman and Chen, C. H. and SN Chettih and SQ Neufeld and IR Drew and CK Agba and I Flaguer and AN Stefano and TJ Kennedy and JE Belinsky and K Robertson and CC Beron and BL Sabatini and CD Harvey and WG Regehr}
}
@article {1329139,
	title = {Tailoring light delivery for optogenetics by modal demultiplexing in tapered optical fibers.},
	journal = {Scientific Reports},
	volume = {8},
	number = {1},
	year = {2018},
	author = {M Pisanello and F Pisano and L Sileo and E Magile and E Bellistri and B Spagnolo and G Mandelbaum and BL Sabatini and M De Vittorio and F Pisanello}
}
@article {1329138,
	title = {A robotic multidimensional directed evolution approach applied to fluorescent voltage reporters },
	journal = {Nature Chemical Biology},
	volume = {14},
	number = {4},
	year = {2018},
	pages = {352-360},
	author = {KD Piatkevich and EE Jung and C Straub and C Linghu and Park, D and HJ Suk and DR Hochbaum and D Goodwin and E Pnevmatikakis and N Pak and T Kawashima and CT Yang and JL Rhoades and Shemesh, O and S Asano and YG Yoon and L Freifeld and JL Saulnier and C Riegler and F Engert and T Hughes and M Drobizhev and B Szabo and MB Ahrens and SW Flavell and BL Sabatini and ES Boyden}
}
@article {1329137,
	title = {Efficient and accurate extraction of in vivo calcium signals from microendoscopic video data},
	journal = {Elife},
	volume = {7},
	year = {2018},
	author = {Zhou, P and SL Resendez and J Rodriguez-Romaguera and JC Jimenez and SQ Neufeld and A Giovannuci and J Friedrich and EA Pnevmatikakis and GD Stuber and R Hen and MA Kheirbik and BL Sabatini and RE Kass and L Paninski}
}
@article {1329132,
	title = {A Caged Enkephalin Optimized for Simultaneously Probing Mu and Delta Opioid Receptors },
	journal = {ACS Chemical Neuroscience},
	volume = {9},
	number = {4},
	year = {2018},
	pages = {684-690},
	author = {MR Banghart and XJ He and BL Sabatini}
}
@article {1329126,
	title = {Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex},
	journal = {Nature Neuroscience},
	volume = {21},
	number = {1},
	year = {2018},
	pages = {120-129},
	author = {S Hrvatin and DR Hochbaum and MA Nagy and M Cicconet and K Robertson and L Cheadle and R Zilionis and A Ratner and R Borges-Monroy and AM Klein and BL Sabatini and ME Greenberg}
}
@article {1789896,
	title = {Dynamic illumination of spatially restricted or large brain volumes via a single tapered optical fiber},
	journal = {Nat Neurosci},
	volume = {20},
	number = {8},
	year = {2017},
	month = {2017 Aug},
	pages = {1180-1188},
	abstract = {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.},
	keywords = {Animals, Brain, Female, Male, Mice, Transgenic, Nerve Net, Neurons, Optical Fibers, Optogenetics, Photic Stimulation, Rhodopsin},
	issn = {1546-1726},
	doi = {10.1038/nn.4591},
	author = {Ferruccio Pisanello and Mandelbaum, Gil and Marco Pisanello and Oldenburg, Ian A and Leonardo Sileo and Markowitz, Jeffrey E and Peterson, Ralph E and Della Patria, Andrea and Haynes, Trevor M and Emara, Mohamed S and Barbara Spagnolo and Datta, Sandeep Robert and Massimo De Vittorio and Sabatini, Bernardo L}
}
@article {1789891,
	title = {Endogenous Gαq-Coupled Neuromodulator Receptors Activate Protein Kinase A},
	journal = {Neuron},
	volume = {96},
	number = {5},
	year = {2017},
	month = {2017 Dec 06},
	pages = {1070-1083.e5},
	abstract = {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.},
	keywords = {Animals, Calcium Signaling, Cyclic AMP-Dependent Protein Kinases, Enzyme Activation, Female, GTP-Binding Protein alpha Subunits, Gq-G11, HEK293 Cells, hippocampus, Humans, Mice, Mice, Inbred C57BL, Phosphorylation, Pregnancy, Protein Kinase C, Receptors, G-Protein-Coupled, Receptors, Muscarinic, Receptors, Neurotransmitter, Signal Transduction},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2017.10.023},
	author = {Chen, Yao and Granger, Adam J and Tran, Trinh and Saulnier, Jessica L and Kirkwood, Alfredo and Sabatini, Bernardo L}
}
@article {1789906,
	title = {Genetically Distinct Parallel Pathways in the Entopeduncular Nucleus for Limbic and Sensorimotor Output of the Basal Ganglia},
	journal = {Neuron},
	volume = {94},
	number = {1},
	year = {2017},
	month = {2017 Apr 05},
	pages = {138-152.e5},
	abstract = {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.},
	keywords = {Animals, Basal Ganglia, entopeduncular nucleus, GABAergic Neurons, Gene Expression Profiling, Globus Pallidus, Glutamic Acid, Habenula, Humans, In Situ Hybridization, Fluorescence, Limbic System, Mice, Neostriatum, Neurons, Parvalbumins, Sensorimotor Cortex, Single-Cell Analysis, Somatostatin, Thalamus},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2017.03.017},
	author = {Wallace, Michael L and Saunders, Arpiar and Huang, Kee Wui and Philson, Adrienne C and Melissa Goldman and Macosko, Evan Z and McCarroll, Steven A and Sabatini, Bernardo L}
}
@article {1789901,
	title = {Multi-transmitter neurons in the mammalian central nervous system},
	journal = {Curr Opin Neurobiol},
	volume = {45},
	year = {2017},
	month = {2017 Aug},
	pages = {85-91},
	abstract = {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.},
	keywords = {Animals, Central Nervous System, Mammals, Neurons, Synaptic Transmission},
	issn = {1873-6882},
	doi = {10.1016/j.conb.2017.04.007},
	author = {Granger, Adam J and Wallace, Michael L and Sabatini, Bernardo L}
}
@article {1329123,
	title = {Endogenous Gαq-Coupled Neuromodulator Receptors Activate Protein Kinase A.},
	journal = {Neuron},
	volume = {20},
	number = {8},
	year = {2017},
	pages = {1180-1188},
	author = {Chen, Y. and AJ Granger and T Tran and JL Saulnier and Kirkwood, A. and BL Sabatini}
}
@article {1180481,
	title = {Multi-transmitter neurons in the mammalian central nervous system},
	journal = {Current Opinion in Neurobiology},
	volume = {45},
	year = {2017},
	pages = {85-91},
	author = {AJ Granger and ML Wallace and BL Sabatini}
}
@article {1180446,
	title = {Dynamic illumination of spatially restricted or large brain volumes via a single tapered optical fiber},
	journal = {Nature Neuroscience},
	volume = {20},
	number = {8},
	year = {2017},
	pages = {1180-1190},
	author = {F Pisanello and G Mandelbaum and M Pisanello and IA Oldenburg and JE Markowitz and RE Peterson and A Della Patria and TM Haynes and MS Emara and B Spagnolo and SR Datta and M De Vittorio and BL Sabatini}
}
@article {1063291,
	title = {Genetically Distinct Parallel Pathways in the Entopeduncular Nucleus for Limbic and Sensorimotor Output of the Basal Ganglia},
	journal = {Neuron},
	volume = {94},
	number = {1},
	year = {2017},
	pages = {138-152},
	author = {ML Wallace and A Saunders and KW Huang and AC Philson and M Goldman and EZ Macosko and SA McCarroll and BL Sabatini}
}
@article {1789916,
	title = {Central Control Circuit for Context-Dependent Micturition},
	journal = {Cell},
	volume = {167},
	number = {1},
	year = {2016},
	month = {2016 Sep 22},
	pages = {73-86.e12},
	abstract = {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.},
	keywords = {Animals, Corticotropin-Releasing Hormone, Female, Glutamic Acid, Mice, Mice, Inbred C57BL, Muscle Contraction, Neurons, Pons, Smell, Spinal Cord, Urinary Bladder, Urination},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2016.08.073},
	author = {Hou, Xun Helen and Hyun, Minsuk and Taranda, Julian and Huang, Kee Wui and Todd, Emmalee and Feng, Danielle and Atwater, Emily and Croney, Donyell and Zeidel, Mark Lawrence and Osten, Pavel and Sabatini, Bernardo Luis}
}
@article {1789946,
	title = {Corrigendum: A PKA activity sensor for quantitative analysis of endogenous GPCR signaling via 2-photon FRET-FLIM imaging},
	journal = {Front Pharmacol},
	volume = {7},
	year = {2016},
	month = {2016},
	pages = {46},
	abstract = {[This corrects the article on p. 56 in vol. 5, PMID: 24765076.].},
	issn = {1663-9812},
	doi = {10.3389/fphar.2016.00046},
	author = {Chen, Yao and Saulnier, Jessica L and Yellen, Gary and Sabatini, Bernardo L}
}
@article {1789956,
	title = {Cotransmission of acetylcholine and GABA},
	journal = {Neuropharmacology},
	volume = {100},
	year = {2016},
	month = {2016 Jan},
	pages = {40-6},
	abstract = {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 {\textquoteright}Synaptopathy--from Biology to Therapy{\textquoteright}.},
	keywords = {Acetylcholine, Animals, Brain, Cholinergic Neurons, gamma-Aminobutyric Acid, Humans, Mice, Optogenetics, Synaptic Transmission},
	issn = {1873-7064},
	doi = {10.1016/j.neuropharm.2015.07.031},
	author = {Granger, Adam J and Mulder, Nicole and Saunders, Arpiar and Sabatini, Bernardo L}
}
@article {1789931,
	title = {Development of Anionically Decorated Caged Neurotransmitters: In Vitro Comparison of 7-Nitroindolinyl- and 2-(p-Phenyl-o-nitrophenyl)propyl-Based Photochemical Probes},
	journal = {Chembiochem},
	volume = {17},
	number = {10},
	year = {2016},
	month = {2016 May 17},
	pages = {953-61},
	abstract = {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.},
	keywords = {Anions, Biphenyl Compounds, GABA-A Receptor Antagonists, Glutamates, Indoles, Light, Microscopy, Fluorescence, Neurotransmitter Agents, Photolysis, Receptors, GABA-A},
	issn = {1439-7633},
	doi = {10.1002/cbic.201600019},
	author = {Kantevari, Srinivas and Passlick, Stefan and Kwon, Hyung-Bae and Richers, Matthew T and Sabatini, Bernardo L and Ellis-Davies, Graham C R}
}
@article {1789921,
	title = {An E3-ligase-based method for ablating inhibitory synapses},
	journal = {Nat Methods},
	volume = {13},
	number = {8},
	year = {2016},
	month = {2016 Aug},
	pages = {673-8},
	abstract = {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.},
	keywords = {Animals, Carrier Proteins, Cells, Cultured, Embryo, Mammalian, Female, hippocampus, Male, Membrane Proteins, Motor Disorders, Neurons, Patch-Clamp Techniques, Rats, Rats, Sprague-Dawley, Spine, Synapses, Synaptic Transmission, Ubiquitin-Protein Ligases, Ubiquitination, Zebrafish},
	issn = {1548-7105},
	doi = {10.1038/nmeth.3894},
	author = {Gross, Garrett G and Christoph Straub and Perez-Sanchez, Jimena and Dempsey, William P and Junge, Jason A and Roberts, Richard W and Trinh, Le A and Fraser, Scott E and De Koninck, Yves and De Koninck, Paul and Sabatini, Bernardo L and Arnold, Don B}
}
@article {1789936,
	title = {Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B(-/-) mice},
	journal = {Nat Neurosci},
	volume = {19},
	number = {5},
	year = {2016},
	month = {2016 May},
	pages = {716-724},
	abstract = {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.},
	keywords = {Action Potentials, Animals, Autistic Disorder, Cerebral Cortex, Corpus Striatum, Disease Models, Animal, Female, Male, Mice, Mice, Knockout, Mice, Transgenic, Microfilament Proteins, Nerve Tissue Proteins, Neural Pathways, Neurons, Synapses},
	issn = {1546-1726},
	doi = {10.1038/nn.4260},
	author = {Peixoto, Rui T and Wengang Wang and Croney, Donyell M and Kozorovitskiy, Yevgenia and Sabatini, Bernardo L}
}
@article {1789951,
	title = {Globus Pallidus Externus Neurons Expressing parvalbumin Interconnect the Subthalamic Nucleus and Striatal Interneurons},
	journal = {PLoS One},
	volume = {11},
	number = {2},
	year = {2016},
	month = {2016},
	pages = {e0149798},
	abstract = {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.},
	keywords = {Animals, Axons, Brain Mapping, Globus Pallidus, Mice, Mice, Transgenic, Parvalbumins, Subthalamic Nucleus, Synapses},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0149798},
	author = {Saunders, Arpiar and Huang, Kee Wui and Sabatini, Bernardo Luis}
}
@article {1789941,
	title = {Mechanisms and functions of GABA co-release},
	journal = {Nat Rev Neurosci},
	volume = {17},
	number = {3},
	year = {2016},
	month = {2016 Mar},
	pages = {139-45},
	abstract = {The {\textquoteright}one neuron, one neurotransmitter{\textquoteright} 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.},
	keywords = {Animals, gamma-Aminobutyric Acid, Neurons, Neurotransmitter Agents, Synapses, Synaptic Transmission},
	issn = {1471-0048},
	doi = {10.1038/nrn.2015.21},
	author = {Tritsch, Nicolas X and Granger, Adam J and Sabatini, Bernardo L}
}
@article {1789926,
	title = {A Postsynaptic AMPK{\textrightarrow}p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons},
	journal = {Neuron},
	volume = {91},
	number = {1},
	year = {2016},
	month = {2016 Jul 06},
	pages = {25-33},
	abstract = {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.},
	keywords = {AMP-Activated Protein Kinases, Animals, dendritic spines, Eating, Energy Metabolism, Fasting, Mice, Transgenic, Neuronal Plasticity, Neurons, Neuropeptide Y, p21-Activated Kinases, Signal Transduction},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2016.05.025},
	author = {Kong, Dong and Dagon, Yossi and Campbell, John N and Guo, Yikun and Yang, Zongfang and Yi, Xinchi and Aryal, Pratik and Wellenstein, Kerry and Kahn, Barbara B and Sabatini, Bernardo L and Lowell, Bradford B}
}
@article {1789911,
	title = {Principles of Synaptic Organization of GABAergic Interneurons in the Striatum},
	journal = {Neuron},
	volume = {92},
	number = {1},
	year = {2016},
	month = {2016 Oct 05},
	pages = {84-92},
	abstract = {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.},
	keywords = {Animals, Corpus Striatum, GABAergic Neurons, Interneurons, Mice, Mice, Knockout, Mice, Transgenic, Neural Pathways, Neuroanatomical Tract-Tracing Techniques, Receptor, Adenosine A2A, Receptors, Dopamine D1, Receptors, Dopamine D2, Synapses},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2016.09.007},
	author = {Christoph Straub and Saulnier, Jessica Lizette and B{\`e}gue, Aurelien and Feng, Danielle D and Huang, Kee Wui and Sabatini, Bernardo Luis}
}
@article {944026,
	title = {Central Control Circuit for Context-Dependent Micturition},
	journal = {Cell},
	volume = {167},
	number = {1},
	year = {2016},
	pages = {73-86},
	author = {XH Hou and M Hyun and J Taranda and KW Huang and E Todd and D Feng and E Atwater and D Croney and ML Zeidel and P Osten and BL Sabatini}
}
@article {944016,
	title = {An E3-ligase-based method for ablating inhibitory synapses},
	journal = {Nature Methods},
	volume = {13},
	number = {8},
	year = {2016},
	pages = {673-8},
	author = {GG Gross and C Straub and J Perez-Sanchez and WP Dempsey and JA Junge and RW Roberts and LA Trinh and SE Fraser and Y De Koninck and P De Koninck and BL Sabatini and DB Arnold}
}
@article {944021,
	title = {A Postsynaptic AMPK{\textrightarrow}p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons},
	journal = {Neuron},
	volume = {91},
	number = {1},
	year = {2016},
	pages = {25-33},
	author = {D Kong and Y Dagon and JN Campbell and Guo, Y and Z Yang and X Yi and P Aryal and K Wellenstein and Kahn, B B and BL Sabatini and B.B. Lowell}
}
@article {944031,
	title = {Principles of Synaptic Organization of GABAergic Interneurons in the Striatum},
	journal = {Neuron},
	volume = {92},
	number = {1},
	year = {2016},
	pages = {84-92},
	author = {C Straub and JL Saulnier and A B{\`e}gue and DD Feng and KW Huang and BL Sabatini}
}
@article {720186,
	title = {Development of Anionically Decorated Caged Neurotransmitters: In Vitro Comparison of 7-Nitroindolinyl- and 2-(p-Phenyl-o-nitrophenyl)propyl-Based Photochemical Probes},
	journal = {Chembiochem},
	volume = {17},
	number = {10},
	year = {2016},
	pages = {953-961},
	author = {S Kantevari and S Passlick and HB Kwon and MT Richers and BL Sabatini and GC Ellis-Davies}
}
@article {720161,
	title = {Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B(-/-) mice},
	journal = {Nature Neuroscience},
	volume = {19},
	number = {5},
	year = {2016},
	pages = {716-724},
	author = {RT Peixoto and Wang, W. and DM Croney and Y Kozorovitskiy and BL Sabatini}
}
@article {714061,
	title = {Cotransmission of acetylcholine and GABA},
	journal = {Neuropharmacology},
	volume = {100},
	year = {2016},
	pages = {40-46},
	author = {AJ Granger and N Mulder and A Saunders and BL Sabatini}
}
@article {714716,
	title = {Globus Pallidus Externus Neurons Expressing parvalbumin Interconnect the Subthalamic Nucleus and Striatal Interneurons},
	journal = {PLoS One},
	volume = {11},
	number = {2},
	year = {2016},
	pages = {e0149798},
	author = {A Saunders and KW Huang and BL Sabatini}
}
@article {714636,
	title = {Mechanisms and functions of GABA co-release},
	journal = {Nature Reviews Neuroscience},
	volume = {17},
	number = {3},
	year = {2016},
	pages = {139-145},
	author = {NX Tritsch and AJ Granger and BL Sabatini}
}
@article {1789981,
	title = {Antagonistic but Not Symmetric Regulation of Primary Motor Cortex by Basal Ganglia Direct and Indirect Pathways},
	journal = {Neuron},
	volume = {86},
	number = {5},
	year = {2015},
	month = {2015 Jun 03},
	pages = {1174-81},
	abstract = {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{\textquoteright}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.},
	keywords = {Animals, Basal Ganglia, Electric Stimulation, Male, Mice, Mice, Transgenic, Motor Cortex, Nerve Net, Neural Pathways},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2015.05.008},
	author = {Oldenburg, Ian A and Sabatini, Bernardo L}
}
@article {1789991,
	title = {Corelease of acetylcholine and GABA from cholinergic forebrain neurons},
	journal = {Elife},
	volume = {4},
	year = {2015},
	month = {2015 Feb 27},
	abstract = {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.},
	keywords = {4-Aminopyridine, Acetylcholine, Animals, Choline O-Acetyltransferase, Cholinergic Neurons, Excitatory Postsynaptic Potentials, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Membrane Potentials, Mice, Transgenic, Microscopy, Confocal, Microscopy, Fluorescence, Multiphoton, Patch-Clamp Techniques, Potassium Channel Blockers, Prosencephalon, Receptors, GABA-A, Receptors, Nicotinic, Sodium Channel Blockers, Synaptic Transmission, Tetrodotoxin, Vesicular Inhibitory Amino Acid Transport Proteins},
	issn = {2050-084X},
	doi = {10.7554/eLife.06412},
	author = {Saunders, Arpiar and Granger, Adam J and Sabatini, Bernardo L}
}
@article {1789976,
	title = {Cre Activated and Inactivated Recombinant Adeno-Associated Viral Vectors for Neuronal Anatomical Tracing or Activity Manipulation},
	journal = {Curr Protoc Neurosci},
	volume = {72},
	year = {2015},
	month = {2015 Jul 01},
	pages = {1.24.1-1.24.15},
	abstract = {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.},
	keywords = {Animals, Dependovirus, Genetic Vectors, Integrases, Luminescent Proteins, Mice, Mice, Transgenic, Neurons, Transduction, Genetic},
	issn = {1934-8576},
	doi = {10.1002/0471142301.ns0124s72},
	author = {Saunders, Arpiar and Sabatini, Bernardo L}
}
@article {1789986,
	title = {A direct GABAergic output from the basal ganglia to frontal cortex},
	journal = {Nature},
	volume = {521},
	number = {7550},
	year = {2015},
	month = {2015 May 07},
	pages = {85-9},
	abstract = {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.},
	keywords = {Acetylcholine, Animals, Antipsychotic Agents, Basal Nucleus of Meynert, Choline O-Acetyltransferase, Electrophysiological Phenomena, Female, Frontal Lobe, gamma-Aminobutyric Acid, Globus Pallidus, Macaca mulatta, Male, Mice, Neural Pathways, Receptors, Dopamine D2, Signal Transduction},
	issn = {1476-4687},
	doi = {10.1038/nature14179},
	author = {Saunders, Arpiar and Oldenburg, Ian A and Berezovskii, Vladimir K and Johnson, Caroline A and Kingery, Nathan D and Elliott, Hunter L and Xie, Tiao and Gerfen, Charles R and Sabatini, Bernardo L}
}
@article {1789961,
	title = {Enkephalin Disinhibits Mu Opioid Receptor-Rich Striatal Patches via Delta Opioid Receptors},
	journal = {Neuron},
	volume = {88},
	number = {6},
	year = {2015},
	month = {2015 Dec 16},
	pages = {1227-1239},
	abstract = {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.},
	keywords = {Animals, Corpus Striatum, Enkephalins, Female, Inhibitory Postsynaptic Potentials, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Opioid, delta, Receptors, Opioid, mu},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2015.11.010},
	author = {Banghart, Matthew Ryan and Neufeld, Shay Quentin and Wong, Nicole Christine and Sabatini, Bernardo Luis}
}
@article {1789996,
	title = {Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1},
	journal = {Science},
	volume = {347},
	number = {6218},
	year = {2015},
	month = {2015 Jan 09},
	pages = {188-94},
	abstract = {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.},
	keywords = {Amino Acid Sequence, Amino Acid Transport Systems, Arginine, HEK293 Cells, Humans, Lysosomes, Mechanistic Target of Rapamycin Complex 1, Molecular Sequence Data, Monomeric GTP-Binding Proteins, Multiprotein Complexes, Protein Structure, Tertiary, Signal Transduction, TOR Serine-Threonine Kinases},
	issn = {1095-9203},
	doi = {10.1126/science.1257132},
	author = {Wang, Shuyu and Tsun, Zhi-Yang and Wolfson, Rachel L and Shen, Kuang and Wyant, Gregory A and Plovanich, Molly E and Yuan, Elizabeth D and Jones, Tony D and Chantranupong, Lynne and Comb, William and Wang, Tim and Bar-Peled, Liron and Zoncu, Roberto and Christoph Straub and Kim, Choah and Park, Jiwon and Sabatini, Bernardo L and Sabatini, David M}
}
@article {1789971,
	title = {Modal demultiplexing properties of tapered and nanostructured optical fibers for in vivo optogenetic control of neural activity},
	journal = {Biomed Opt Express},
	volume = {6},
	number = {10},
	year = {2015},
	month = {2015 Oct 01},
	pages = {4014-26},
	abstract = {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.},
	issn = {2156-7085},
	doi = {10.1364/BOE.6.004014},
	author = {Marco Pisanello and Della Patria, Andrea and Leonardo Sileo and Sabatini, Bernardo L and Massimo De Vittorio and Ferruccio Pisanello}
}
@article {1789966,
	title = {Neuromodulation of excitatory synaptogenesis in striatal development},
	journal = {Elife},
	volume = {4},
	year = {2015},
	month = {2015 Nov 09},
	abstract = {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.},
	keywords = {Animals, Cyclic AMP-Dependent Protein Kinases, Dopamine Agents, Mice, Inbred C57BL, Neuronal Plasticity, Receptors, G-Protein-Coupled, Receptors, Glutamate, Visual Cortex},
	issn = {2050-084X},
	doi = {10.7554/eLife.10111},
	author = {Kozorovitskiy, Yevgenia and Peixoto, Rui and Wengang Wang and Saunders, Arpiar and Sabatini, Bernardo L}
}
@article {713921,
	title = {Antagonistic but Not Symmetric Regulation of Primary Motor Cortex by Basal Ganglia Direct and Indirect Pathways},
	journal = {Neuron},
	volume = {868},
	number = {5},
	year = {2015},
	pages = {1174-1181},
	author = {IA Oldenburg and BL Sabatini}
}
@article {713841,
	title = {Corelease of acetylcholine and GABA from cholinergic forebrain neurons},
	journal = {Elife},
	volume = {27},
	number = {4},
	year = {2015},
	author = {A Saunders and AJ Granger and BL Sabatini}
}
@article {713996,
	title = {Cre Activated and Inactivated Recombinant Adeno-Associated Viral Vectors for Neuronal Anatomical Tracing or Activity Manipulation},
	journal = {Current Protocols in Neuroscience},
	year = {2015},
	author = {A Saunders and BL Sabatini}
}
@article {713911,
	title = {A direct GABAergic output from the basal ganglia to frontal cortex},
	journal = {Nature},
	volume = {521},
	number = {7550},
	year = {2015},
	pages = {85-89},
	author = {A Saunders and IA Oldenburg and VK Berezovskii and Johnson, CA and ND Kingery and HL Elliott and T Xie and CR Gerfen and BL Sabatini}
}
@article {714616,
	title = {Enkephalin Disinhibits Mu Opioid Receptor-Rich Striatal Patches via Delta Opioid Receptors},
	journal = {Neuron},
	volume = {88},
	number = {6},
	year = {2015},
	pages = {1227-1239},
	author = {MR Banghart and SQ Neufeld and NC Wong and BL Sabatini}
}
@article {713826,
	title = {Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1},
	journal = {Science},
	volume = {347},
	number = {6218},
	year = {2015},
	pages = {188-194},
	author = {S. Wang and ZY Tsun and RL Wolfson and K Shen and GA Wyant and ME Plovanich and ED Yuan and TD Jones and L Chantranupong and W Comb and Wang, T. and L Bar-Peled and R Zoncu and C Straub and Kim, C. and J Park and BL Sabatini and DM Sabatini}
}
@article {714071,
	title = {Modal demultiplexing properties of tapered and nanostructured optical fibers for in vivo optogenetic control of neural activity},
	journal = {Biomedical Optics Express},
	volume = {6},
	number = {10},
	year = {2015},
	pages = {4014-4026},
	author = {M Pisanello and A Della Patria and L Sileo and BL Sabatini and M De Vittorio and F Pisanello}
}
@article {714221,
	title = {Neuromodulation of excitatory synaptogenesis in striatal development},
	journal = {Elife},
	year = {2015},
	author = {Y Kozorovitskiy and R Peixoto and Wang, W. and A Saunders and BL Sabatini}
}
@article {1790011,
	title = {All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins},
	journal = {Nat Methods},
	volume = {11},
	number = {8},
	year = {2014},
	month = {2014 Aug},
	pages = {825-33},
	abstract = {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.},
	keywords = {Animals, Directed Molecular Evolution, Mammals, Neurons, Recombinant Proteins, Rhodopsin, Synaptic Transmission},
	issn = {1548-7105},
	doi = {10.1038/nmeth.3000},
	author = {Hochbaum, Daniel R and Yongxin Zhao and Farhi, Samouil L and Nathan Klapoetke and Werley, Christopher A and Kapoor, Vikrant and Zou, Peng and Kralj, Joel M and Dougal Maclaurin and Niklas Smedemark-Margulies and Saulnier, Jessica L and Boulting, Gabriella L and Christoph Straub and Yong Ku Cho and Michael Melkonian and Gane Ka-Shu Wong and Harrison, D Jed and Murthy, Venkatesh N and Sabatini, Bernardo L and Edward S Boyden and Campbell, Robert E and Adam E. Cohen}
}
@article {1790006,
	title = {CRISPR/Cas9-mediated gene knock-down in post-mitotic neurons},
	journal = {PLoS One},
	volume = {9},
	number = {8},
	year = {2014},
	month = {2014},
	pages = {e105584},
	abstract = {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.},
	keywords = {Animals, CRISPR-Cas Systems, Gene Knockdown Techniques, Mice, Nerve Tissue Proteins, Pyramidal Cells, Receptors, N-Methyl-D-Aspartate, Synaptic Potentials},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0105584},
	author = {Christoph Straub and Granger, Adam J and Saulnier, Jessica L and Sabatini, Bernardo L}
}
@article {1790001,
	title = {A direct projection from mouse primary visual cortex to dorsomedial striatum},
	journal = {PLoS One},
	volume = {9},
	number = {8},
	year = {2014},
	month = {2014},
	pages = {e104501},
	abstract = {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.},
	keywords = {Animals, Axons, Corpus Striatum, Mice, Neural Pathways, Neurons, Visual Cortex},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0104501},
	author = {Khibnik, Lena A and Tritsch, Nicolas X and Sabatini, Bernardo L}
}
@article {1790046,
	title = {High content image analysis identifies novel regulators of synaptogenesis in a high-throughput RNAi screen of primary neurons},
	journal = {PLoS One},
	volume = {9},
	number = {3},
	year = {2014},
	month = {2014},
	pages = {e91744},
	abstract = {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{\textquoteright}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.},
	keywords = {Algorithms, Animals, Automation, Laboratory, Gene Expression Regulation, High-Throughput Screening Assays, Mice, Microscopy, Fluorescence, Neurons, RNA Interference, RNA, Small Interfering, Synapses},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0091744},
	author = {Nieland, Thomas J F and Logan, David J and Saulnier, Jessica and Lam, Daniel and Johnson, Caroline and Root, David E and Carpenter, Anne E and Sabatini, Bernardo L}
}
@article {1790036,
	title = {How to grow a synapse},
	journal = {Neuron},
	volume = {82},
	number = {2},
	year = {2014},
	month = {2014 Apr 16},
	pages = {256-7},
	abstract = {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.},
	keywords = {Animals, dendritic spines, hippocampus, Humans, Long-Term Potentiation, Neuronal Plasticity, Neurons, Synapses},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2014.03.033},
	author = {Christoph Straub and Sabatini, Bernardo L}
}
@article {1790031,
	title = {Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis},
	journal = {Elife},
	volume = {3},
	year = {2014},
	month = {2014 Apr 24},
	pages = {e01936},
	abstract = {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.},
	keywords = {Animals, Biological Transport, Corpus Striatum, Dopaminergic Neurons, GABA Agents, GABA Plasma Membrane Transport Proteins, gamma-Aminobutyric Acid, Inhibitory Postsynaptic Potentials, Mesencephalon, Mice, Inbred C57BL, Mice, Transgenic, Neural Inhibition, Synapses, Synaptic Transmission, Time Factors},
	issn = {2050-084X},
	doi = {10.7554/eLife.01936},
	author = {Tritsch, Nicolas X and Oh, Won-Jong and Gu, Chenghua and Sabatini, Bernardo L}
}
@article {1790016,
	title = {Multiphasic modulation of cholinergic interneurons by nigrostriatal afferents},
	journal = {J Neurosci},
	volume = {34},
	number = {25},
	year = {2014},
	month = {2014 Jun 18},
	pages = {8557-69},
	abstract = {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.},
	keywords = {Action Potentials, Afferent Pathways, Animals, Cholinergic Neurons, Corpus Striatum, Female, Gene Knock-In Techniques, Interneurons, Male, Mice, Mice, Transgenic, Substantia Nigra},
	issn = {1529-2401},
	doi = {10.1523/JNEUROSCI.0589-14.2014},
	author = {Christoph Straub and Tritsch, Nicolas X and Hagan, Nellwyn A and Gu, Chenghua and Sabatini, Bernardo L}
}
@article {1790021,
	title = {Multipoint-emitting optical fibers for spatially addressable in vivo optogenetics},
	journal = {Neuron},
	volume = {82},
	number = {6},
	year = {2014},
	month = {2014 Jun 18},
	pages = {1245-54},
	abstract = {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.},
	keywords = {Animals, Brain, Electrodes, Implanted, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microelectrodes, Nerve Net, Optical Fibers, Optogenetics, Photic Stimulation},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2014.04.041},
	author = {Ferruccio Pisanello and Leonardo Sileo and Oldenburg, Ian A and Marco Pisanello and Martiradonna, Luigi and Assad, John A and Sabatini, Bernardo L and Massimo De Vittorio}
}
@article {1790051,
	title = {Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines},
	journal = {J Neurosci},
	volume = {34},
	number = {3},
	year = {2014},
	month = {2014 Jan 15},
	pages = {869-79},
	abstract = {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.},
	keywords = {Animals, Animals, Newborn, Calcium Signaling, Cells, Cultured, Cyclic AMP-Dependent Protein Kinases, dendritic spines, Foxes, HEK293 Cells, hippocampus, Humans, Neural Inhibition, Phosphorylation, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate, Serine, Stress, Psychological, Synapses},
	issn = {1529-2401},
	doi = {10.1523/JNEUROSCI.4538-13.2014},
	author = {Murphy, Jessica A and Stein, Ivar S and Lau, C Geoffrey and Peixoto, Rui T and Aman, Teresa K and Kaneko, Naoki and Aromolaran, Kelly and Saulnier, Jessica L and Popescu, Gabriela K and Sabatini, Bernardo L and Hell, Johannes W and Zukin, R Suzanne}
}
@article {1790041,
	title = {A PKA activity sensor for quantitative analysis of endogenous GPCR signaling via 2-photon FRET-FLIM imaging},
	journal = {Front Pharmacol},
	volume = {5},
	year = {2014},
	month = {2014},
	pages = {56},
	abstract = {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.},
	issn = {1663-9812},
	doi = {10.3389/fphar.2014.00056},
	author = {Chen, Yao and Saulnier, Jessica L and Yellen, Gary and Sabatini, Bernardo L}
}
@article {1790026,
	title = {Super-resolution 2-photon microscopy reveals that the morphology of each dendritic spine correlates with diffusive but not synaptic properties},
	journal = {Front Neuroanat},
	volume = {8},
	year = {2014},
	month = {2014},
	pages = {29},
	abstract = {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.},
	issn = {1662-5129},
	doi = {10.3389/fnana.2014.00029},
	author = {Takasaki, Kevin and Sabatini, Bernardo L}
}
@article {708871,
	title = {All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins},
	journal = {Nature Methods},
	volume = {11},
	number = {8},
	year = {2014},
	pages = {825-833},
	author = {DR Hochbaum and Zhao, Y. and SL Farhi and N Klapoetke and CA Werley and Kapoor, V and P Zou and JM Kralj and D Maclaurin and N Smedemark-Margulies and JL Saulnier and GL Boulting and C Straub and YK Cho and M Melkonian and GK Wong and DJ Harrison and V.N. Murthy and BL Sabatini and ES Boyden and RE Campbell and AE Cohen}
}
@article {711231,
	title = {CRISPR/Cas9-mediated gene knock-down in post-mitotic neurons},
	journal = {PLoS One},
	volume = {9},
	number = {8},
	year = {2014},
	pages = {e105584},
	author = {C Straub and AJ Granger and JL Saulnier and BL Sabatini}
}
@article {708916,
	title = {A direct projection from mouse primary visual cortex to dorsomedial striatum},
	journal = {PLoS One},
	volume = {9},
	number = {8},
	year = {2014},
	pages = {e104501},
	author = {LA Khibnik and NX Tritsch and BL Sabatini}
}
@article {708796,
	title = {High content image analysis identifies novel regulators of synaptogenesis in a high-throughput RNAi screen of primary neurons},
	journal = {PLoS One},
	volume = {9},
	number = {3},
	year = {2014},
	pages = {e91744},
	author = {TJ Nieland and DJ Logan and JL Saulnier and D Lam and C. Johnson and DE Root and AE Carpenter and BL Sabatini}
}
@article {711656,
	title = {Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis},
	journal = {Elife},
	volume = {24},
	number = {3},
	year = {2014},
	pages = {e01936},
	author = {NX Tritsch and WJ Oh and C Gu and BL Sabatini}
}
@article {711621,
	title = {Multiphasic modulation of cholinergic interneurons by nigrostriatal afferents},
	journal = {Journal of Neuroscience},
	volume = {34},
	number = {25},
	year = {2014},
	pages = {8557-8569},
	author = {C Straub and AJ Granger and NA Hagan and C Gu and BL Sabatini}
}
@article {711631,
	title = {Multipoint-emitting optical fibers for spatially addressable in vivo optogenetics},
	journal = {Neuron},
	volume = {82},
	number = {6},
	year = {2014},
	pages = {1245-1254},
	author = {F Pisanello and L Sileo and IA Oldenburg and M Pisanello and L Martiradonna and JA Assad and BL Sabatini and M De Vittorio}
}
@article {708786,
	title = {Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines},
	journal = {Journal of Neuroscience},
	volume = {34},
	number = {3},
	year = {2014},
	pages = {869-879},
	author = {JA Murphy and IS Stein and CG Lau and RT Peixoto and TK Aman and N Kaneko and K Aromolaran and JL Saulnier and GK Popescu and BL Sabatini and JW Hell and RS Zukin}
}
@article {711641,
	title = {A PKA activity sensor for quantitative analysis of endogenous GPCR signaling via 2-photon FRET-FLIM imaging},
	journal = {Frontiers in Pharmacology},
	volume = {2},
	number = {5},
	year = {2014},
	pages = {56},
	author = {Chen, Y. and JL Saulnier and G Yellen and BL Sabatini}
}
@article {711636,
	title = {Super-resolution 2-photon microscopy reveals that the morphology of each dendritic spine correlates with diffusive but not synaptic properties},
	journal = {Frontiers in Neuroanatomy},
	volume = {7},
	number = {8},
	year = {2014},
	pages = {29},
	author = {K Takasaki and BL Sabatini}
}
@article {1790056,
	title = {Caged naloxone reveals opioid signaling deactivation kinetics},
	journal = {Mol Pharmacol},
	volume = {84},
	number = {5},
	year = {2013},
	month = {2013 Nov},
	pages = {687-95},
	abstract = {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.},
	keywords = {Animals, Brain, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-, Humans, Kinetics, Naloxone, Narcotic Antagonists, Rats, Receptors, Opioid, mu, Signal Transduction},
	issn = {1521-0111},
	doi = {10.1124/mol.113.088096},
	author = {Banghart, Matthew R and Williams, John T and Shah, Ruchir C and Lavis, Luke D and Sabatini, Bernardo L}
}
@article {1790081,
	title = {Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis},
	journal = {Neuron},
	volume = {78},
	number = {3},
	year = {2013},
	month = {2013 May 08},
	pages = {510-22},
	abstract = {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.},
	keywords = {Animals, Disease Models, Animal, hippocampus, Mice, Mice, Knockout, Nerve Net, Signal Transduction, Synapses, TOR Serine-Threonine Kinases, Tuberous Sclerosis, Tuberous Sclerosis Complex 1 Protein, Tumor Suppressor Proteins},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2013.03.017},
	author = {Bateup, Helen S and Johnson, Caroline A and Denefrio, Cassandra L and Saulnier, Jessica L and Kornacker, Karl and Sabatini, Bernardo L}
}
@article {1790091,
	title = {Live-cell superresolution imaging by pulsed STED two-photon excitation microscopy},
	journal = {Biophys J},
	volume = {104},
	number = {4},
	year = {2013},
	month = {2013 Feb 19},
	pages = {770-7},
	abstract = {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.},
	keywords = {Animals, CA1 Region, Hippocampal, dendritic spines, Mice, Mice, Inbred C57BL, Microscopy, Confocal, Microscopy, Fluorescence, Multiphoton, Nanospheres},
	issn = {1542-0086},
	doi = {10.1016/j.bpj.2012.12.053},
	author = {Takasaki, Kevin T and Ding, Jun B and Sabatini, Bernardo L}
}
@article {1790071,
	title = {A nanobody-based system using fluorescent proteins as scaffolds for cell-specific gene manipulation},
	journal = {Cell},
	volume = {154},
	number = {4},
	year = {2013},
	month = {2013 Aug 15},
	pages = {928-39},
	abstract = {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.},
	keywords = {Animals, Animals, Genetically Modified, Electrophysiological Phenomena, Genetic Techniques, Green Fluorescent Proteins, Humans, Mice, Recombinant Fusion Proteins, Transcription Factors, Transcription, Genetic, Zebrafish},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2013.07.021},
	author = {Tang, Jonathan C Y and Szikra, Tamas and Kozorovitskiy, Yevgenia and Teixiera, Miguel and Sabatini, Bernardo L and Roska, Botond and Cepko, Constance L}
}
@article {1790086,
	title = {Optically selective two-photon uncaging of glutamate at 900 nm},
	journal = {J Am Chem Soc},
	volume = {135},
	number = {16},
	year = {2013},
	month = {2013 Apr 24},
	pages = {5954-7},
	abstract = {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.},
	keywords = {Animals, Brain Chemistry, Coumarins, Excitatory Postsynaptic Potentials, Glutamic Acid, Hydrogen-Ion Concentration, In Vitro Techniques, Indicators and Reagents, Mice, Neuroimaging, Patch-Clamp Techniques, Photolysis, Pyramidal Cells, Signal Transduction, Spectrophotometry, Ultraviolet},
	issn = {1520-5126},
	doi = {10.1021/ja4019379},
	author = {Olson, Jeremy P and Kwon, Hyung-Bae and Takasaki, Kevin T and Chiu, Chiayu Q and Higley, Michael J and Sabatini, Bernardo L and Ellis-Davies, Graham C R}
}
@article {1790076,
	title = {Recombinant probes for visualizing endogenous synaptic proteins in living neurons},
	journal = {Neuron},
	volume = {78},
	number = {6},
	year = {2013},
	month = {2013 Jun 19},
	pages = {971-85},
	abstract = {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.},
	keywords = {Animals, Carrier Proteins, Chlorocebus aethiops, COS Cells, Disks Large Homolog 4 Protein, Gene Expression Profiling, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Nerve Tissue Proteins, Neurons, Recombinant Proteins, Synapses},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2013.04.017},
	author = {Gross, Garrett G and Junge, Jason A and Mora, Rudy J and Kwon, Hyung-Bae and Olson, C Anders and Takahashi, Terry T and Liman, Emily R and Ellis-Davies, Graham C R and McGee, Aaron W and Sabatini, Bernardo L and Roberts, Richard W and Arnold, Don B}
}
@article {1790061,
	title = {Spectral evolution of a photochemical protecting group for orthogonal two-color uncaging with visible light},
	journal = {J Am Chem Soc},
	volume = {135},
	number = {42},
	year = {2013},
	month = {2013 Oct 23},
	pages = {15948-54},
	abstract = {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.},
	keywords = {Aminocoumarins, Color, Coumarins, Cyclic AMP, gamma-Aminobutyric Acid, Hydrolysis, Light, Molecular Structure, Photochemical Processes},
	issn = {1520-5126},
	doi = {10.1021/ja408225k},
	author = {Olson, Jeremy P and Banghart, Matthew R and Sabatini, Bernardo L and Ellis-Davies, Graham C R}
}
@article {1790066,
	title = {Temporal dynamics of a homeostatic pathway controlling neural network activity},
	journal = {Front Mol Neurosci},
	volume = {6},
	year = {2013},
	month = {2013},
	pages = {28},
	abstract = {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.},
	issn = {1662-5099},
	doi = {10.3389/fnmol.2013.00028},
	author = {Bateup, Helen S and Denefrio, Cassandra L and Johnson, Caroline A and Saulnier, Jessica L and Sabatini, Bernardo L}
}
@article {1790096,
	title = {Vesicular stomatitis virus with the rabies virus glycoprotein directs retrograde transsynaptic transport among neurons in vivo},
	journal = {Front Neural Circuits},
	volume = {7},
	year = {2013},
	month = {2013},
	pages = {11},
	abstract = {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.},
	keywords = {Animals, Animals, Newborn, HEK293 Cells, Humans, Membrane Glycoproteins, Mice, Neurons, Organ Culture Techniques, Protein Transport, Rabies virus, Rats, Rats, Sprague-Dawley, Synapses, Viral Envelope Proteins},
	issn = {1662-5110},
	doi = {10.3389/fncir.2013.00011},
	author = {Beier, Kevin T and Saunders, Arpiar B and Oldenburg, Ian A and Sabatini, Bernardo L and Cepko, Constance L}
}
@article {704491,
	title = {Caged Naloxone Reveals Opioid Signaling Deactivation Kinetics},
	journal = {Molecular Pharmacology},
	volume = {84},
	number = {5},
	year = {2013},
	pages = {687-695},
	author = {MR Banghart and JT Williams and RC Shah and LD Lavis and BL Sabatini}
}
@article {704506,
	title = {Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis},
	journal = {Neuron},
	volume = {78},
	number = {3},
	year = {2013},
	pages = {510-522},
	author = {HS Bateup and Johnson, CA and CL Denefrio and JL Saulnier and K Kornacker and BL Sabatini}
}
@article {704521,
	title = {Live-Cell Superresolution Imaging by Pulsed STED Two-Photon Excitation Microscopy},
	journal = {Biophysical Journal},
	volume = {104},
	number = {4},
	year = {2013},
	pages = {770-777},
	author = {KT Takasaki and JB Ding and BL Sabatini}
}
@article {704476,
	title = {A nanobody-based system using fluorescent proteins as scaffolds for cell-specific gene manipulation},
	journal = {Cell},
	volume = {154},
	number = {4},
	year = {2013},
	pages = {928-939},
	author = {JC Tang and T Szikra and Y Kozorovitskiy and M Teixiera and BL Sabatini and B Roska and CL Cepko}
}
@article {704496,
	title = {Optically selective two-photon uncaging of glutamate at 900 nm},
	journal = {Journal of the American Chemical Society},
	volume = {135},
	number = {16},
	year = {2013},
	pages = {5954-5957},
	author = {JP Olson and HB Kwon and KT Takasaki and CQ Chiu and MJ Higley and BL Sabatini and GC Ellis-Davies}
}
@article {704516,
	title = {Recombinant probes for visualizing endogenous synaptic proteins in living neurons},
	journal = {Neuron},
	volume = {78},
	number = {6},
	year = {2013},
	pages = {971-985},
	author = {GG Gross and JA Junge and RJ Mora and HB Kwon and CA Olson and TT Takahashi and Liman, E R and GC Ellis-Davies and McGee, A. W. and BL Sabatini and RW Roberts and DB Arnold}
}
@article {704531,
	title = {Vesicular stomatitis virus with the rabies virus glycoprotein directs retrograde transsynaptic transport among neurons in vivo},
	journal = {Frontiers in Neural Circuits},
	volume = {7},
	number = {11},
	year = {2013},
	author = {KT Beier and AB Saunders and IA Oldenburg and BL Sabatini and CL Cepko}
}
@article {1790146,
	title = {Calcium signaling in dendritic spines},
	journal = {Cold Spring Harb Perspect Biol},
	volume = {4},
	number = {4},
	year = {2012},
	month = {2012 Apr 01},
	pages = {a005686},
	abstract = {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.},
	keywords = {Action Potentials, Animals, Calcium Signaling, dendritic spines, Mammals, Neuronal Plasticity},
	issn = {1943-0264},
	doi = {10.1101/cshperspect.a005686},
	author = {Higley, Michael J and Sabatini, Bernardo L}
}
@article {1790116,
	title = {Dopaminergic modulation of synaptic transmission in cortex and striatum},
	journal = {Neuron},
	volume = {76},
	number = {1},
	year = {2012},
	month = {2012 Oct 04},
	pages = {33-50},
	abstract = {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{\textquoteright}s disease (PD), addiction, schizophrenia, obsessive compulsive disorder, and Tourette{\textquoteright}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.},
	keywords = {Animals, Brain, Dopamine, Humans, Neurons, Synaptic Transmission},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2012.09.023},
	author = {Tritsch, Nicolas X and Sabatini, Bernardo L}
}
@article {1790111,
	title = {Dopaminergic neurons inhibit striatal output through non-canonical release of GABA},
	journal = {Nature},
	volume = {490},
	number = {7419},
	year = {2012},
	month = {2012 Oct 11},
	pages = {262-6},
	abstract = {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.},
	keywords = {Animals, Corpus Striatum, Dopaminergic Neurons, GABA Plasma Membrane Transport Proteins, gamma-Aminobutyric Acid, Gene Expression Profiling, Gene Expression Regulation, Gene Knock-In Techniques, Mice, Mice, Transgenic, Vesicular Monoamine Transport Proteins},
	issn = {1476-4687},
	doi = {10.1038/nature11466},
	author = {Tritsch, Nicolas X and Ding, Jun B and Sabatini, Bernardo L}
}
@article {1790151,
	title = {Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone},
	journal = {Neuron},
	volume = {73},
	number = {3},
	year = {2012},
	month = {2012 Feb 09},
	pages = {511-22},
	abstract = {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.},
	keywords = {2-Amino-5-phosphonovalerate, 6-Cyano-7-nitroquinoxaline-2,3-dione, Age Factors, Agouti-Related Protein, Animals, Body Composition, Brain, Carrier Proteins, dendritic spines, Eating, Energy Metabolism, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Fasting, Female, GABA Antagonists, Gene Expression Regulation, Green Fluorescent Proteins, In Vitro Techniques, Male, Membrane Potentials, Mice, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Neuropeptide Y, Patch-Clamp Techniques, Picrotoxin, Pro-Opiomelanocortin, Proto-Oncogene Proteins c-fos, Receptors, N-Methyl-D-Aspartate, RNA, Messenger, Time Factors},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2011.11.027},
	author = {Liu, Tiemin and Kong, Dong and Shah, Bhavik P and Ye, Chianping and Koda, Shuichi and Saunders, Arpiar and Ding, Jun B and Yang, Zongfang and Sabatini, Bernardo L and Lowell, Bradford B}
}
@article {1790101,
	title = {Neuroligin-1-dependent competition regulates cortical synaptogenesis and synapse number},
	journal = {Nat Neurosci},
	volume = {15},
	number = {12},
	year = {2012},
	month = {2012 Dec},
	pages = {1667-74},
	abstract = {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.},
	keywords = {Animals, Cell Adhesion Molecules, Neuronal, Cell Communication, Cell Count, Cells, Cultured, Cerebral Cortex, Coculture Techniques, Female, HEK293 Cells, Humans, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, neurogenesis, Organ Culture Techniques, Pregnancy, Rats, Rats, Sprague-Dawley, Synapses},
	issn = {1546-1726},
	doi = {10.1038/nn.3256},
	author = {Kwon, Hyung-Bae and Kozorovitskiy, Yevgenia and Oh, Won-Jong and Peixoto, Rui T and Akhtar, Nazia and Saulnier, Jessica L and Gu, Chenghua and Sabatini, Bernardo L}
}
@article {1790126,
	title = {Novel recombinant adeno-associated viruses for Cre activated and inactivated transgene expression in neurons},
	journal = {Front Neural Circuits},
	volume = {6},
	year = {2012},
	month = {2012},
	pages = {47},
	abstract = {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.},
	issn = {1662-5110},
	doi = {10.3389/fncir.2012.00047},
	author = {Saunders, Arpiar and Johnson, Caroline A and Sabatini, Bernardo L}
}
@article {1790156,
	title = {Optical super-resolution microscopy in neurobiology},
	journal = {Curr Opin Neurobiol},
	volume = {22},
	number = {1},
	year = {2012},
	month = {2012 Feb},
	pages = {86-93},
	abstract = {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.},
	keywords = {Animals, Brain, Diagnostic Imaging, Humans, Microscopy, Neurons, Neurosciences, Optics and Photonics},
	issn = {1873-6882},
	doi = {10.1016/j.conb.2011.10.014},
	author = {Sigrist, Stephan J and Sabatini, Bernardo L}
}
@article {1790161,
	title = {Photoactivatable neuropeptides for spatiotemporally precise delivery of opioids in neural tissue},
	journal = {Neuron},
	volume = {73},
	number = {2},
	year = {2012},
	month = {2012 Jan 26},
	pages = {249-59},
	abstract = {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: [Leu$^{5}$]-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.},
	keywords = {Analgesics, Opioid, Animals, Dynorphins, Enkephalins, Neurons, Neuropeptides, Rats, Receptors, Opioid, mu, Ultraviolet Rays},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2011.11.016},
	author = {Banghart, Matthew R and Sabatini, Bernardo L}
}
@article {1790136,
	title = {Recurrent network activity drives striatal synaptogenesis},
	journal = {Nature},
	volume = {485},
	number = {7400},
	year = {2012},
	month = {2012 May 13},
	pages = {646-50},
	abstract = {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.},
	keywords = {Animals, Basal Ganglia, Cerebral Cortex, Feedback, Physiological, Female, gamma-Aminobutyric Acid, Male, Mice, Mice, Transgenic, Models, Neurological, Neostriatum, Neural Inhibition, Neural Pathways, Synapses, Thalamus, Vesicular Inhibitory Amino Acid Transport Proteins},
	issn = {1476-4687},
	doi = {10.1038/nature11052},
	author = {Kozorovitskiy, Yevgenia and Saunders, Arpiar and Johnson, Caroline A and Lowell, Bradford B and Sabatini, Bernardo L}
}
@article {1790131,
	title = {Signaling in dendritic spines and spine microdomains},
	journal = {Curr Opin Neurobiol},
	volume = {22},
	number = {3},
	year = {2012},
	month = {2012 Jun},
	pages = {389-96},
	abstract = {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.},
	keywords = {Animals, dendritic spines, Membrane Microdomains, Models, Biological, Signal Transduction, Synapses},
	issn = {1873-6882},
	doi = {10.1016/j.conb.2012.03.003},
	author = {Chen, Yao and Sabatini, Bernardo L}
}
@article {1790141,
	title = {Synapses and Alzheimer{\textquoteright}s disease},
	journal = {Cold Spring Harb Perspect Biol},
	volume = {4},
	number = {5},
	year = {2012},
	month = {2012 May 01},
	abstract = {Alzheimer{\textquoteright}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.},
	keywords = {Alzheimer Disease, Amyloid beta-Peptides, Gene Transfer Techniques, Humans, Models, Biological, Presenilins, Synapses, Synaptic Transmission, tau Proteins},
	issn = {1943-0264},
	doi = {10.1101/cshperspect.a005777},
	author = {Sheng, Morgan and Sabatini, Bernardo L and S{\"u}dhof, Thomas C}
}
@article {1790121,
	title = {Transient sodium current at subthreshold voltages: activation by EPSP waveforms},
	journal = {Neuron},
	volume = {75},
	number = {6},
	year = {2012},
	month = {2012 Sep 20},
	pages = {1081-93},
	abstract = {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{\textdegree}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.},
	keywords = {Animals, Animals, Newborn, Biophysical Phenomena, Cerebellum, Electric Stimulation, Excitatory Postsynaptic Potentials, Glutamic Acid, hippocampus, In Vitro Techniques, Markov Chains, Mice, Mice, Inbred C57BL, Models, Neurological, Neurons, Patch-Clamp Techniques, Sodium Channel Blockers, Sodium Channels, Tetrodotoxin},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2012.08.033},
	author = {Carter, Brett C and Giessel, Andrew J and Sabatini, Bernardo L and Bean, Bruce P}
}
@article {1790106,
	title = {Transsynaptic signaling by activity-dependent cleavage of neuroligin-1},
	journal = {Neuron},
	volume = {76},
	number = {2},
	year = {2012},
	month = {2012 Oct 18},
	pages = {396-409},
	abstract = {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.},
	keywords = {Animals, Animals, Newborn, Biotinylation, Calcium-Binding Proteins, Cell Adhesion Molecules, Neuronal, Cells, Cultured, Cerebral Cortex, Chlorocebus aethiops, Dark Adaptation, Dendrites, Disease Models, Animal, Electric Stimulation, Electroporation, Enzyme Inhibitors, Excitatory Amino Acid Agents, Excitatory Postsynaptic Potentials, Female, Glutamic Acid, Green Fluorescent Proteins, hippocampus, Luminescent Proteins, Matrix Metalloproteinase 9, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Confocal, Muscarinic Agonists, Mutation, Neural Cell Adhesion Molecules, Neurons, Organ Culture Techniques, Patch-Clamp Techniques, Photons, Pilocarpine, Plant Lectins, Potassium Chloride, Pregnancy, Pyridinium Compounds, Quaternary Ammonium Compounds, Red Fluorescent Protein, Signal Transduction, Status Epilepticus, Synaptic Transmission, Threonine, Transfection, Vesicular Glutamate Transport Protein 1},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2012.07.006},
	author = {Peixoto, Rui T and Kunz, Portia A and Kwon, Hyungbae and Mabb, Angela M and Sabatini, Bernardo L and Philpot, Benjamin D and Ehlers, Michael D}
}
@article {704436,
	title = {Calcium Signaling in Dendritic Spines.},
	journal = {Cold Spring Harbor Perspectives in Biology},
	volume = {4},
	number = {4},
	year = {2012},
	author = {MJ Higley and BL Sabatini}
}
@article {704221,
	title = {Dopaminergic modulation of synaptic transmission in cortex and striatum},
	journal = {Neuron},
	volume = {76},
	number = {1},
	year = {2012},
	pages = {33-50},
	author = {NX Tritsch and BL Sabatini}
}
@article {704361,
	title = {Dopaminergic neurons inhibit striatal output through non-canonical release of GABA},
	journal = {Nature},
	volume = {490},
	number = {7419},
	year = {2012},
	pages = {262-266},
	author = {NX Tritsch and JB Ding and BL Sabatini}
}
@article {704446,
	title = {Fasting Activation of AgRP Neurons Requires NMDA Receptors and Involves Spinogenesis and Increased Excitatory Tone},
	journal = {Neuron},
	volume = {73},
	number = {3},
	year = {2012},
	pages = {511-522},
	author = {Liu, T and D Kong and B.P. Shah and C Ye and S Koda and A Saunders and JB Ding and Z Yang and BL Sabatini and B.B. Lowell}
}
@article {704216,
	title = {Neuroligin-1-dependent competition regulates cortical synaptogenesis and synapse number},
	journal = {Nature Neuroscience},
	volume = {15},
	number = {12},
	year = {2012},
	pages = {1667-1674},
	author = {HB Kwon and Y Kozorovitskiy and WJ Oh and RT Peixoto and N Akhtar and JL Saulnier and C Gu and BL Sabatini}
}
@article {704366,
	title = {Novel recombinant adeno-associated viruses for Cre activated and inactivated transgene expression},
	journal = {Frontiers in Neural Circuits},
	volume = {6},
	number = {47},
	year = {2012},
	author = {A Saunders and C. Johnson and BL Sabatini}
}
@article {704451,
	title = {Photoactivatable Neuropeptides for Spatiotemporally Precise Delivery of Opioids in Neural Tissue},
	journal = {Neuron},
	volume = {73},
	number = {2},
	year = {2012},
	pages = {249-259},
	author = {MR Banghart and BL Sabatini}
}
@article {704376,
	title = {Recurrent network activity drives striatal synaptogenesis},
	journal = {Nature},
	volume = {485},
	number = {7415},
	year = {2012},
	pages = {646-650},
	author = {Y Kozorovitskiy and A Saunders and Johnson, CA and B.B. Lowell and BL Sabatini}
}
@article {704386,
	title = {Signaling in dendritic spines and spine microdomains},
	journal = {Current Opinion in Neurobiology},
	volume = {22},
	number = {3},
	year = {2012},
	pages = {389-396},
	author = {Chen, Y. and BL Sabatini}
}
@article {704391,
	title = {Synapses and Alzheimer{\textquoteright}s disease},
	journal = {Cold Spring Harbor Perspectives in Biology},
	volume = {4},
	number = {5},
	year = {2012},
	author = {M Sheng and BL Sabatini and TC S{\"u}dhof}
}
@article {704206,
	title = {Transient Sodium Current at Subthreshold Voltages: Activation by EPSP Waveforms},
	journal = {Neuron},
	volume = {75},
	number = {6},
	year = {2012},
	pages = {1081-93},
	author = {BC Carter and AJ Giessel and BL Sabatini and BP Bean}
}
@article {704211,
	title = {Transsynaptic signaling by activity-dependent cleavage of neuroligin-1},
	journal = {Neuron},
	volume = {76},
	number = {2},
	year = {2012},
	pages = {396-409},
	author = {RT Peixoto and PA Kunz and HB Kwon and AM Mabb and BL Sabatini and BD Philpot and MD Ehlers}
}
@article {1790191,
	title = {Boosting of synaptic potentials and spine Ca transients by the peptide toxin SNX-482 requires alpha-1E-encoded voltage-gated Ca channels},
	journal = {PLoS One},
	volume = {6},
	number = {6},
	year = {2011},
	month = {2011},
	pages = {e20939},
	abstract = {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.},
	keywords = {Animals, Calcium, Calcium Channels, R-Type, Cation Transport Proteins, dendritic spines, Gene Knockout Techniques, Mice, Peptides, Signal Transduction, Spider Venoms, Synaptic Potentials},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0020939},
	author = {Giessel, Andrew J and Sabatini, Bernardo L}
}
@article {1790181,
	title = {Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum},
	journal = {PLoS One},
	volume = {6},
	number = {4},
	year = {2011},
	month = {2011 Apr 22},
	pages = {e19155},
	abstract = {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.},
	keywords = {Amino Acid Transport Systems, Acidic, Animals, Central Nervous System Stimulants, Channelrhodopsins, Corpus Striatum, Evoked Potentials, Female, Interneurons, Male, Mecamylamine, Mice, Picrotoxin, Receptors, Cholinergic, Receptors, N-Methyl-D-Aspartate, Scopolamine},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0019155},
	author = {Higley, Michael J and Gittis, Aryn H and Oldenburg, Ian A and Balthasar, Nina and Seal, Rebecca P and Edwards, Robert H and Lowell, Bradford B and Kreitzer, Anatol C and Sabatini, Bernardo L}
}
@article {1790176,
	title = {Glutamate induces de novo growth of functional spines in developing cortex},
	journal = {Nature},
	volume = {474},
	number = {7349},
	year = {2011},
	month = {2011 Jun 02},
	pages = {100-4},
	abstract = {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.},
	keywords = {Animals, Calcium, Cerebral Cortex, dendritic spines, Electric Stimulation, Glutamic Acid, Mice, Mice, Inbred C57BL, Neurotransmitter Agents, Pyramidal Cells},
	issn = {1476-4687},
	doi = {10.1038/nature09986},
	author = {Kwon, Hyung-Bae and Sabatini, Bernardo L}
}
@article {1790171,
	title = {Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function},
	journal = {J Neurosci},
	volume = {31},
	number = {24},
	year = {2011},
	month = {2011 Jun 15},
	pages = {8862-9},
	abstract = {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.},
	keywords = {alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Animals, Animals, Newborn, CA1 Region, Hippocampal, dendritic spines, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Green Fluorescent Proteins, Long-Term Synaptic Depression, Mice, Mice, Transgenic, Microscopy, Confocal, N-Methylaspartate, Neurons, Organ Culture Techniques, Receptors, Glutamate, Serine, Symporters, Synapses},
	issn = {1529-2401},
	doi = {10.1523/JNEUROSCI.1617-11.2011},
	author = {Bateup, Helen S and Takasaki, Kevin T and Saulnier, Jessica L and Denefrio, Cassandra L and Sabatini, Bernardo L}
}
@article {1790166,
	title = {Semaphorin 3E-Plexin-D1 signaling controls pathway-specific synapse formation in the striatum},
	journal = {Nat Neurosci},
	volume = {15},
	number = {2},
	year = {2011},
	month = {2011 Dec 18},
	pages = {215-23},
	abstract = {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.},
	keywords = {Animals, Animals, Newborn, Biophysics, Brain, Cell Adhesion Molecules, Neuronal, Channelrhodopsins, Corpus Striatum, Cytoskeletal Proteins, Dependovirus, Electric Stimulation, Excitatory Postsynaptic Potentials, Gene Expression Regulation, Developmental, Glycoproteins, In Vitro Techniques, Intracellular Signaling Peptides and Proteins, Luminescent Proteins, Membrane Glycoproteins, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Patch-Clamp Techniques, Receptors, AMPA, Receptors, Dopamine D1, Receptors, Dopamine D2, Semaphorins, Signal Transduction, Statistics, Nonparametric, Synapses, Vesicular Glutamate Transport Protein 2},
	issn = {1546-1726},
	doi = {10.1038/nn.3003},
	author = {Ding, Jun B and Oh, Won-Jong and Sabatini, Bernardo L and Gu, Chenghua}
}
@article {1790186,
	title = {Synaptic function and regulation},
	journal = {Curr Opin Neurobiol},
	volume = {21},
	number = {2},
	year = {2011},
	month = {2011 Apr},
	pages = {205-7},
	keywords = {Animals, Humans, Neuronal Plasticity, Periodicals as Topic, Synapses, Synaptic Transmission},
	issn = {1873-6882},
	doi = {10.1016/j.conb.2011.03.004},
	author = {Goda, Yukiko and Sabatini, Bernardo L}
}
@article {704191,
	title = {Anterograde or retrograde transsynaptic labeling of CNS neurons with vesicular stomatitis virus vectors},
	journal = {Proc Natl Acad Sci U S A},
	volume = {109},
	number = {23},
	year = {2011},
	pages = {15414-15419},
	author = {KT Beier and A Saunders and IA Oldenburg and K Miyamichi and N Akhtar and Luo, L and SP Whelan and BL Sabatini and CL Cepko}
}
@article {704176,
	title = {Boosting of synaptic potentials and spine Ca transients by the peptide toxin SNX-482 requires alpha-1E-encoded voltage-gated Ca channels},
	journal = {PLoS One},
	volume = {6},
	number = {6},
	year = {2011},
	pages = { e20939},
	author = {AJ Giessel and BL Sabatini}
}
@article {704161,
	title = {Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum},
	journal = {PLoS One},
	volume = {6},
	number = {4},
	year = {2011},
	pages = {e19155},
	author = {MJ Higley and AH Gittis and IA Oldenburg and N Balthasar and RP Seal and RH Edwards and B.B. Lowell and AC Kreitzer and BL Sabatini}
}
@article {704156,
	title = {Glutamate induces de novo growth of functional spines in developing cortex},
	journal = {Nature},
	volume = {474},
	number = {7349},
	year = {2011},
	pages = {100-104},
	author = {HB Kwon and BL Sabatini}
}
@article {704196,
	title = {Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function},
	journal = {Journal of Neuroscience},
	volume = {31},
	number = {24},
	year = {2011},
	pages = {8862-8869},
	author = {HS Bateup and KT Takasaki and JL Saulnier and CL Denefrio and BL Sabatini}
}
@article {704151,
	title = {Optical super-resolution microscopy in neurobiology},
	journal = {Current Opinion in Neurobiology},
	volume = {22},
	number = {1},
	year = {2011},
	pages = {86-93},
	author = {SJ Sigrist and BL Sabatini}
}
@article {704181,
	title = {Semaphorin 3E-Plexin-D1 signaling controls pathway-specific synapse formation in the striatum},
	journal = {Nature Neuroscience},
	volume = {15},
	number = {2},
	year = {2011},
	pages = {215-223},
	author = {JB Ding and WJ Oh and BL Sabatini and C Gu}
}
@article {704166,
	title = {Synaptic function and regulation},
	journal = {Current Opinion in Neurobiology},
	volume = {21},
	number = {2},
	year = {2011},
	pages = {205-207},
	author = {Y Goda and BL Sabatini}
}
@article {1790206,
	title = {Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors},
	journal = {Nat Neurosci},
	volume = {13},
	number = {8},
	year = {2010},
	month = {2010 Aug},
	pages = {958-66},
	abstract = {Striatal D2-type dopamine receptors (D2Rs) have been implicated in the pathophysiology of neuropsychiatric disorders, including Parkinson{\textquoteright}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.},
	keywords = {Animals, Calcium, Calcium Channels, Calcium Signaling, Corpus Striatum, Cyclic AMP-Dependent Protein Kinases, dendritic spines, Excitatory Postsynaptic Potentials, Female, Male, Mice, Microscopy, Confocal, Organ Culture Techniques, Patch-Clamp Techniques, Receptor, Adenosine A2A, Receptors, Dopamine D2, Receptors, N-Methyl-D-Aspartate, Synapses, Synaptic Transmission},
	issn = {1546-1726},
	doi = {10.1038/nn.2592},
	author = {Higley, Michael J and Sabatini, Bernardo L}
}
@article {1790211,
	title = {For synapses, it{\textquoteright}s depression not death},
	journal = {Cell},
	volume = {141},
	number = {5},
	year = {2010},
	month = {2010 May 28},
	pages = {750-2},
	abstract = {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.},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2010.05.013},
	author = {Bateup, Helen S and Sabatini, Bernardo L}
}
@article {1790196,
	title = {M1 muscarinic receptors boost synaptic potentials and calcium influx in dendritic spines by inhibiting postsynaptic SK channels},
	journal = {Neuron},
	volume = {68},
	number = {5},
	year = {2010},
	month = {2010 Dec 09},
	pages = {936-47},
	abstract = {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.},
	keywords = {Acetylcholine, Animals, CA1 Region, Hippocampal, Calcium, Casein Kinase II, dendritic spines, Feedback, Physiological, In Vitro Techniques, Mice, Mice, Inbred C57BL, Pyramidal Cells, Receptor Cross-Talk, Receptor, Muscarinic M1, Second Messenger Systems, Signal Transduction, Small-Conductance Calcium-Activated Potassium Channels, Synaptic Potentials},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2010.09.004},
	author = {Giessel, Andrew J and Sabatini, Bernardo L}
}
@article {1790201,
	title = {Oriented Markov random field based dendritic spine segmentation for fluorescence microscopy images},
	journal = {Neuroinformatics},
	volume = {8},
	number = {3},
	year = {2010},
	month = {2010 Oct},
	pages = {157-70},
	abstract = {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.},
	keywords = {Algorithms, Animals, Cell Shape, Computer Simulation, dendritic spines, hippocampus, Image Cytometry, Markov Chains, Microscopy, Fluorescence, Organ Culture Techniques, Pattern Recognition, Automated, Rats},
	issn = {1559-0089},
	doi = {10.1007/s12021-010-9073-y},
	author = {Cheng, Jie and Zhou, Xiaobo and Eric L. Miller and Alvarez, Veronica A and Sabatini, Bernardo L and Wong, Stephen T C}
}
@article {704121,
	title = {Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors},
	journal = {Nature Neuroscience},
	volume = {13},
	number = {8},
	year = {2010},
	pages = {958-966},
	author = {MJ Higley and BL Sabatini}
}
@article {704146,
	title = {For synapses, it{\textquoteright}s depression not death},
	journal = {Cell},
	volume = {141},
	number = {5},
	year = {2010},
	pages = {750-752},
	author = {HS Bateup and BL Sabatini}
}
@article {704126,
	title = {M1 muscarinic receptors boost synaptic potentials and calcium influx in dendritic spines by inhibiting postsynaptic SK channels},
	journal = {Neuron},
	volume = {68},
	number = {5},
	year = {2010},
	pages = {936-947},
	author = {AJ Giessel and BL Sabatini}
}
@article {704136,
	title = {Oriented Markov random field based dendritic spine segmentation for fluorescence microscopy images},
	journal = {Neuroinformatics},
	volume = {8},
	number = {3},
	year = {2010},
	pages = {157-170},
	author = {J Cheng and X Zhou and EL Miller and VA Alvarez and BL Sabatini and ST Wong}
}
@article {1790221,
	title = {Biphasic synaptic Ca influx arising from compartmentalized electrical signals in dendritic spines},
	journal = {PLoS Biol},
	volume = {7},
	number = {9},
	year = {2009},
	month = {2009 Sep},
	pages = {e1000190},
	abstract = {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.},
	keywords = {Animals, Calcium Channels, Calcium Signaling, dendritic spines, Electrical Synapses, Glutamic Acid, hippocampus, Mice, Neural Conduction, Receptors, AMPA, Receptors, N-Methyl-D-Aspartate, Synaptic Potentials, Synaptic Transmission},
	issn = {1545-7885},
	doi = {10.1371/journal.pbio.1000190},
	author = {Bloodgood, Brenda L and Giessel, Andrew J and Sabatini, Bernardo L}
}
@article {1790226,
	title = {Cholinergic modulation of multivesicular release regulates striatal synaptic potency and integration},
	journal = {Nat Neurosci},
	volume = {12},
	number = {9},
	year = {2009},
	month = {2009 Sep},
	pages = {1121-8},
	abstract = {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.},
	keywords = {Animals, Calcium, Calcium Channels, N-Type, Corpus Striatum, dendritic spines, Excitatory Postsynaptic Potentials, Glutamic Acid, In Vitro Techniques, Membrane Potentials, Presynaptic Terminals, Probability, Rats, Rats, Sprague-Dawley, Receptors, Muscarinic, Receptors, N-Methyl-D-Aspartate, Synapses, Synaptic Transmission, Synaptic Vesicles, Time Factors},
	issn = {1546-1726},
	doi = {10.1038/nn.2368},
	author = {Higley, Michael J and Soler-Llavina, Gilberto J and Sabatini, Bernardo L}
}
@article {1790216,
	title = {Distinct domains within PSD-95 mediate synaptic incorporation, stabilization, and activity-dependent trafficking},
	journal = {J Neurosci},
	volume = {29},
	number = {41},
	year = {2009},
	month = {2009 Oct 14},
	pages = {12845-54},
	abstract = {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.},
	keywords = {Animals, Animals, Newborn, Calcium-Calmodulin-Dependent Protein Kinase Kinase, dendritic spines, Disks Large Homolog 4 Protein, Excitatory Amino Acid Agonists, Green Fluorescent Proteins, hippocampus, Immunosuppressive Agents, Intracellular Signaling Peptides and Proteins, Lipoylation, Membrane Proteins, Mutation, N-Methylaspartate, Organ Culture Techniques, PDZ Domains, Protein Structure, Tertiary, Protein Transport, Rats, Receptors, AMPA, Signal Transduction, Synapses, Tacrolimus, Time Factors, Transfection},
	issn = {1529-2401},
	doi = {10.1523/JNEUROSCI.1841-09.2009},
	author = {Sturgill, James F and Steiner, Pascal and Czervionke, Brian L and Sabatini, Bernardo L}
}
@article {1790231,
	title = {Supraresolution imaging in brain slices using stimulated-emission depletion two-photon laser scanning microscopy},
	journal = {Neuron},
	volume = {63},
	number = {4},
	year = {2009},
	month = {2009 Aug 27},
	pages = {429-37},
	abstract = {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.},
	keywords = {Animals, Brain, In Vitro Techniques, Mice, Mice, Inbred C57BL, Microscopy, Confocal, Microscopy, Fluorescence, Multiphoton},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2009.07.011},
	author = {Ding, Jun B and Takasaki, Kevin T and Sabatini, Bernardo L}
}
@article {704106,
	title = {Biphasic synaptic Ca influx arising from compartmentalized electrical signals in dendritic spines},
	journal = {PLoS Biology},
	volume = {7},
	number = {9},
	year = {2009},
	pages = {e1000190},
	author = {BL Bloodgood and AJ Giessel and BL Sabatini}
}
@article {704086,
	title = {Cholinergic modulation of multivesicular release regulates striatal synaptic potency and integration},
	journal = {Nature Neuroscience},
	volume = {12},
	number = {9},
	year = {2009},
	pages = {1121-1128},
	author = {MJ Higley and GJ Soler-Llavina and BL Sabatini}
}
@article {704081,
	title = {Distinct domains within PSD-95 mediate synaptic incorporation, stabilization, and activity-dependent trafficking},
	journal = {Journal of Neuroscience},
	volume = {29},
	number = {41},
	year = {2009},
	pages = {12845-12854},
	author = {JF Sturgill and P Steiner and BL Czervionke and BL Sabatini}
}
@article {704111,
	title = {An Image Driven Systems Biology Approach for Neurodegenerative Disease Studies in the TSC-mTOR Pathway},
	journal = {IEEE/NIH Life Science Systems and Applications Workshop},
	year = {2009},
	pages = {36-39},
	author = {D Beck and X Zhou and T Pham and BL Sabatini and ST Wong}
}
@inbook {704101,
	title = {NMDA Receptor-Mediated Calcium Transients in Dendritic Spines},
	booktitle = {Biology of the NMDA Receptor},
	year = {2009},
	publisher = {CRC Press},
	organization = {CRC Press},
	address = {Boca Raton, FL},
	author = {BL Bloodgood and BL Sabatini},
	editor = {AM Van Dongen}
}
@article {704096,
	title = {Supraresolution imaging in brain slices using stimulated-emission depletion two-photon laser scanning microscopy},
	journal = {Neuron},
	volume = {63},
	number = {4},
	year = {2009},
	pages = {429-437},
	author = {JB Ding and KT Takasaki and BL Sabatini}
}
@article {1790251,
	title = {Amyloid-beta protein dimers isolated directly from Alzheimer{\textquoteright}s brains impair synaptic plasticity and memory},
	journal = {Nat Med},
	volume = {14},
	number = {8},
	year = {2008},
	month = {2008 Aug},
	pages = {837-42},
	abstract = {Alzheimer{\textquoteright}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{\textquoteright}s disease has not been achieved. We extracted soluble amyloid-beta protein (Abeta) oligomers directly from the cerebral cortex of subjects with Alzheimer{\textquoteright}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{\textquoteright}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{\textquoteright}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{\textquoteright}s disease brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species.},
	keywords = {Alzheimer Disease, Amyloid beta-Peptides, Animals, Brain, dendritic spines, Dimerization, hippocampus, Humans, Learning, Memory, Mice, Neuronal Plasticity, Neurons, Rats, Synapses},
	issn = {1546-170X},
	doi = {10.1038/nm1782},
	author = {Shankar, Ganesh M and Shaomin Li and Mehta, Tapan H and Garcia-Munoz, Amaya and Shepardson, Nina E and Smith, Imelda and Brett, Francesca M and Farrell, Michael A and Rowan, Michael J and Lemere, Cynthia A and Regan, Ciaran M and Walsh, Dominic M and Sabatini, Bernardo L and Selkoe, Dennis J}
}
@article {1790246,
	title = {Calcium signaling in dendrites and spines: practical and functional considerations},
	journal = {Neuron},
	volume = {59},
	number = {6},
	year = {2008},
	month = {2008 Sep 25},
	pages = {902-13},
	abstract = {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.},
	keywords = {Animals, Calcium, Calcium Channels, Calcium Signaling, Cytoplasm, Dendrites, dendritic spines, Fluorescent Dyes, Humans, Membrane Microdomains, Models, Neurological, Second Messenger Systems, Synaptic Transmission},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2008.08.020},
	author = {Higley, Michael J and Sabatini, Bernardo L}
}
@article {1790241,
	title = {Destabilization of the postsynaptic density by PSD-95 serine 73 phosphorylation inhibits spine growth and synaptic plasticity},
	journal = {Neuron},
	volume = {60},
	number = {5},
	year = {2008},
	month = {2008 Dec 10},
	pages = {788-802},
	abstract = {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.},
	keywords = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Animals, Animals, Newborn, dendritic spines, Disks Large Homolog 4 Protein, Electric Stimulation, Enzyme Inhibitors, Excitatory Amino Acid Antagonists, Glutamates, Green Fluorescent Proteins, hippocampus, Indoles, Intracellular Signaling Peptides and Proteins, Long-Term Potentiation, Membrane Proteins, Nerve Tissue Proteins, Neuronal Plasticity, Neurons, Organ Culture Techniques, Patch-Clamp Techniques, Phosphorylation, Piperazines, Point Mutation, Protein Structure, Tertiary, Protein Transport, Rats, Rats, Sprague-Dawley, Serine, Time Factors},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2008.10.014},
	author = {Steiner, Pascal and Higley, Michael J and Xu, Weifeng and Czervionke, Brian L and Malenka, Robert C and Sabatini, Bernardo L}
}
@article {1790261,
	title = {Developmental presence and disappearance of postsynaptically silent synapses on dendritic spines of rat layer 2/3 pyramidal neurons},
	journal = {J Physiol},
	volume = {586},
	number = {6},
	year = {2008},
	month = {2008 Mar 15},
	pages = {1519-27},
	abstract = {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.},
	keywords = {Action Potentials, Aging, Animals, Cells, Cultured, dendritic spines, Nerve Net, Neural Inhibition, Neuronal Plasticity, Pyramidal Cells, Rats, Rats, Sprague-Dawley, Synapses},
	issn = {1469-7793},
	doi = {10.1113/jphysiol.2007.149336},
	author = {Busetto, Giuseppe and Higley, Michael J and Sabatini, Bernardo L}
}
@article {1790256,
	title = {Pam (Protein associated with Myc) functions as an E3 ubiquitin ligase and regulates TSC/mTOR signaling},
	journal = {Cell Signal},
	volume = {20},
	number = {6},
	year = {2008},
	month = {2008 Jun},
	pages = {1084-91},
	abstract = {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.},
	keywords = {Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Cells, Cultured, Humans, Mixed Function Oxygenases, Molecular Sequence Data, Mutation, Missense, Neurons, Phosphorylation, Protein Kinases, Protein Structure, Tertiary, Rats, Signal Transduction, TOR Serine-Threonine Kinases, Tuberous Sclerosis, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitination},
	issn = {0898-6568},
	doi = {10.1016/j.cellsig.2008.01.020},
	author = {Han, Sangyeul and Witt, Rochelle M and Santos, T{\'u}lio M and Polizzano, Carolyn and Sabatini, Bernardo L and Ramesh, Vijaya}
}
@article {1790266,
	title = {Regulation of synaptic signalling by postsynaptic, non-glutamate receptor ion channels},
	journal = {J Physiol},
	volume = {586},
	number = {6},
	year = {2008},
	month = {2008 Mar 15},
	pages = {1475-80},
	abstract = {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.},
	keywords = {Animals, Calcium Signaling, Excitatory Postsynaptic Potentials, Feedback, Ion Channel Gating, Pyramidal Cells, Receptors, Glutamate, Receptors, N-Methyl-D-Aspartate, Synaptic Transmission},
	issn = {1469-7793},
	doi = {10.1113/jphysiol.2007.148353},
	author = {Bloodgood, Brenda L and Sabatini, Bernardo L}
}
@article {701996,
	title = {Amyloid-beta protein dimers isolated directly from Alzheimer{\textquoteright}s brains impair synaptic plasticity and memory},
	journal = {Nature Medicine},
	volume = {14},
	number = {8},
	year = {2008},
	pages = {837-842},
	author = {GM Shankar and Li, S and TH Mehta and A Garcia-Munoz and NE Shepardson and I Smith and FM Brett and MA Farrell and MJ Rowan and CA Lemere and CM Regan and DM Walsh and BL Sabatini and DJ Selkoe}
}
@inbook {702001,
	title = {Ca2+ Signaling in Dendritic Spines},
	booktitle = {Structural and Functional Organization of the Synapse},
	year = {2008},
	publisher = {Springer},
	organization = {Springer},
	author = {BL Sabatini and K Svoboda},
	editor = {MD Ehlers and JW Hell}
}
@article {702006,
	title = {Calcium signaling in dendrites and spines: practical and functional considerations},
	journal = {Neuron},
	volume = {59},
	number = {6},
	year = {2008},
	pages = {902-913},
	author = {MJ Higley and BL Sabatini}
}
@article {701991,
	title = {Destabilization of the postsynaptic density by PSD-95 serine 73 phosphorylation inhibits spine growth and synaptic plasticity},
	journal = {Neuron},
	volume = {60},
	number = {5},
	year = {2008},
	pages = {788-802},
	author = {P Steiner and MJ Higley and W Xu and BL Czervionke and BL Sabatini and RC Malenka}
}
@article {702021,
	title = { Developmental presence and disappearance of postsynaptically silent synapses on dendritic spines of rat layer 2/3 pyramidal neurons},
	journal = {The Journal of Physiology},
	volume = {586},
	number = {6},
	year = {2008},
	pages = {1519-1527},
	author = {G Busetto and MJ Higley and BL Sabatini}
}
@article {701986,
	title = {Molecular dissociation of the role of PSD-95 in regulating synaptic strength and LTD},
	journal = {Neuron},
	volume = {57},
	number = {2},
	year = {2008},
	pages = {248-262},
	author = {W Xu and OM Schluter and P Steiner and BL Czervionke and BL Sabatini and RC Malenka}
}
@inbook {702036,
	title = {Multiple levels of synaptic regulation by NMDA-type glutamate receptors in normal and disease states},
	booktitle = {Synaptic plasticity and the mechanism of Alzheimer{\textquoteright}s disease},
	year = {2008},
	publisher = {Springer},
	organization = {Springer},
	address = {Berlin},
	author = {VA Alvarez and GM Shankar and BL Bloodgood and DJ Selkoe and BL Sabatini},
	editor = {DJ Selkoe and A Triller and Y Christen}
}
@article {702011,
	title = { Pam (Protein associated with Myc) functions as an E3 ubiquitin ligase and regulates TSC/mTOR signaling},
	journal = {Cell Signalling},
	volume = {20},
	number = {6},
	year = {2008},
	pages = {1084-1091},
	author = {Han, S. and RM Witt and TM Santos and C Polizzano and BL Sabatini and V Ramesh}
}
@article {702026,
	title = { Regulation of synaptic signalling by postsynaptic, non-glutamate receptor ion channels},
	journal = {The Journal of Physiology},
	volume = {586},
	number = {6},
	year = {2008},
	pages = {1475-1480},
	author = {BL Bloodgood and BL Sabatini}
}
@inbook {702016,
	title = {Spine calcium signaling},
	booktitle = {Dendrites},
	year = {2008},
	publisher = {Oxford University Press},
	organization = {Oxford University Press},
	edition = {2},
	author = {AG Carter and BL Sabatini},
	editor = {G Stuart and N Spruston and M Hausser}
}
@article {1790311,
	title = {Anatomical and physiological plasticity of dendritic spines},
	journal = {Annu Rev Neurosci},
	volume = {30},
	year = {2007},
	month = {2007},
	pages = {79-97},
	abstract = {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.},
	keywords = {Aging, Animals, Brain, dendritic spines, Humans, Membrane Potentials, Neural Pathways, Neuronal Plasticity, Sensation, Synapses, Synaptic Transmission},
	issn = {0147-006X},
	doi = {10.1146/annurev.neuro.30.051606.094222},
	author = {Alvarez, Veronica A and Sabatini, Bernardo L}
}
@article {1790291,
	title = {Ca(2+) signaling in dendritic spines},
	journal = {Curr Opin Neurobiol},
	volume = {17},
	number = {3},
	year = {2007},
	month = {2007 Jun},
	pages = {345-51},
	abstract = {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.},
	keywords = {Animals, Calcium, Calcium Channels, Calcium Signaling, dendritic spines, Models, Biological, Neurons, Receptors, Glutamate},
	issn = {0959-4388},
	doi = {10.1016/j.conb.2007.04.003},
	author = {Bloodgood, Brenda L and Sabatini, Bernardo L}
}
@article {1790296,
	title = {Dendritic spine detection using curvilinear structure detector and LDA classifier},
	journal = {Neuroimage},
	volume = {36},
	number = {2},
	year = {2007},
	month = {2007 Jun},
	pages = {346-60},
	abstract = {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.},
	keywords = {Algorithms, Artificial Intelligence, Computer graphics, Dendrites, Discriminant Analysis, Image Enhancement, Image Interpretation, Computer-Assisted, Imaging, Three-Dimensional, Numerical Analysis, Computer-Assisted, Pattern Recognition, Automated, Reproducibility of Results, Sensitivity and Specificity, Ultrasonography},
	issn = {1053-8119},
	doi = {10.1016/j.neuroimage.2007.02.044},
	author = {Zhang, Yong and Zhou, Xiaobo and Witt, Rochelle M and Sabatini, Bernardo L and Adjeroh, Donald and Wong, Stephen T C}
}
@article {1790286,
	title = {Distinct structural and ionotropic roles of NMDA receptors in controlling spine and synapse stability},
	journal = {J Neurosci},
	volume = {27},
	number = {28},
	year = {2007},
	month = {2007 Jul 11},
	pages = {7365-76},
	abstract = {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.},
	keywords = {Animals, dendritic spines, Disks Large Homolog 4 Protein, Electric Conductivity, Excitatory Postsynaptic Potentials, hippocampus, In Vitro Techniques, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Neuronal Plasticity, Pyramidal Cells, Rats, Rats, Sprague-Dawley, Receptors, AMPA, Receptors, N-Methyl-D-Aspartate, RNA Interference, Signal Transduction, Synapses},
	issn = {1529-2401},
	doi = {10.1523/JNEUROSCI.0956-07.2007},
	author = {Alvarez, Veronica A and Ridenour, Dennis A and Sabatini, Bernardo L}
}
@article {1790301,
	title = {Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway},
	journal = {J Neurosci},
	volume = {27},
	number = {11},
	year = {2007},
	month = {2007 Mar 14},
	pages = {2866-75},
	abstract = {Alzheimer{\textquoteright}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.},
	keywords = {Alzheimer Disease, Amyloid beta-Peptides, Animals, Cells, Cultured, CHO Cells, Cricetinae, Cricetulus, Excitatory Postsynaptic Potentials, Humans, Rats, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate, Signal Transduction, Synapses},
	issn = {1529-2401},
	doi = {10.1523/JNEUROSCI.4970-06.2007},
	author = {Shankar, Ganesh M and Bloodgood, Brenda L and Townsend, Matthew and Walsh, Dominic M and Selkoe, Dennis J and Sabatini, Bernardo L}
}
@article {1790271,
	title = {Neuroscience: neighbourly synapses},
	journal = {Nature},
	volume = {450},
	number = {7173},
	year = {2007},
	month = {2007 Dec 20},
	pages = {1173-5},
	keywords = {Animals, Dendrites, Glutamic Acid, Humans, Learning, Long-Term Potentiation, Mice, Models, Neurological, Pyramidal Cells, Synapses},
	issn = {1476-4687},
	doi = {10.1038/4501173a},
	author = {Sabatini, Bernardo L}
}
@article {1790306,
	title = {Nonlinear regulation of unitary synaptic signals by CaV(2.3) voltage-sensitive calcium channels located in dendritic spines},
	journal = {Neuron},
	volume = {53},
	number = {2},
	year = {2007},
	month = {2007 Jan 18},
	pages = {249-60},
	abstract = {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.},
	keywords = {Animals, Calcium, Calcium Channels, R-Type, Cation Transport Proteins, dendritic spines, Electrophysiology, Excitatory Postsynaptic Potentials, hippocampus, In Vitro Techniques, Ion Channel Gating, Mice, Mice, Inbred C57BL, Protein Structure, Tertiary, Pyramidal Cells, Receptors, N-Methyl-D-Aspartate, Small-Conductance Calcium-Activated Potassium Channels, Sodium Channels, Synapses, Temperature},
	issn = {0896-6273},
	doi = {10.1016/j.neuron.2006.12.017},
	author = {Bloodgood, Brenda L and Sabatini, Bernardo L}
}
@article {1790276,
	title = {A novel computational approach for automatic dendrite spines detection in two-photon laser scan microscopy},
	journal = {J Neurosci Methods},
	volume = {165},
	number = {1},
	year = {2007},
	month = {2007 Sep 15},
	pages = {122-34},
	abstract = {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.},
	keywords = {Algorithms, dendritic spines, Image Processing, Computer-Assisted, Microscopy, Confocal, Photons},
	issn = {0165-0270},
	doi = {10.1016/j.jneumeth.2007.05.020},
	author = {Cheng, Jie and Zhou, Xiaobo and Eric Miller and Witt, Rochelle M and Zhu, Jinmin and Sabatini, Bernardo L and Wong, Steven T C}
}
@article {1790281,
	title = {Timing and location of synaptic inputs determine modes of subthreshold integration in striatal medium spiny neurons},
	journal = {J Neurosci},
	volume = {27},
	number = {33},
	year = {2007},
	month = {2007 Aug 15},
	pages = {8967-77},
	abstract = {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.},
	keywords = {Animals, Animals, Newborn, Calcium, Corpus Striatum, dendritic spines, Electric Stimulation, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Glutamic Acid, In Vitro Techniques, Neurons, Nonlinear Dynamics, Patch-Clamp Techniques, Rats, Rats, Sprague-Dawley, Receptors, AMPA, Synapses},
	issn = {1529-2401},
	doi = {10.1523/JNEUROSCI.2798-07.2007},
	author = {Carter, Adam G and Soler-Llavina, Gilberto J and Sabatini, Bernardo L}
}
@article {701906,
	title = { Anatomical and physiological plasticity of dendritic spines},
	journal = {Annual Review of Neuroscience},
	volume = {30},
	year = {2007},
	pages = {79-97},
	author = {VA Alvarez and BL Sabatini}
}
@article {701896,
	title = {Ca(2+) signaling in dendritic spines},
	journal = {Current Opinion in Neurobiology},
	volume = {17},
	number = {3},
	year = {2007},
	pages = {345-351},
	author = {BL Bloodgood and BL Sabatini}
}
@article {701846,
	title = {Dendritic spine detection using curvilinear structure detector and LDA classifier},
	journal = {Neuroimage},
	volume = {36},
	number = {2},
	year = {2007},
	pages = {346-360},
	author = {Zhang, Y. and X. Zhou and R.M. Witt and B.L. Sabatini and D. Adjeroh and S.T. Wong}
}
@article {701916,
	title = {Distinct structural and ionotropic roles of NMDA receptors in controlling spine and synapse stability},
	journal = {Journal of Neuroscience},
	volume = {27},
	number = {28},
	year = {2007},
	pages = {7365-7376},
	author = {VA Alvarez and DA Ridenour and BL Sabatini}
}
@article {701861,
	title = {Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway},
	journal = {Journal of Neuroscience},
	volume = {27},
	number = {11},
	year = {2007},
	pages = {2866-2875},
	author = {G.M. Shankar and B.L. Bloodgood and M. Townsend and D.M. Walsh and D.J. Selkoe and B.L. Sabatini}
}
@article {701871,
	title = {Neuroscience: neighbourly synapses},
	journal = {Nature},
	volume = {450},
	number = {7173},
	year = {2007},
	pages = {1173-1175},
	author = {B.L. Sabatini}
}
@article {701901,
	title = {Nonlinear regulation of unitary synaptic signals by CaV(2.3) voltage-sensitive calcium channels located in dendritic spines},
	journal = {Neuron},
	volume = {53},
	number = {2},
	year = {2007},
	pages = {249-260},
	author = {BL Bloodgood and BL Sabatini}
}
@article {701886,
	title = { A novel computational approach for automatic dendrite spines detection in two-photon laser scan microscopy},
	journal = {Journal of Neuroscience Methods},
	volume = {165},
	number = {1},
	year = {2007},
	pages = {122-134},
	author = {J Cheng and X Zhou and E. Miller and RM Witt and Zhu, J. and BL Sabatini and ST Wong}
}
@article {701891,
	title = {Timing and location of synaptic inputs determine modes of subthreshold integration in striatal medium spiny neurons},
	journal = {Journal of Neuroscience},
	volume = {27},
	number = {33},
	year = {2007},
	pages = {8967-8977},
	author = {AG Carter and GJ Soler-Llavina and BL Sabatini}
}
@article {1790326,
	title = {Mutual information-based feature selection in studying perturbation of dendritic structure caused by TSC2 inactivation},
	journal = {Neuroinformatics},
	volume = {4},
	number = {1},
	year = {2006},
	month = {2006 Winter},
	pages = {81-94},
	abstract = {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.},
	keywords = {Algorithms, Animals, Cell Differentiation, Cell Shape, Cerebral Cortex, dendritic spines, Gene Silencing, Green Fluorescent Proteins, Image Cytometry, Microscopy, Confocal, Molecular Chaperones, Organ Culture Techniques, Pyramidal Cells, Rats, RNA Interference, Sirolimus, Software, Tuberous Sclerosis, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins},
	issn = {1539-2791},
	doi = {10.1385/NI:4:1:81},
	author = {Zhou, Xiaobo and Zhu, Jinmin and Liu, Kuang-Yu and Sabatini, Bernardo L and Wong, Stephen T C}
}
@article {1790316,
	title = {Retraction of synapses and dendritic spines induced by off-target effects of RNA interference},
	journal = {J Neurosci},
	volume = {26},
	number = {30},
	year = {2006},
	month = {2006 Jul 26},
	pages = {7820-5},
	abstract = {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.},
	keywords = {Adaptation, Physiological, Animals, Cells, Cultured, dendritic spines, hippocampus, Nerve Tissue Proteins, Rats, Rats, Sprague-Dawley, RNA Interference, Synapses},
	issn = {1529-2401},
	doi = {10.1523/JNEUROSCI.1957-06.2006},
	author = {Alvarez, Veronica A and Ridenour, Dennis A and Sabatini, Bernardo L}
}
@article {1790321,
	title = {Synapse-specific plasticity and compartmentalized signaling in cerebellar stellate cells},
	journal = {Nat Neurosci},
	volume = {9},
	number = {6},
	year = {2006},
	month = {2006 Jun},
	pages = {798-806},
	abstract = {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.},
	keywords = {Animals, Calcium, Calcium Channels, Calcium Signaling, Cell Compartmentation, Cerebellar Cortex, Dendrites, Electric Stimulation, Excitatory Amino Acid Antagonists, Interneurons, Long-Term Synaptic Depression, Neuronal Plasticity, Organ Culture Techniques, Parvalbumins, Patch-Clamp Techniques, Rats, Receptor, Cannabinoid, CB1, Receptors, AMPA, Receptors, Metabotropic Glutamate, Signal Transduction, Synapses, Synaptic Membranes, Synaptic Transmission},
	issn = {1097-6256},
	doi = {10.1038/nn1698},
	author = {Soler-Llavina, Gilberto J and Sabatini, Bernardo L}
}
@article {701806,
	title = {Mutual information-based feature selection in studying perturbation of dendritic structure caused by TSC2 inactivation},
	journal = {Neuroinformatics},
	volume = {4},
	number = {1},
	year = {2006},
	pages = {81-94},
	author = {X. Zhou and Zhu, J. and K.Y. Liu and B.L. Sabatini and S.T. Wong}
}
@article {701831,
	title = {Retraction of synapses and dendritic spines induced by off-target effects of RNA interference},
	journal = {Journal of Neuroscience},
	volume = {26},
	number = {30},
	year = {2006},
	pages = {7820-7825},
	author = {V.A. Alvarez and D.A. Ridenour and B.L. Sabatini}
}
@article {701816,
	title = {Synapse-specific plasticity and compartmentalized signaling in cerebellar stellate cells},
	journal = {Nature Neuroscience},
	volume = {9},
	number = {6},
	year = {2006},
	pages = {798-806},
	author = {G.J. Soler-Llavina and B.L. Sabatini}
}
@article {1790336,
	title = {Neuronal activity regulates diffusion across the neck of dendritic spines},
	journal = {Science},
	volume = {310},
	number = {5749},
	year = {2005},
	month = {2005 Nov 04},
	pages = {866-9},
	abstract = {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.},
	keywords = {Action Potentials, Animals, Cytoplasm, Dendrites, dendritic spines, Diffusion, Excitatory Postsynaptic Potentials, Fluorescence, GABA-A Receptor Antagonists, Glutamic Acid, Green Fluorescent Proteins, hippocampus, Neurons, Organ Culture Techniques, Patch-Clamp Techniques, Pyramidal Cells, Rats, Rats, Sprague-Dawley, Receptors, AMPA, Receptors, GABA-A, Receptors, N-Methyl-D-Aspartate, Synapses, Synaptic Transmission, Transfection, Viscosity},
	issn = {1095-9203},
	doi = {10.1126/science.1114816},
	author = {Bloodgood, Brenda L and Sabatini, Bernardo L}
}
@article {1790331,
	title = {Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2},
	journal = {Nat Neurosci},
	volume = {8},
	number = {12},
	year = {2005},
	month = {2005 Dec},
	pages = {1727-34},
	abstract = {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.},
	keywords = {Animals, Brain, Cell Differentiation, Cell Line, Cell Shape, Cofilin 1, dendritic spines, Gene Expression Regulation, Developmental, hippocampus, Humans, Mice, Mice, Knockout, Mice, Transgenic, Neurons, Phosphorylation, Pyramidal Cells, Rats, Rats, Sprague-Dawley, Tuberous Sclerosis, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins},
	issn = {1097-6256},
	doi = {10.1038/nn1566},
	author = {Tavazoie, Sohail F and Alvarez, Veronica A and Ridenour, Dennis A and Kwiatkowski, David J and Sabatini, Bernardo L}
}
@article {1790341,
	title = {SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines},
	journal = {Nat Neurosci},
	volume = {8},
	number = {5},
	year = {2005},
	month = {2005 May},
	pages = {642-9},
	abstract = {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.},
	keywords = {Animals, Animals, Newborn, Apamin, Calcium, Calcium Signaling, Cells, Cultured, dendritic spines, Excitatory Postsynaptic Potentials, Feedback, Physiological, hippocampus, Immunohistochemistry, Magnesium, Mice, Mice, Inbred C57BL, Neuronal Plasticity, Organ Culture Techniques, Potassium Channel Blockers, Potassium Channels, Calcium-Activated, Receptors, N-Methyl-D-Aspartate, Small-Conductance Calcium-Activated Potassium Channels, Synaptic Transmission},
	issn = {1097-6256},
	doi = {10.1038/nn1449},
	author = {Ngo-Anh, Thu Jennifer and Bloodgood, Brenda L and Lin, Michael and Sabatini, Bernardo L and Maylie, James and Adelman, John P}
}
@article {701796,
	title = {Neuronal activity regulates diffusion across the neck of dendritic spines},
	journal = {Science},
	volume = {310},
	number = {5749},
	year = {2005},
	pages = {866-869},
	author = {B.L. Bloodgood and B.L. Sabatini}
}
@article {701781,
	title = {Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2},
	journal = {Nature Neuroscience},
	volume = {8},
	number = {12},
	year = {2005},
	pages = {1727-1734},
	author = {S.F. Tavazoie and V.A. Alvarez and D.A. Ridenour and B.L. Sabatini}
}
@article {701791,
	title = {SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines},
	journal = {Nature Neuroscience},
	volume = {8},
	number = {5},
	year = {2005},
	pages = {642-649},
	author = {T.J. Ngo-Anh and B.L. Bloodgood and M. Lin and B.L. Sabatini and J. Maylie and J.P. Adelman}
}
@article {1790351,
	title = {Imaging calcium concentration dynamics in small neuronal compartments},
	journal = {Sci STKE},
	volume = {2004},
	number = {219},
	year = {2004},
	month = {2004 Feb 03},
	pages = {pl5},
	abstract = {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.},
	keywords = {Animals, Calcium Signaling, Cell Compartmentation, Dendrites, hippocampus, Image Processing, Computer-Assisted, Lasers, Microscopy, Fluorescence, Multiphoton, Neurons, Patch-Clamp Techniques, Rats},
	issn = {1525-8882},
	doi = {10.1126/stke.2192004pl5},
	author = {Yasuda, Ryohei and Nimchinsky, Esther A and Scheuss, Volker and Pologruto, Thomas A and Oertner, Thomas G and Sabatini, Bernardo L and Svoboda, Karel}
}
@article {1790346,
	title = {State-dependent calcium signaling in dendritic spines of striatal medium spiny neurons},
	journal = {Neuron},
	volume = {44},
	number = {3},
	year = {2004},
	month = {2004 Oct 28},
	pages = {483-93},
	abstract = {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.},
	keywords = {Animals, Calcium, Calcium Channel Blockers, Calcium Signaling, Corpus Striatum, dendritic spines, Dose-Response Relationship, Radiation, Drug Combinations, Electric Stimulation, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Glutamates, In Vitro Techniques, Magnesium, Membrane Potentials, Microscopy, Confocal, Neurons, Patch-Clamp Techniques, Rats, Synapses, Tetrodotoxin},
	issn = {0896-6273},
	doi = {10.1016/j.neuron.2004.10.013},
	author = {Carter, Adam G and Sabatini, Bernardo L}
}
@article {701751,
	title = {State-dependent calcium signaling in dendritic spines of striatal medium spiny neurons},
	journal = {Neuron},
	volume = {44},
	number = {3},
	year = {2004},
	pages = {483-493},
	author = {Adam G. Carter and Bernardo L. Sabatini}
}
@article {1790356,
	title = {Plasticity of calcium channels in dendritic spines},
	journal = {Nat Neurosci},
	volume = {6},
	number = {9},
	year = {2003},
	month = {2003 Sep},
	pages = {948-55},
	abstract = {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.},
	keywords = {Action Potentials, Animals, Calcium, Calcium Channels, R-Type, Dendrites, hippocampus, In Vitro Techniques, Neuronal Plasticity, Rats},
	issn = {1097-6256},
	doi = {10.1038/nn1112},
	author = {Yasuda, Ryohei and Sabatini, Bernardo L and Svoboda, Karel}
}
@article {1790361,
	title = {ScanImage: flexible software for operating laser scanning microscopes},
	journal = {Biomed Eng Online},
	volume = {2},
	year = {2003},
	month = {2003 May 17},
	pages = {13},
	abstract = {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.},
	keywords = {Equipment Design, Image Enhancement, Microscopy, Confocal, Signal Processing, Computer-Assisted, Software, Software Design, User-Computer Interface},
	issn = {1475-925X},
	doi = {10.1186/1475-925X-2-13},
	author = {Pologruto, Thomas A and Sabatini, Bernardo L and Svoboda, Karel}
}
@article {1790366,
	title = {Facilitation at single synapses probed with optical quantal analysis},
	journal = {Nat Neurosci},
	volume = {5},
	number = {7},
	year = {2002},
	month = {2002 Jul},
	pages = {657-64},
	abstract = {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 (\&gt;5) independent release sites per active zone, suggesting that multivesicular release contributes to facilitation at these synapses.},
	keywords = {2-Chloroadenosine, Action Potentials, Animals, Calcium, Calcium Signaling, Electric Stimulation, Excitatory Postsynaptic Potentials, Glutamic Acid, In Vitro Techniques, Neuronal Plasticity, Neurotransmitter Agents, Presynaptic Terminals, Pyramidal Cells, Rats, Receptors, N-Methyl-D-Aspartate, Receptors, Purinergic P1, Sensory Thresholds, Synapses},
	issn = {1097-6256},
	doi = {10.1038/nn867},
	author = {Oertner, Thomas G and Sabatini, Bernardo L and Nimchinsky, Esther A and Svoboda, Karel}
}
@article {1790371,
	title = {The life cycle of Ca(2+) ions in dendritic spines},
	journal = {Neuron},
	volume = {33},
	number = {3},
	year = {2002},
	month = {2002 Jan 31},
	pages = {439-52},
	abstract = {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+).},
	keywords = {Action Potentials, Animals, Bicuculline, Buffers, Calcium, Cells, Cultured, Dendrites, Excitatory Amino Acid Antagonists, Fluorescent Dyes, GABA Antagonists, hippocampus, In Vitro Techniques, Mathematics, Microscopy, Confocal, Models, Neurological, Neurons, Quinoxalines, Rats, Receptors, N-Methyl-D-Aspartate},
	issn = {0896-6273},
	doi = {10.1016/s0896-6273(02)00573-1},
	author = {Sabatini, Bernardo L and Oertner, Thomas G and Svoboda, Karel}
}
@article {1790376,
	title = {Structure and function of dendritic spines},
	journal = {Annu Rev Physiol},
	volume = {64},
	year = {2002},
	month = {2002},
	pages = {313-53},
	abstract = {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.},
	keywords = {Animals, Calcium Channels, Dendrites, Receptors, N-Methyl-D-Aspartate},
	issn = {0066-4278},
	doi = {10.1146/annurev.physiol.64.081501.160008},
	author = {Nimchinsky, Esther A and Sabatini, Bernardo L and Svoboda, Karel}
}
@article {1790381,
	title = {Ca(2+) signaling in dendritic spines},
	journal = {Curr Opin Neurobiol},
	volume = {11},
	number = {3},
	year = {2001},
	month = {2001 Jun},
	pages = {349-56},
	abstract = {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.},
	keywords = {Action Potentials, Animals, Calcium Channels, Calcium Signaling, Cell Compartmentation, Dendrites, Humans, Ion Channel Gating, Ion Transport, Mice, Mice, Knockout, Nerve Tissue Proteins, Neuronal Plasticity, Purkinje Cells, Pyramidal Cells, Rats, Rats, Mutant Strains, Receptors, N-Methyl-D-Aspartate, Signal Transduction, Synaptic Transmission},
	issn = {0959-4388},
	doi = {10.1016/s0959-4388(00)00218-x},
	author = {BL Sabatini and Maravall, M and K Svoboda}
}
@article {1790386,
	title = {Analysis of calcium channels in single spines using optical fluctuation analysis},
	journal = {Nature},
	volume = {408},
	number = {6812},
	year = {2000},
	month = {2000 Nov 30},
	pages = {589-93},
	abstract = {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.},
	keywords = {Action Potentials, Animals, Calcium Channels, Dendrites, In Vitro Techniques, Membrane Potentials, Microscopy, Confocal, Pyramidal Cells, Rats, Receptors, GABA-B, Synaptic Membranes},
	issn = {0028-0836},
	doi = {10.1038/35046076},
	author = {BL Sabatini and K Svoboda}
}
@article {1790391,
	title = {Estimating intracellular calcium concentrations and buffering without wavelength ratioing},
	journal = {Biophys J},
	volume = {78},
	number = {5},
	year = {2000},
	month = {2000 May},
	pages = {2655-67},
	abstract = {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{\textquoteright}, N{\textquoteright}-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.},
	keywords = {Action Potentials, Animals, Biophysical Phenomena, Biophysics, Buffers, Calcium, Calcium Signaling, In Vitro Techniques, Intracellular Fluid, Models, Biological, Pyramidal Cells, Rats},
	issn = {0006-3495},
	doi = {10.1016/S0006-3495(00)76809-3},
	author = {Maravall, M and Z.F. Mainen and BL Sabatini and K Svoboda}
}
@article {1790396,
	title = {Timing of synaptic transmission},
	journal = {Annu Rev Physiol},
	volume = {61},
	year = {1999},
	month = {1999},
	pages = {521-42},
	abstract = {Many behaviors require rapid and precisely timed synaptic transmission. These include the determination of a sound{\textquoteright}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.},
	keywords = {Action Potentials, Animals, Calcium, Neural Conduction, Presynaptic Terminals, Reaction Time, Synapses, Synaptic Transmission, Time Factors},
	issn = {0066-4278},
	doi = {10.1146/annurev.physiol.61.1.521},
	author = {BL Sabatini and WG Regehr}
}
@article {1790401,
	title = {Optical measurement of presynaptic calcium currents},
	journal = {Biophys J},
	volume = {74},
	number = {3},
	year = {1998},
	month = {1998 Mar},
	pages = {1549-63},
	abstract = {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.},
	keywords = {Action Potentials, Animals, Calcium, Calcium Channels, Cerebellum, Electric Stimulation, Evoked Potentials, Fluorescent Dyes, Fura-2, In Vitro Techniques, Kinetics, Models, Chemical, Nerve Fibers, Presynaptic Terminals, Rats, Rats, Sprague-Dawley, Spectrometry, Fluorescence, Temperature},
	issn = {0006-3495},
	doi = {10.1016/S0006-3495(98)77867-1},
	author = {BL Sabatini and WG Regehr}
}
@article {1790406,
	title = {Control of neurotransmitter release by presynaptic waveform at the granule cell to Purkinje cell synapse},
	journal = {J Neurosci},
	volume = {17},
	number = {10},
	year = {1997},
	month = {1997 May 15},
	pages = {3425-35},
	abstract = {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.},
	keywords = {Action Potentials, Animals, Calcium, Calcium Channels, Fluorescent Dyes, Glutamic Acid, Ion Channel Gating, Neurotransmitter Agents, Patch-Clamp Techniques, Potassium Channel Blockers, Presynaptic Terminals, Purkinje Cells, Pyridinium Compounds, Rats, Rats, Sprague-Dawley, Sensitivity and Specificity, Synapses, Synaptic Transmission, Tetraethylammonium, Tetraethylammonium Compounds},
	issn = {0270-6474},
	doi = {10.1523/JNEUROSCI.17-10-03425.1997},
	author = {BL Sabatini and WG Regehr}
}
@article {1790411,
	title = {Timing of neurotransmission at fast synapses in the mammalian brain},
	journal = {Nature},
	volume = {384},
	number = {6605},
	year = {1996},
	month = {1996 Nov 14},
	pages = {170-2},
	abstract = {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.},
	keywords = {Action Potentials, Animals, Calcium, Cerebellum, In Vitro Techniques, Models, Neurological, Rats, Reaction Time, Synapses, Synaptic Transmission, Temperature},
	issn = {0028-0836},
	doi = {10.1038/384170a0},
	author = {BL Sabatini and WG Regehr}
}
@article {1790421,
	title = {Calcium control of transmitter release at a cerebellar synapse},
	journal = {Neuron},
	volume = {15},
	number = {3},
	year = {1995},
	month = {1995 Sep},
	pages = {675-88},
	abstract = {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.},
	keywords = {Animals, Benzofurans, Cadmium, Calcium, Calcium Channel Blockers, Calcium Channels, Cerebellum, Electric Conductivity, Fluorescent Dyes, Fura-2, Neurotransmitter Agents, omega-Agatoxin IVA, omega-Conotoxin GVIA, Oxazoles, Peptides, Purkinje Cells, Rats, Spider Venoms, Synapses},
	issn = {0896-6273},
	doi = {10.1016/0896-6273(95)90155-8},
	author = {Mintz, I M and BL Sabatini and WG Regehr}
}
@article {1790416,
	title = {Detecting changes in calcium influx which contribute to synaptic modulation in mammalian brain slice},
	journal = {Neuropharmacology},
	volume = {34},
	number = {11},
	year = {1995},
	month = {1995 Nov},
	pages = {1453-67},
	abstract = {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.},
	keywords = {1-Methyl-3-isobutylxanthine, Animals, Calcium, Calcium Channels, Cerebellum, Electrophysiology, Fluorescent Dyes, In Vitro Techniques, Phosphodiesterase Inhibitors, Presynaptic Terminals, Purinergic P1 Receptor Antagonists, Rats, Spectrometry, Fluorescence, Synaptic Transmission},
	issn = {0028-3908},
	doi = {10.1016/0028-3908(95)00129-t},
	author = {BL Sabatini and WG Regehr}
}
@article {1790236,
	year = {Published}
}
