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      Cell-type Specific Optogenetic Mice for Dissecting Neural Circuitry Function

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          Abstract

          Optogenetic methods have emerged as powerful tools for dissecting neural circuit connectivity, function, and dysfunction. We used a Bacterial Artificial Chromosome (BAC) transgenic strategy to express Channelrhodopsin2 (ChR2) under the control of cell-type specific promoter elements. We provide a detailed functional characterization of the newly established VGAT-ChR2-EYFP, ChAT-ChR2-EYFP, TPH2-ChR2-EYFP and Pvalb-ChR2-EYFP BAC transgenic mouse lines and demonstrate the utility of these lines for precisely controlling action potential firing of GABAergic, cholinergic, serotonergic, and parvalbumin+ neuron subsets using blue light. This resource of cell type-specific ChR2 mouse lines will facilitate the precise mapping of neuronal connectivity and the dissection of the neural basis of behavior.

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          Most cited references 36

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          Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

          Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. Shank3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for development of 22q13 deletion syndrome (Phelan-McDermid Syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for Shank3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic like-behaviours in mice.
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            Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning.

            Natural rewards and drugs of abuse can alter dopamine signaling, and ventral tegmental area (VTA) dopaminergic neurons are known to fire action potentials tonically or phasically under different behavioral conditions. However, without technology to control specific neurons with appropriate temporal precision in freely behaving mammals, the causal role of these action potential patterns in driving behavioral changes has been unclear. We used optogenetic tools to selectively stimulate VTA dopaminergic neuron action potential firing in freely behaving mammals. We found that phasic activation of these neurons was sufficient to drive behavioral conditioning and elicited dopamine transients with magnitudes not achieved by longer, lower-frequency spiking. These results demonstrate that phasic dopaminergic activity is sufficient to mediate mammalian behavioral conditioning.
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              Neural substrates of awakening probed with optogenetic control of hypocretin neurons.

              The neural underpinnings of sleep involve interactions between sleep-promoting areas such as the anterior hypothalamus, and arousal systems located in the posterior hypothalamus, the basal forebrain and the brainstem. Hypocretin (Hcrt, also known as orexin)-producing neurons in the lateral hypothalamus are important for arousal stability, and loss of Hcrt function has been linked to narcolepsy. However, it is unknown whether electrical activity arising from Hcrt neurons is sufficient to drive awakening from sleep states or is simply correlated with it. Here we directly probed the impact of Hcrt neuron activity on sleep state transitions with in vivo neural photostimulation, genetically targeting channelrhodopsin-2 to Hcrt cells and using an optical fibre to deliver light deep in the brain, directly into the lateral hypothalamus, of freely moving mice. We found that direct, selective, optogenetic photostimulation of Hcrt neurons increased the probability of transition to wakefulness from either slow wave sleep or rapid eye movement sleep. Notably, photostimulation using 5-30 Hz light pulse trains reduced latency to wakefulness, whereas 1 Hz trains did not. This study establishes a causal relationship between frequency-dependent activity of a genetically defined neural cell type and a specific mammalian behaviour central to clinical conditions and neurobehavioural physiology.
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                Author and article information

                Journal
                101215604
                32338
                Nat Methods
                Nature methods
                1548-7091
                1548-7105
                8 August 2011
                2011
                12 October 2011
                : 8
                : 9
                : 745-752
                Affiliations
                [1 ]Department of Neurobiology, Duke University Medical Center, Durham NC 27710, USA
                [2 ]McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA
                [3 ]National Institute of Biological Sciences, Beijing, 102206, China
                [4 ]Duke NeuroTransgenic Laboratory, Duke University Medical Center, Durham NC 27710, USA
                [5 ]Center for Functional Connectomics, Korea Institute of Science and Technology, 39-1 Hawolgokdong, Seongbukgu, Seoul, 136-791 Republic of Korea
                [6 ]Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore
                [7 ]A*STAR/Duke-NUS Neuroscience Research Partnership, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
                [8 ]Department of Bioengineering, Stanford University, CA 94305, USA
                Author notes
                [9]

                These authors contributed equally to this work.

                Corresponding author – Guoping Feng ( fengg@ 123456mit.edu )
                Article
                nihpa311754
                3191888
                21985008

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