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      Genetic dissection of an amygdala microcircuit that gates conditioned fear

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          Abstract

          The role of different amygdala nuclei (neuroanatomical subdivisions) in processing Pavlovian conditioned fear has been studied extensively, but the function of the heterogeneous neuronal subtypes within these nuclei remains poorly understood. We used molecular genetic approaches to map the functional connectivity of a subpopulation of GABAergic neurons, located in the lateral subdivision of the central amygdala (CEl), which express protein kinase C-delta (PKCδ). Channelrhodopsin-2 assisted circuit mapping in amygdala slices and cell-specific viral tracing indicate that PKCδ + neurons inhibit output neurons in the medial CE (CEm), and also make reciprocal inhibitory synapses with PKCδ neurons in CEl. Electrical silencing of PKCδ + neurons in vivo suggests that they correspond to physiologically identified units that are inhibited by the conditioned stimulus (CS), called CEl off units (Ciocchi et al, this issue). This correspondence, together with behavioral data, defines an inhibitory microcircuit in CEl that gates CEm output to control the level of conditioned freezing.

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          Most cited references36

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          A gene expression atlas of the central nervous system based on bacterial artificial chromosomes.

          The mammalian central nervous system (CNS) contains a remarkable array of neural cells, each with a complex pattern of connections that together generate perceptions and higher brain functions. Here we describe a large-scale screen to create an atlas of CNS gene expression at the cellular level, and to provide a library of verified bacterial artificial chromosome (BAC) vectors and transgenic mouse lines that offer experimental access to CNS regions, cell classes and pathways. We illustrate the use of this atlas to derive novel insights into gene function in neural cells, and into principal steps of CNS development. The atlas, library of BAC vectors and BAC transgenic mice generated in this screen provide a rich resource that allows a broad array of investigations not previously available to the neuroscience community.
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            Correction of multi-gene deficiency in vivo using a single 'self-cleaving' 2A peptide-based retroviral vector.

            Attempts to generate reliable and versatile vectors for gene therapy and biomedical research that express multiple genes have met with limited success. Here we used Picornavirus 'self-cleaving' 2A peptides, or 2A-like sequences from other viruses, to generate multicistronic retroviral vectors with efficient translation of four cistrons. Using the T-cell receptor:CD3 complex as a test system, we show that a single 2A peptide-linked retroviral vector can be used to generate all four CD3 proteins (CD3epsilon, gamma, delta, zeta), and restore T-cell development and function in CD3-deficient mice. We also show complete 2A peptide-mediated 'cleavage' and stoichiometric production of two fluorescent proteins using a fluorescence resonance energy transfer-based system in multiple cell types including blood, thymus, spleen, bone marrow and early stem cell progenitors.
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              Switching on and off fear by distinct neuronal circuits.

              Switching between exploratory and defensive behaviour is fundamental to survival of many animals, but how this transition is achieved by specific neuronal circuits is not known. Here, using the converse behavioural states of fear extinction and its context-dependent renewal as a model in mice, we show that bi-directional transitions between states of high and low fear are triggered by a rapid switch in the balance of activity between two distinct populations of basal amygdala neurons. These two populations are integrated into discrete neuronal circuits differentially connected with the hippocampus and the medial prefrontal cortex. Targeted and reversible neuronal inactivation of the basal amygdala prevents behavioural changes without affecting memory or expression of behaviour. Our findings indicate that switching between distinct behavioural states can be triggered by selective activation of specific neuronal circuits integrating sensory and contextual information. These observations provide a new framework for understanding context-dependent changes of fear behaviour.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                8 February 2013
                11 November 2010
                14 March 2013
                : 468
                : 7321
                : 270-276
                Affiliations
                [1 ]Division of Biology 216-76, California Institute of Technology, Pasadena, CA USA 91125
                [2 ]Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA USA 91125
                [3 ]Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland
                [4 ]Systems Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037
                [5 ]Department of Psychology and the Brain Research Institute, University of California, Los Angeles, Los Angeles, CA 90095
                [6 ]Laboratory for Neuroimaging, University of California, Los Angeles, Los Angeles, CA 90095
                [7 ]Department of Bioengineering, Stanford University, Stanford, CA 94305
                Author notes
                [8 ]Author for correspondence: wuwei@ 123456caltech.edu , Tel: (626) 395-6821/8374 FAX: (626) 564-8243
                [*]

                These authors made equal contributions

                Article
                NIHMS243118
                10.1038/nature09553
                3597095
                21068836
                b98e9d8e-8ead-4611-8f68-efc5dcfb8142

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