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      A Circuit Mechanism for Differentiating Positive and Negative Associations

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          Abstract

          The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Synaptic plasticity in the basolateral amygdala complex (BLA) mediates the acquisition of associative memories, both positive 1, 2 and negative 37 . Different populations of BLA neurons may encode fearful or rewarding associations 810 , but the identifying features of these populations and the synaptic mechanisms of differentiating positive and negative emotional valence have remained an enigma. Here, we show that BLA neurons projecting to the nucleus accumbens (NAc projectors) or the centromedial amygdala (CeM projectors) underwent opposing synaptic changes following fear or reward conditioning. We found that photostimulation of NAc projectors supports positive reinforcement while photostimulation of CeM projectors mediates negative reinforcement. Photoinhibition of CeM projectors impaired fear conditioning and enhanced reward conditioning. We then characterized these functionally-distinct neuronal populations by comparing their electrophysiological, morphological and genetic features. We provide a mechanistic explanation for the representation of positive and negative associations within the amygdala.

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          Most cited references30

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          Dendritic organization in the neurons of the visual and motor cortices of the cat.

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            The role of the amygdala in fear and anxiety.

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              Amygdala circuitry mediating reversible and bidirectional control of anxiety.

              Anxiety--a sustained state of heightened apprehension in the absence of immediate threat--becomes severely debilitating in disease states. Anxiety disorders represent the most common of psychiatric diseases (28% lifetime prevalence) and contribute to the aetiology of major depression and substance abuse. Although it has been proposed that the amygdala, a brain region important for emotional processing, has a role in anxiety, the neural mechanisms that control anxiety remain unclear. Here we explore the neural circuits underlying anxiety-related behaviours by using optogenetics with two-photon microscopy, anxiety assays in freely moving mice, and electrophysiology. With the capability of optogenetics to control not only cell types but also specific connections between cells, we observed that temporally precise optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala (CeA)--achieved by viral transduction of the BLA with a codon-optimized channelrhodopsin followed by restricted illumination in the downstream CeA--exerted an acute, reversible anxiolytic effect. Conversely, selective optogenetic inhibition of the same projection with a third-generation halorhodopsin (eNpHR3.0) increased anxiety-related behaviours. Importantly, these effects were not observed with direct optogenetic control of BLA somata, possibly owing to recruitment of antagonistic downstream structures. Together, these results implicate specific BLA-CeA projections as critical circuit elements for acute anxiety control in the mammalian brain, and demonstrate the importance of optogenetically targeting defined projections, beyond simply targeting cell types, in the study of circuit function relevant to neuropsychiatric disease.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                18 March 2015
                30 April 2015
                30 October 2015
                : 520
                : 7549
                : 675-678
                Affiliations
                [1 ]The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
                [2 ]Neuroscience Graduate Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
                [3 ]Undergraduate Program in Neuroscience, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
                [4 ]Master’s Program in Biomedical Sciences, University of Amsterdam, Amsterdam, The Netherlands
                [5 ]Undergraduate Program in Neuroscience, Wellesley College, Wellesley, MA 02481, USA
                [6 ]Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 356, Boston, MA 02115, USA
                [7 ]McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
                Author notes
                [8 ]To Whom Correspondence Should be Addressed: Kay M. Tye, PhD, Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, 77 Massachusetts Ave, Bldg-Rm 46-6263, Massachusetts Institute of Technology, Cambridge, MA 01239. kaytye@ 123456mit.edu
                [*]

                These authors contributed equally

                Article
                NIHMS669413
                10.1038/nature14366
                4418228
                25925480
                bc6ee97d-629f-46f1-9b2e-94a74e356e8e
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