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      Prefrontal cortical control of a brainstem social behavior circuit

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          Summary

          The prefrontal cortex plays a critical role in adjusting an organism's behavior to its environment. In particular, numerous studies have implicated the prefrontal cortex in the control of social behavior, but the neural circuits that mediate these effects remain unknown. Here we investigated behavioral adaptation to social defeat in mice and uncovered a critical contribution of neural projections from the medial prefrontal cortex to the dorsal periaqueductal grey, a brainstem area vital for defensive responses. Social defeat caused a weakening of functional connectivity between these two areas and selective inhibition of these projections mimicked the behavioral effects of social defeat. These findings define a specific neural projection by which the prefrontal cortex can control and adapt social behavior.

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          Most cited references60

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          A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex.

          A key obstacle to understanding neural circuits in the cerebral cortex is that of unraveling the diversity of GABAergic interneurons. This diversity poses general questions for neural circuit analysis: how are these interneuron cell types generated and assembled into stereotyped local circuits and how do they differentially contribute to circuit operations that underlie cortical functions ranging from perception to cognition? Using genetic engineering in mice, we have generated and characterized approximately 20 Cre and inducible CreER knockin driver lines that reliably target major classes and lineages of GABAergic neurons. More select populations are captured by intersection of Cre and Flp drivers. Genetic targeting allows reliable identification, monitoring, and manipulation of cortical GABAergic neurons, thereby enabling a systematic and comprehensive analysis from cell fate specification, migration, and connectivity, to their functions in network dynamics and behavior. As such, this approach will accelerate the study of GABAergic circuits throughout the mammalian brain. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants.

            Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.
              • Record: found
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              Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.

              Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.

                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nat. Neurosci.
                Nature neuroscience
                1097-6256
                1546-1726
                22 August 2017
                09 January 2017
                February 2017
                01 September 2017
                : 20
                : 2
                : 260-270
                Affiliations
                [1 ]Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), via Ramarini 32, 00015 Monterotondo, Italy
                [2 ]Department of Psychology and Neuroscience, Dalhousie University, 1355 Oxford Street, Halifax, Canada B3H 4R2
                [3 ]MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
                [4 ]Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China, 518055
                [5 ]Institute of Neuroinformatics, University of Zürich and Swiss Federal Institute of Technology (ETH), Winterthurerstr. 190, 8057 Zurich, Switzerland
                [6 ]Schaller Research Group on Neuropeptides, German Cancer Research Center DKFZ, Cell Network Cluster of Excellence, University of Heidelberg, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany
                Author notes
                [* ]Correspondence to: gross@ 123456embl.it
                [**]

                Current address: Sainsbury Wellcome Centre, University College London, UK

                Article
                EMS73792
                10.1038/nn.4470
                5580810
                28067904
                235e068c-eaca-4636-ab8b-d05108a45920

                The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.

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