Aversive experiences can lead to complex behavioral adaptations including increased levels of anxiety and fear generalization. The neuronal mechanisms underlying such maladaptive behavioral changes, however, are poorly understood. Here, using a combination of behavioral, physiological and optogenetic approaches in mouse, we identify a specific subpopulation of central amygdala neurons expressing protein kinase C δ (PKCδ) as key elements of the neuronal circuitry controlling anxiety. Moreover, we show that aversive experiences induce anxiety and fear generalization by regulating the activity of PKCδ+ neurons via extrasynaptic inhibition mediated by α5 subunit-containing GABAA receptors. Our findings reveal that the neuronal circuits that mediate fear and anxiety overlap at the level of defined subpopulations of central amygdala neurons and demonstrate that persistent changes in the excitability of a single cell type can orchestrate complex behavioral changes.
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We thank all members of the Lüthi laboratory for discussions and critical comments on the manuscript. In particularly, we thank P. Tovote, S. Wolff, S. Ciocchi, F. Grenier, J. Gruendemann, C. Müller, K. Bylund and A. Loche for comments and for technical support, and W. Sieghart (Medical University of Vienna) and D. Anderson (California Institute of Technology) for antibodies and mice. This work was supported by the Novartis Research Foundation, by the National Center of Competences in Research program 'SYNAPSY — The Synaptic Bases of Mental Diseases' (financed by the Swiss National Science Foundation (SNSF)) as well as by an SNSF core grant to A.L. J.P.F. was supported by a NARSAD fellowship. C.X. was supported by an EMBO Long-Term Fellowship. P.S. and L.X. were supported by the Australian National Health and Medical Research Council. U.R. was supported by grant R01MH080006 from the US National Institute of Mental Health, National Institutes of Health. Funding for J.M.C. was provided by the National Institute of Neurological Disorders and Stroke (R01NS076517) and the National Institute of Mental Health (R01MH096463), US National Institutes of Health. Y.K. and F.F. were supported by Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung) Sonderforschungsbereich grant F44-17.
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Molecular Neurobiology (2018)