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Amygdala circuitry mediating reversible and bidirectional control of anxiety

Tye, Kay M. and Prakash, Rohit and Kim, Sung-Yon and Fenno, Lief E. and Grosenick, Logan and Zarabi, Hosniya and Thompson, Kimberly R. and Gradinaru, Viviana and Ramakrishnan, Charu and Deisseroth, Karl (2011) Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature, 471 (7338). pp. 358-362. ISSN 0028-0836. PMCID PMC3154022.

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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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Gradinaru, Viviana0000-0001-5868-348X
Additional Information:© 2011 Macmillan Publishers Limited. Received 7 November 2010; accepted 14 January 2011. Published online 9 March 2011. We would like to thank Drs. P. Janak, H. Fields, G. Stuber, E. Thomas, F. Zhang, I. Witten, V. Sohal, T. Davidson and M. Warden as well as J. Mattis, R. Durand, M. Mogri, J. Mirzabekov and E. Steinberg for helpful discussion, and the entire Deisseroth lab for their support. All viruses were packaged at UNC vector Core. Supported by NIMH (1F32MH088010-01, K.M.T), NARSAD (K.R.T), Samsung Scholarship (S-Y.K.), NSF IGERT Award 0801700 (L.G.) and McKnight Foundations, as well as NIDA, NIMH and the NIH Pioneer Award (K.D.). Author Contributions: K.M.T., R.P., S-Y. K., L.E.F. and K.D. contributed to study design and data interpretation. K.M.T., R.P., S-Y. K. and L.E.F. contributed to data collection and K.M.T. coordinated data collection and analysis. K.M.T., S-Y.K., H.Z. and K.R.T. contributed to immunohistochemical processing, fluorescence imaging and quantitative analyses. K.M.T. and L.G. performed the behavioral and ex vivo electrophysiology statistical analyses. V.G. and C.R. contributed to the design of eNpHR 3.0. C.R. cloned all constructs and managed viral packaging processes. K.D. supervised all aspects of the work. All authors contributed to writing the paper.
Funding AgencyGrant Number
National Institute of Mental Health (NIMH)1F32MH088010-01
Samsung Scholarship UNSPECIFIED
Defense Advanced Research Projects Agency (DARPA)N66001-10-C-2010
H. L. Snyder Medical FoundationUNSPECIFIED
National Institute on Drug AbuseUNSPECIFIED
Albert Yu and Mary Bechmann FoundationUNSPECIFIED
Vincent V.C. Woo FoundationUNSPECIFIED
McKnight FoundationUNSPECIFIED
Subject Keywords:Neuroscience
Issue or Number:7338
PubMed Central ID:PMC3154022
Record Number:CaltechAUTHORS:20121206-133910388
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:35860
Deposited By: Tony Diaz
Deposited On:07 Dec 2012 21:58
Last Modified:03 Oct 2019 04:32

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