Letter | Published:

Amygdala circuitry mediating reversible and bidirectional control of anxiety

Nature volume 471, pages 358362 (17 March 2011) | Download Citation

Abstract

Anxiety—a sustained state of heightened apprehension in the absence of immediate threat—becomes severely debilitating in disease states1. Anxiety disorders represent the most common of psychiatric diseases (28% lifetime prevalence)2 and contribute to the aetiology of major depression and substance abuse3,4. Although it has been proposed that the amygdala, a brain region important for emotional processing5,6,7,8, has a role in anxiety9,10,11,12,13, 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 optogenetics14,15,16 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 halorhodopsin15 (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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Acknowledgements

We would like to thank 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 discussions, and the entire K.D. laboratory for their support. All viruses were packaged at University of North Carolina (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 the Defense Advanced Research Projects Agency Reorganization and Plasticity to Accelerate Injury Recovery (N66001-10-C-2010), the Alice Woo, Albert Yu, Snyder, and McKnight Foundations, as well as NIDA, NIMH and the NIH Pioneer Award (K.D.)

Author information

Author notes

    • Kay M. Tye
    • , Rohit Prakash
    • , Sung-Yon Kim
    •  & Lief E. Fenno

    These authors contributed equally to this work.

Affiliations

  1. Department of Bioengineering, Stanford University, Stanford, California 94305, USA

    • Kay M. Tye
    • , Rohit Prakash
    • , Sung-Yon Kim
    • , Lief E. Fenno
    • , Logan Grosenick
    • , Hosniya Zarabi
    • , Kimberly R. Thompson
    • , Viviana Gradinaru
    • , Charu Ramakrishnan
    •  & Karl Deisseroth
  2. Neurosciences Program, Stanford University, Stanford, California 94305, USA

    • Rohit Prakash
    • , Sung-Yon Kim
    • , Lief E. Fenno
    • , Logan Grosenick
    • , Viviana Gradinaru
    •  & Karl Deisseroth
  3. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, USA

    • Karl Deisseroth
  4. Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA

    • Karl Deisseroth
  5. CNC Program, Stanford University, Stanford, California 94305, USA

    • Karl Deisseroth

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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 behavioural and ex vivo electrophysiology statistical analyses. V.G. and C.R. contributed to the design of eNpHR3.0. 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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Karl Deisseroth.

Supplementary information

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  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-15 with legends, Supplementary Materials and Methods and additional references.

Videos

  1. 1.

    Supplementary Movie 1

    This movie shows a representative mouse from the ChR2:BLA-CeA group on elevated plus maze. The 15-minute elevated plus maze session is shown at 5x speed; each 5-min epoch is shown in 1 min and the duration of the light epoch is indicated by the appearance of blue text detailing light stimulation parameters. During the light-on epoch, the mouse increased open arm entry and open arm time.

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DOI

https://doi.org/10.1038/nature09820

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