Letter | Published:

Diverging neural pathways assemble a behavioural state from separable features in anxiety

Nature volume 496, pages 219223 (11 April 2013) | Download Citation



Behavioural states in mammals, such as the anxious state, are characterized by several features that are coordinately regulated by diverse nervous system outputs, ranging from behavioural choice patterns to changes in physiology (in anxiety, exemplified respectively by risk-avoidance and respiratory rate alterations)1,2. Here we investigate if and how defined neural projections arising from a single coordinating brain region in mice could mediate diverse features of anxiety. Integrating behavioural assays, in vivo and in vitro electrophysiology, respiratory physiology and optogenetics, we identify a surprising new role for the bed nucleus of the stria terminalis (BNST) in the coordinated modulation of diverse anxiety features. First, two BNST subregions were unexpectedly found to exert opposite effects on the anxious state: oval BNST activity promoted several independent anxious state features, whereas anterodorsal BNST-associated activity exerted anxiolytic influence for the same features. Notably, we found that three distinct anterodorsal BNST efferent projections—to the lateral hypothalamus, parabrachial nucleus and ventral tegmental area—each implemented an independent feature of anxiolysis: reduced risk-avoidance, reduced respiratory rate, and increased positive valence, respectively. Furthermore, selective inhibition of corresponding circuit elements in freely moving mice showed opposing behavioural effects compared with excitation, and in vivo recordings during free behaviour showed native spiking patterns in anterodorsal BNST neurons that differentiated safe and anxiogenic environments. These results demonstrate that distinct BNST subregions exert opposite effects in modulating anxiety, establish separable anxiolytic roles for different anterodorsal BNST projections, and illustrate circuit mechanisms underlying selection of features for the assembly of the anxious state.

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We thank M. Davis, D. Walker, D. Paré, D. Rainnie, H. Shin, K. Thompson, P. Anikeeva, T. Davidson, I. Goshen, A. Andalman, L. Gunaydin, A. Bryant, C. Lee, J. Mirzabekov and the entire Deisseroth laboratory for discussions. Supported by a Samsung Scholarship (to S.-Y.K.), the US National Institute of Mental Health (NIMH; to R.C.M.), and a Berry Fellowship (to A.A.). K.D. and M.R.W. are NARSAD grant awardees, and K.D. was supported by the Wiegers Family Fund, the NIMH, the US National Institute on Drug Abuse (NIDA), the DARPA REPAIR Program, the Keck Foundation, the McKnight Foundation, the Gatsby Charitable Foundation, the Snyder Foundation, the Woo Foundation, the Tarlton Foundation, and the Albert Yu and Mary Bechman Foundation. All tools and methods are distributed and supported freely (http://www.optogenetics.org).

Author information

Author notes

    • Sung-Yon Kim
    •  & Avishek Adhikari

    These authors contributed equally to this work.


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

    • Sung-Yon Kim
    • , Avishek Adhikari
    • , Soo Yeun Lee
    • , James H. Marshel
    • , Christina K. Kim
    • , Caitlin S. Mallory
    • , Maisie Lo
    • , Sally Pak
    • , Joanna Mattis
    • , Melissa R. Warden
    • , Kay M. Tye
    •  & Karl Deisseroth
  2. Neurosciences Program, Stanford University, Stanford, California 94305, USA

    • Sung-Yon Kim
    • , Christina K. Kim
    • , Caitlin S. Mallory
    • , Joanna Mattis
    •  & Karl Deisseroth
  3. CNC Program, Stanford University, Stanford, California 94305, USA

    • Soo Yeun Lee
    •  & Karl Deisseroth
  4. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, USA

    • Byung Kook Lim
    • , Robert C. Malenka
    •  & Karl Deisseroth
  5. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Rachael Neve
    •  & Kay M. Tye
  6. Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA

    • Karl Deisseroth


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S.-Y.K., A.A. and K.D. designed the study, interpreted results and wrote the paper. S.-Y.K. coordinated the experiments. S.-Y.K., A.A., S.Y.L., C.S.M., M.R.W. and K.M.T. performed optogenetic behaviour and electrophysiology experiments. S.-Y.K., M.L., S.P. and J.M. performed immunohistochemistry. J.H.M. and C.K.K. performed calcium imaging. B.K.L., R.C.M. and R.N. provided viruses. All authors contributed to editing. K.D. supervised all aspects of the project.

Competing interests

S.-Y.K., A.A. and K.D. have disclosed these findings to the Stanford Office of Technology Licensing regarding the possible use of the findings and methods in identifying new treatments for anxiety. All materials, methods and reagents remain freely available for academic and non-profit research in perpetuity through the Deisseroth optogenetics website (http://www.optogenetics.org).

Corresponding author

Correspondence to Karl Deisseroth.

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    Supplementary Information

    This file contains Supplementary Statistical Analysis, Supplementary Methods and Data, Supplementary References and Supplementary Figures 1-24.

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