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Research Article

Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance

View ORCID ProfileNatalia Duque-Wilckens, Lisette Y. Torres, View ORCID ProfileSae Yokoyama, Vanessa A. Minie, View ORCID ProfileAmy M. Tran, Stela P. Petkova, Rebecca Hao, Stephanie Ramos-Maciel, Roberto A. Rios, Kenneth Jackson, Francisco J. Flores-Ramirez, Israel Garcia-Carachure, Patricia A. Pesavento, View ORCID ProfileSergio D. Iñiguez, View ORCID ProfileValery Grinevich, and View ORCID ProfileBrian C. Trainor
PNAS October 20, 2020 117 (42) 26406-26413; first published October 5, 2020; https://doi.org/10.1073/pnas.2011890117
Natalia Duque-Wilckens
aDepartment of Psychology, University of California, Davis, CA 95616;
bDepartment of Physiology, Michigan State University, East Lansing, MI 48824;
cDepartment of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI 48824;
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  • ORCID record for Natalia Duque-Wilckens
Lisette Y. Torres
aDepartment of Psychology, University of California, Davis, CA 95616;
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Sae Yokoyama
aDepartment of Psychology, University of California, Davis, CA 95616;
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Vanessa A. Minie
aDepartment of Psychology, University of California, Davis, CA 95616;
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Amy M. Tran
aDepartment of Psychology, University of California, Davis, CA 95616;
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Stela P. Petkova
dNeuroscience Graduate Group, University of California, Davis, CA 95616;
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Rebecca Hao
aDepartment of Psychology, University of California, Davis, CA 95616;
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Stephanie Ramos-Maciel
aDepartment of Psychology, University of California, Davis, CA 95616;
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Roberto A. Rios
aDepartment of Psychology, University of California, Davis, CA 95616;
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Kenneth Jackson
eDepartment of Pathobiology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616;
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Francisco J. Flores-Ramirez
fDepartment of Psychology, The University of Texas at El Paso, El Paso, TX 79902;
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Israel Garcia-Carachure
fDepartment of Psychology, The University of Texas at El Paso, El Paso, TX 79902;
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Patricia A. Pesavento
eDepartment of Pathobiology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616;
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Sergio D. Iñiguez
fDepartment of Psychology, The University of Texas at El Paso, El Paso, TX 79902;
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Valery Grinevich
gDepartment of Neuropeptide Research in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany
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Brian C. Trainor
aDepartment of Psychology, University of California, Davis, CA 95616;
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  • For correspondence: bctrainor@ucdavis.edu
  1. Edited by Susan G. Amara, National Institutes of Health, Bethesda, MD, and approved September 8, 2020 (received for review June 11, 2020)

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Significance

The neuropeptide oxytocin is an important regulator of social behavior and is widely considered to reduce anxiety-related behaviors. However, growing evidence suggests that sometimes oxytocin increases anxiety. How can the same molecule have such different effects on behavior? Here we provide evidence that oxytocin produced outside of the hypothalamus is necessary and sufficient for stress-induced social anxiety behaviors. This suggests that the diverse effects of oxytocin on anxiety-related behaviors are mediated by circuit-specific oxytocin action.

Abstract

Oxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons mediate different effects on behavior. Here we inhibited oxytocin synthesis in a stress-sensitive population of oxytocin neurons specifically within the medioventral bed nucleus of the stria terminalis (BNSTmv). Oxytocin knockdown prevented social stress-induced increases in social vigilance and decreases in social approach. Viral tracing of BNSTmv oxytocin neurons revealed fibers in regions controlling defensive behaviors, including lateral hypothalamus, anterior hypothalamus, and anteromedial BNST (BNSTam). Oxytocin infusion into BNSTam in stress naïve mice increased social vigilance and reduced social approach. These results show that a population of extrahypothalamic oxytocin neurons plays a key role in controlling stress-induced social anxiety behaviors.

  • anxiety
  • bed nucleus of the stria terminalis
  • extended amygdala
  • California mouse
  • morpholino

Footnotes

  • ↵1To whom correspondence may be addressed. Email: bctrainor{at}ucdavis.edu.
  • Author contributions: N.D.-W., P.A.P., S.D.I., and B.C.T. designed research; N.D.-W., L.Y.T., S.Y., V.A.M., A.M.T., S.P.P., R.H., S.R.-M., R.A.R., K.J., F.J.F.-R., I.G.-C., and S.D.I. performed research; V.G. contributed new reagents/analytic tools; N.D.-W. and B.C.T. analyzed data; and N.D.-W., V.G., and B.C.T. wrote the paper.

  • The authors declare no competing interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2011890117/-/DCSupplemental.

Data Availability.

Data have been deposited in Figshare (10.6084/m9.figshare.12811745, 10.6084/m9.figshare.12811760, 10.6084/m9.figshare.12811787, and 10.6084/m9.figshare.12811763).

Published under the PNAS license.

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Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance
Natalia Duque-Wilckens, Lisette Y. Torres, Sae Yokoyama, Vanessa A. Minie, Amy M. Tran, Stela P. Petkova, Rebecca Hao, Stephanie Ramos-Maciel, Roberto A. Rios, Kenneth Jackson, Francisco J. Flores-Ramirez, Israel Garcia-Carachure, Patricia A. Pesavento, Sergio D. Iñiguez, Valery Grinevich, Brian C. Trainor
Proceedings of the National Academy of Sciences Oct 2020, 117 (42) 26406-26413; DOI: 10.1073/pnas.2011890117

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Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance
Natalia Duque-Wilckens, Lisette Y. Torres, Sae Yokoyama, Vanessa A. Minie, Amy M. Tran, Stela P. Petkova, Rebecca Hao, Stephanie Ramos-Maciel, Roberto A. Rios, Kenneth Jackson, Francisco J. Flores-Ramirez, Israel Garcia-Carachure, Patricia A. Pesavento, Sergio D. Iñiguez, Valery Grinevich, Brian C. Trainor
Proceedings of the National Academy of Sciences Oct 2020, 117 (42) 26406-26413; DOI: 10.1073/pnas.2011890117
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