Cited by 139Neuroendocrine regulation and behaviorNeuropeptides and Animal PhysiologyStress Responses and Cortisol

The DOI matches its Crossref record; 87 of the 87 references it cites were found in a registry or an index; none of the 34 sources its claims cite is checked for support yet.

Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance

Open access
Duque-Wilckens, Natalia, Torres, Lisette Y., Yokoyama, Sae, Minie, Vanessa A., Tran, Amy M., Petkova, Stela P., Hao, Rebecca, Ramos-Maciel, Stephanie, Rios, Roberto A., Jackson, Kenneth, Flores-Ramirez, Francisco J., Garcia-Carachure, Israel, Pesavento, Patricia A., Iñiguez, Sergio D., Grinevich, Valery, Trainor, Brian C.·2020·Proceedings of the National Academy of Sciences

Published version of a preprint

Abstract

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.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In female California mice, oxytocin synthesis in medioventral bed nucleus of the stria terminalis (BNSTmv) is necessary for social defeat–induced reductions in social approach and increases in social vigilance. BNSTmv oxytocin neurons project to anteromedial BNST (BNSTam), where oxytocin infusion is sufficient to induce social avoidance and vigilance in stress-naïve males and females.

Key findings

  • BNSTmv antisense morpholino reduced oxytocin-immunoreactive cells compared with missense controls (F1,28=5.4, p=0.02) and prevented stress-induced reductions in social approach (stress×treatment F1,31=5.7, p=0.02) and increases in social vigilance (stress×treatment F1,31=6.2, p=0.02) in female California mice.
  • Male California mice tested 10 min after a third social defeat episode showed reduced social approach (t14=2.46, p=0.02, d=1.23) and increased social vigilance (t14=2.36, p=0.03, d=1.18) versus naïve males.
  • Viral tracing showed BNSTmv oxytocin neurons project to BNSTam and anterior/lateral hypothalamus; on average 63% of oxytocin-immunoreactive cells expressed Venus, and all Venus-positive cells coexpressed oxytocin.
  • Oxytocin infusion into BNSTam in stress-naïve mice reduced social approach and increased social vigilance; in females, 1.0 ng reduced approach (p<0.001, d=4.8) and increased vigilance (p<0.001, d=2.3), and in males, 1.0 ng reduced approach (p=0.00, d=1.93) and increased vigilance (p<0.001, d=1.27). In C57BL/6 mice, vicarious defeat increased vigilance in females (p<0.0001, d=1.9) and BNST oxytocin cell number (t14=2.721, p=0.01, d=1.4), but not PVN oxytocin cells.

Methods

  • California mice underwent social defeat or control handling; one week later, females received BNSTmv antisense or missense morpholino injections, followed by social interaction testing. Male California mice were tested 10 min after a third defeat episode.
  • C57BL/6 mice underwent vicarious social defeat or control handling and social interaction testing; BNST and PVN oxytocin cells were assessed immunohistochemically.
  • Circuit mapping used AAV-OTpr-Venus tracing from BNSTmv; qPCR and fluorescent in situ hybridization assessed Oxtr/Gad1/vGlut2 in BNSTam; site-specific oxytocin infusions into BNSTam were tested in stress-naïve females and males. Analyses used 2-way ANOVAs, t-tests, planned comparisons, and Cohen’s d.

Limitations

  • Stated: the authors do not know whether BNST oxytocin neurons synapse within target regions, and non-synaptic/periaxonal or en passant release is possible; a role of PVN oxytocin is not excluded; future single-cell analysis is needed to understand how Oxtr activation in BNSTam modulates behavior.
  • Evident: oxytocin synthesis knockdown in BNSTmv was tested only in female California mice, while males received acute defeat testing and BNSTam oxytocin infusion but not antisense knockdown.
  • Evident: the study does not directly measure oxytocin release in BNSTam during stress or social interaction.

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Integrity signals

Registry

Crossref · 10.1073/pnas.2011890117

Cites

87 of 87 references verified0 citation errors · 0 not checkable

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  • It may state two separate claims as one. 21
  • Probably not a substantial claim. 11
  • The quote only partly states this claim. 2
32 of 32
  • The paper relies on this without support.

    Exogenous oxytocin infused into BNSTam acts through oxytocin receptors to produce its effects on social behavior.

    “Next, we tested whether administration of oxytocin within the BNSTam is sufficient to reduce social approach and increase vigilance in stress naïve females and males (fig.4A).”
  • The paper relies on this without support.

    Morpholino oligos inhibit protein synthesis by blocking the translation initiation complex.

    “Morpholino oligos inhibit protein synthesis by blocking the translation initiation complex.”
2 of 2

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Citations

Cites

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Research works printed but not linked: 1

  1. J. Wahis Oxytocin acts on astrocytes in the central amygdala to promote a positive emotional state. bioRxiv :2020.02.25.963884 (2020). Posted 26 February 2020.

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Metadata

Authors
Duque-Wilckens, N., Torres, L. Y., Yokoyama, S., Minie, V. A., Tran, A. M., Petkova, S. P., Hao, R., Ramos-Maciel, S., Rios, R. A., Jackson, K., Flores-Ramirez, F. J., Garcia-Carachure, I., Pesavento, P. A., Iñiguez, S. D., Grinevich, V., & Trainor, B. C.
Affiliations
  • Department of Psychology, University of California, Davis, CA 95616;
  • University of California, Davis (US)
  • Department of Psychology, The University of Texas at El Paso, El Paso, TX 79902;
  • The University of Texas at El Paso (US)
  • Heidelberg University (DE)
Venue
Proceedings of the National Academy of Sciences
Published
2020-10-05
Volume
117
Issue
42
Pages
26406-26413
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W3091710413
Cited by
139
References
86
Citations by year
2026: 21 · 2025: 29 · 2024: 17 · 2023: 20 · 2022: 17 · 2021: 29 · 2020: 6
FWCI
19.70
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • HHS | NIH | National Institute of Mental Health (R01 MH121829-01)
  • HHS | NIH | National Institute of General Medical Sciences (SC3GM130467)
  • Deutsche Forschungsgemeinschaft (Collaborative Research Center (SFB) 1158, GR 3619/701, GR 3619/4-1)
  • SFB (1158)
  • SNSF-DFG (GR 3619/8-1)
  • Fritz Thyssen Stiftung (10.16.2.018 MN)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
oxytocin neurons, social stress, social vigilance, social avoidance, social anxiety, lateral hypothalamus, anterior hypothalamus, viral tracing, defensive behavior
MeSH terms
Animals, Anxiety, Avoidance Learning, Brain, Brain Mapping, Female, Hypothalamus, Male, Neurons, Oxytocin, Peromyscus, Septal Nuclei, Social Behavior, Stress, Psychological, Receptors, Oxytocin, Mice

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