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Sex-Specific Effects of Stress on Oxytocin Neurons Correspond With Responses to Intranasal Oxytocin
Open accessAbstract
Background Oxytocin (OT) is considered to be a stress-buffering hormone, dampening the physiologic effects of stress. However, OT can also be anxiogenic. We examined acute and long-lasting effects of social defeat on OT neurons in male and female California mice.Methods We used immunohistochemistry for OT and c-fos cells to examine OT neuron activity immediately after defeat (n = 6-9) and 2 weeks (n = 6-9) and 10 weeks (n = 4-5) later. We quantified Oxt messenger RNA with quantitative polymerase chain reaction (n = 5-9). Intranasal OT was administered to naïve and stressed mice tested in social interaction and resident-intruder tests (n = 8-14).Results Acute exposure to a third episode of defeat increased OT/c-fos colocalizations in the paraventricular nucleus of both sexes. In the medioventral bed nucleus of the stria terminalis, defeat increased Oxt messenger RNA, total OT neurons, and OT/c-fos colocalizations in female mice but not male mice. Intranasal OT failed to reverse stress-induced social withdrawal in female mice and reduced social interaction behavior in female mice naïve to defeat. In contrast, intranasal OT increased social interaction in stressed male mice and reduced freezing in the resident-intruder test.Conclusions Social defeat induces long-lasting increases in OT production and OT/c-fos cells in the medioventral bed nucleus of the stria terminalis of female mice but not male mice. Intranasal OT largely reversed the effects of stress on behavior in male mice, but effects were mixed in female mice. These results suggest that changes in OT-sensitive networks contribute to sex differences in behavioral responses to stress.
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“Social defeat stress increases c-fos expression in oxytocin neurons in the Paraventricular Nucleus of the Hypothalamus (PVN) (37), a response that has been associated with heightened immediate early gene expression in the anteromedial BNST (40).”
From Sexual differentiation of neural mechanisms of stress sensitivity during puberty (2023) · cites this paper as [37]
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“Previous work in California mice (Peromyscus californicus) shows that social defeat stress has stronger effects on BNST structure and function in adult females than males (37, 38) and that these changes drive stress-induced social avoidance and social vigilance (39–41).”
From Sexual differentiation of neural mechanisms of stress sensitivity during puberty (2023) · cites this paper as [37]
In the citing paper
“Oxytocin OXT neurons have been reported in the extended medial amygdala (eg, the BNST and medial amygdala proper [MeA]) in rats (63), California mice (64), and marmosets (65).”
From Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities (2022) · cites this paper as [64]
In the citing paper
“We previously observed that social defeat increases the activity of OT neurons in the medioventral bed nucleus of the stria terminalis (BNSTmv) and paraventricular nucleus (PVN) in female but not male California mice (15).”
From Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in female California mice (2018) · cites this paper as [15]
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“In males, social defeat stress did not reduce social interaction behavior, consistent with previous studies (15, 41, 42).”
From Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in female California mice (2018) · cites this paper as [15]
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“Intranasal OT reduced social interaction behavior in female but not male California mice (15)”
From Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in female California mice (2018) · cites this paper as [15]
In the citing paper
“The current findings combined with our previous work (15) suggest a model that social defeat induces hyperactivity of BNSTmv and PVN OT neurons which in turn increase the activation of OTR in the BNSTam to induce avoidance of unfamiliar social contexts in females.”
From Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in female California mice (2018) · cites this paper as [15]
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Metadata
- Authors
- Steinman, M. Q., Duque-Wilckens, N., Greenberg, G. D., Hao, R., Campi, K. L., Laredo, S. A., Laman-Maharg, A., Manning, C. E., Doig, I. E., Lopez, E. M., Walch, K., Bales, K. L., & Trainor, B. C.
- Affiliations
- University of California, Davis (US)
- Corresponding author
- Trainor, Brian C.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 80
- Issue
- 5
- Pages
- 406-414
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4837091
- OpenAlex
- W2173794558
- Cited by
- 131
- References
- 49
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 9 · 2023: 11 · 2022: 10 · 2021: 24 · 2020: 15 · 2019: 14 · 2018: 17 · 2017: 9 · 2016: 7
- FWCI
- 18.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Scholar Commons (Santa Clara University) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (T32AA007456)
- National Institute of Mental Health (F31MH095253, R01MH085069)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- oxytocin, social defeat, stress, sex differences, oxytocin neurons, c-fos, paraventricular nucleus, bed nucleus of the stria terminalis, intranasal oxytocin, social interaction, social withdrawal, anxiety
- MeSH terms
- Administration, Intranasal, Animals, Disease Models, Animal, Female, Male, Neurons, Oxytocin, Paraventricular Hypothalamic Nucleus, RNA, Messenger, Sex Characteristics, Social Behavior, Stress, Psychological, Time Factors, Proto-Oncogene Proteins c-fos, Mice
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