Chronic variable stress alters hypothalamic–pituitary–adrenal axis function in the female mouse
Open accessAbstract
Chronic stress is often associated with a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which can greatly increase risk for a number of stress-related diseases, including neuropsychiatric disorders. Despite a striking sex-bias in the prevalence of many of these disorders, few preclinical studies have examined female subjects. Hence, the present study aimed to explore the effects of chronic stress on the basal and acute stress-induced activity of the HPA axis in the female C57BL/6 mouse. We used a chronic variable stress (CVS) paradigm in these studies, which successfully induces physiological and behavioral changes that are similar to those reported for some patients with mood disorders. Using this model, we found pronounced, time-dependent effects of chronic stress on the HPA axis. CVS-treated females exhibited adrenal hypertrophy, yet their pattern of glucocorticoid secretion in the morning resembled that of controls. CVS-treated and control females had similar morning basal corticosterone (CORT) levels, which were both significantly elevated following a restraint stressor. Although morning basal gene expression of the key HPA-controlling neuropeptides corticotropin releasing hormone (CRH), arginine vasopressin (AVP) and oxytocin (OT) was unaltered within the paraventricular nucleus (PVN) by CVS, CVS altered the PVN OT and AVP mRNA responses to acute restraint. In control females, acute stress decreased AVP, but not OT mRNA; whereas, in CVS females, it decreased OT, but not, AVP mRNA. Unlike the morning pattern of HPA activity, in the evening, CVS-treated females showed increased basal CORT with hypoactive responses of CORT and PVN c-Fos immunoreactivity to restraint stress. Furthermore, CVS elevated evening PVN CRH and OT mRNAs in the PVN, but it did not influence anxiety- or depressive-like behavior after a light/dark box or tail suspension test. Taken together, these findings indicate that CVS is an effective model for HPA axis dysregulation in the female mouse and may be relevant for stress-related diseases.
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Over time, this can lead to adrenal hypertrophy and increased hormonal secretion, as demonstrated in animal models.
“Over time, this can lead to adrenal hypertrophy and increased hormonal secretion, as demonstrated in animal models [19].”
From Chronic Stress and Autoimmunity: The Role of HPA Axis and Cortisol Dysregulation (2025) · cites this paper as [19]
The Results report increased adrenal weight after chronic variable stress in female mice and elevated basal corticosterone in the evening. Increased hormonal secretion was not a general finding: morning corticosterone was unchanged, and evening stress-induced corticosterone was lower than in controls. The claim omits those time-of-day and testing-condition limits. (LLM, conf=0.86)
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Chronic Stress and Autoimmunity: The Role of HPA Axis and Cortisol Dysregulation
Nunez, S. G., Rabelo, S. P., Subotic, N., Caruso, J. W., & Knezevic, N. N. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26209994 · Cited by 138 · see citing works
“Over time, this can lead to adrenal hypertrophy and increased hormonal secretion, as demonstrated in animal models [19].”
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- Authors
- Borrow, A. P., Heck, A. L., Miller, A. M., Sheng, J. A., Stover, S. A., Daniels, R. M., Bales, N. J., Fleury, T. K., & Handa, R. J.
- Affiliations
- Colorado State University (US)
- Corresponding author
- Handa, Robert J.
- ORCID
- Venue
- Physiology & Behavior
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 209
- Pages
- 112613
- ISSN
- 0031-9384 (ISSN-L)
- PMC
- PMC6693655
- OpenAlex
- W2956601333
- Cited by
- 68
- References
- 75
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 13 · 2023: 10 · 2022: 8 · 2021: 9 · 2020: 6 · 2019: 1
- FWCI
- 3.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Physiology & Behavior (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- chronic variable stress, hypothalamic-pituitary-adrenal axis, female mice, corticosterone, adrenal hypertrophy, paraventricular nucleus, oxytocin, vasopressin, corticotropin-releasing factor, c-fos, restraint stress, sex differences, stress-related disorders, anxiety-like behavior, depression-like behavior
- MeSH terms
- Animals, Anxiety, Arginine Vasopressin, Chronic Disease, Corticotropin-Releasing Hormone, Depression, Female, Gene Expression Regulation, Glucocorticoids, Hypothalamo-Hypophyseal System, Mice, Inbred C57BL, Oxytocin, Paraventricular Hypothalamic Nucleus, Pituitary-Adrenal System, Restraint, Physical, Stress, Psychological, Mice
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