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Peer-reviewedCC BYFrontiers in cellular neuroscience

Glucocorticoid dynamics predict susceptibility and resilience to traumatic stress in male and female rats.

  • Emily A Devine1,2
  • James B Chambers1
  • Taylorae Dunn1
  • Ava Musarra1
  • Sophie Porter1,2
  • Christine E Moore1,2
  • Marissa Smail1,2,3
  • Nawshaba Nawreen1,2,4
  • Ben A Packard1
  • James P Herman1,5
5 affiliations
  1. 1Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati, Cincinnati, OH, United States.
  2. 2Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH, United States.
  3. 3Department of Psychology, Ohio State University, Columbus, OH, United States.
  4. 4Eli Lilly and Company, Indianapolis, IN, United States.
  5. 5Veterans Affairs Medical Center, Cincinnati, OH, United States.
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Abstract

Introduction

The mammalian stress response relies on tightly regulated HPA axis signaling, and disruptions in glucocorticoid feedback are implicated in stress-related disorders such as PTSD. Although many individuals experience trauma, only some develop pathology, suggesting that individual differences in glucocorticoid responsivity may help predict susceptibility or resilience. Here, we examined whether corticosterone (CORT) responses to a mild stressor predict behavioral outcomes following single-prolonged stress (SPS) in male and female rats.Methods

Mild stress reactivity was quantified using area-under-the-curve (AUC) CORT responses to light-dark box exposure, after which animals underwent SPS, behavioral assays, and post-reinstatement cFos immunohistochemical analysis.Results

Females exhibited SPS-induced reductions in basal AM CORT and displayed a robust traumatic stress-related phenotype in which high CORT responders displayed increased anxiety-like behavior, impaired fear extinction, and enhanced reinstatement. Correlational and permutation analyses revealed a consistent pattern in SPS-exposed females in which lower pre-stress basal AM CORT and higher mild stress-induced CORT (AUC) predicted increased fear expression, indicating a dissociation between resting and stress-evoked glucocorticoid signals. In males, mild stress reactivity did not predict SPS-related outcomes; however, reduced pre-stress basal AM CORT in control males predicted increased fear expression, suggesting sex-specific differences in the potential predictive value of CORT dynamics. SPS and CORT responder status also differentially modulated cFos expression across stress-related brain regions, including the PVN, infralimbic cortex, and amygdala in both males and females.Conclusion

These findings demonstrate that mild stress reactivity and basal glucocorticoid dynamics can predict trauma-related phenotypes in a sex-specific manner, identifying them as a potential biomarker of PTSD susceptibility in females.

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Cite

BibTeXRIS
BibTeX
@article{devine2026glucocorticoid,
  title = {{Glucocorticoid dynamics predict susceptibility and resilience to traumatic stress in male and female rats.}},
  author = {Emily A Devine and James B Chambers and Taylorae Dunn and Ava Musarra and Sophie Porter and Christine E Moore and Marissa Smail and Nawshaba Nawreen and Ben A Packard and James P Herman},
  journal = {Frontiers in cellular neuroscience},
  year = {2026},
  month = oct,
  doi = {10.3389/fncel.2026.1880559},
  url = {https://europepmc.org/article/MED/42921195},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Glucocorticoid dynamics predict susceptibility and resilience to traumatic stress in male and female rats.
AU  - Emily A Devine
AU  - James B Chambers
AU  - Taylorae Dunn
AU  - Ava Musarra
AU  - Sophie Porter
AU  - Christine E Moore
AU  - Marissa Smail
AU  - Nawshaba Nawreen
AU  - Ben A Packard
AU  - James P Herman
PY  - 2026
DA  - 2026/10/09
JO  - Frontiers in cellular neuroscience
DO  - 10.3389/fncel.2026.1880559
UR  - https://europepmc.org/article/MED/42921195
AB  - Introduction  The mammalian stress response relies on tightly regulated HPA axis signaling, and disruptions in glucocorticoid feedback are implicated in stress-related disorders such as PTSD. Although many individuals experience trauma, only some develop pathology, suggesting that individual differences in glucocorticoid responsivity may help predict susceptibility or resilience. Here, we examined whether corticosterone (CORT) responses to a mild stressor predict behavioral outcomes following single-prolonged stress (SPS) in male and female rats.Methods  Mild stress reactivity was quantified using area-under-the-curve (AUC) CORT responses to light-dark box exposure, after which animals underwent SPS, behavioral assays, and post-reinstatement cFos immunohistochemical analysis.Results  Females exhibited SPS-induced reductions in basal AM CORT and displayed a robust traumatic stress-related phenotype in which high CORT responders displayed increased anxiety-like behavior, impaired fear extinction, and enhanced reinstatement. Correlational and permutation analyses revealed a consistent pattern in SPS-exposed females in which lower pre-stress basal AM CORT and higher mild stress-induced CORT (AUC) predicted increased fear expression, indicating a dissociation between resting and stress-evoked glucocorticoid signals. In males, mild stress reactivity did not predict SPS-related outcomes; however, reduced pre-stress basal AM CORT in control males predicted increased fear expression, suggesting sex-specific differences in the potential predictive value of CORT dynamics. SPS and CORT responder status also differentially modulated cFos expression across stress-related brain regions, including the PVN, infralimbic cortex, and amygdala in both males and females.Conclusion  These findings demonstrate that mild stress reactivity and basal glucocorticoid dynamics can predict trauma-related phenotypes in a sex-specific manner, identifying them as a potential biomarker of PTSD susceptibility in females.
SN  - 1662-5102
ER  -