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

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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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