Sex differences in hypothalamic–pituitary–adrenal axis regulation after chronic unpredictable stress

INTRODUCTION: Exposure to stress, mediated through the hypothalamic–pituitary–adrenal (HPA) axis, elicits sex differences in endocrine, neurological, and behavioral responses. However, the sex‐specific factors that confer resilience or vulnerability to stress and stress‐associated psychiatric disorders remain largely unknown. The evident sex differences in stress‐related disease prevalence suggest the underlying differences in the neurobiological underpinnings of HPA axis regulation. METHOD: Here, we used a chronic unpredictable stress (CUS) model to investigate the behavioral and biochemical responses of the HPA axis in C57BL/6 mice. Animals were tested in the open field and forced swim test to examine anxiety‐like and depressive‐like behaviors. Plasma corticosterone levels were measured after behavior and CUS, and glucocorticoid receptor (GR) expression and cytosolic and nuclear fractions of binding protein FKBP51 expression were taken to measure function and regulation of the stress response. RESULTS: Our results indicate increased depressive‐like behavior in males and females which correlated with increased corticosterone levels following CUS. However, females displayed more anxiety‐like behaviors with and without CUS. Interestingly, we found trends toward dysregulation of GR protein expression in CUS females, and an increase in the GR inhibitory protein, FKBP51, in the cytosol of CUS males but not females. CONCLUSION: These results suggest biochemical alterations to the HPA axis regulation which may elicit a glucocorticoid resistance in females after chronic stress and may contribute to the sex‐biased vulnerability to stress‐related psychiatric disorders.