Similar patterns of activation in stress-sensitive brain regions during acute and chronic stress in adult male and female rats.

Exposure to stress is a risk factor for many psychiatric disorders, with females often exhibiting greater vulnerability than males. Chronic stress produces sex-specific changes in the structure and function of rat medial prefrontal cortex (mPFC). A possible explanation for these sex-dependent effects is that activation of the hypothalamic-pituitary-adrenal axis and of stress-sensitive brain regions during restraint is different in males and females. Here, we examined serum corticosterone concentrations and c-Fos expression in the mPFC, basolateral amygdala (BLA), and paraventricular nucleus (PVN) in adult male (N = 54) and female rats (N = 57) during restraint stress. Acutely stressed rats were restrained for 0, 60, or 180 min, whereas chronically stressed rats underwent 180 min of restraint for 9 consecutive days and were then restrained for 0, 60, or 180 min on day 10. Restraint stress robustly increased serum corticosterone and c-Fos expression across all regions examined except the BLA. Corticosterone responses were independent of stress chronicity but were higher overall in females. Acute stress produced greater neural activation than chronic stress in the prelimbic cortex and PVN, indicating partial habituation following repeated stress exposure, while infralimbic (IL) and orbitofrontal cortex responses were unaffected by chronicity or sex. Estrous phase effects were limited to IL under chronic stress. Females exhibited greater enhanced network-level integration of stress responses. These findings indicate that male and female rats show similar endocrine and corticolimbic responses during chronic restraint stress, suggesting that sex-dependent morphological and behavioral consequences of chronic stress are unlikely to arise from differential activation during stress exposure.