Sex-specific neural activation in response to acute and chronic restraint stress in mice

Stress responses are essential for coping with immediate threats and maintaining physiological homeostasis. While acute stress activates adaptive neuroendocrine and behavioral mechanisms, chronic stress leads to desensitization of these responses, disrupting hormone secretion, neuronal activity, and behavior. Chronic stress is a well-established risk factor for neuropsychiatric disorders, many of which show distinct prevalence and presentation patterns between sexes. However, the neurobiological mechanisms underlying these sex-dependent effects remain poorly understood. This study investigated how acute and chronic stress differentially affect neural activation patterns in male and female mice, with the hypothesis that sex-specific adaptations to chronic stress underlie divergent vulnerabilities to neuropsychiatric disorders. We employed three experimental groups: a control group (no stress), an acute stress group (1 h of restraint stress), and a chronic stress group (1 h of restraint stress daily for ten days). Neural activity was assessed by quantifying c-Fos density using immunohistochemistry. Acute stress induced widespread neural activation in both sexes, with notable sex differences in c-Fos expression patterns in regions of the thalamus, hypothalamus, amygdala, and brain stem. Chronic stress led to the desensitization of neuronal activity in most of these regions. Notably, chronically stressed females exhibited more desensitization in specific hypothalamic and amygdaloid regions compared to males. Despite this, corticosterone release remained elevated longer in stressed females than stressed males, indicating a nuanced relationship between HPA activity and neural responses. These findings suggest that restraint stress elicits distinct neural responses between acute and chronic exposure in males and females, potentially contributing to the sex-specific vulnerability to neuropsychiatric disorders. Understanding these mechanisms may inform targeted interventions for stress-related pathologies.