Sex-Specific Neural Adaptations 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 (one hour of restraint stress), and a chronic stress group (one hour of restraint stress daily for ten days). Neural activity was assessed by quantifying c-Fos-positive cells using immunohistochemistry. Acute stress induced widespread neural activation in both sexes, with notable sex differences in c-Fos expression in regions of the hypothalamus, amygdala, and midbrain. 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 in stressed females, indicating a decoupling of hormonal and neural responses. These findings suggest that chronic stress elicits distinct neural adaptations 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.