Li, A.-J. | bioRxiv Science

bioRxiv2025

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.

neuroscience↗

bioRxiv2024

Divergent changes in social stress-induced motivation in male and female mice

Exposure to stressors has been shown to dysregulate motivated behaviors in a bidirectional manner over time. The relationship between stress and motivation is relevant to psychological disorders, including depression, binge eating, and substance abuse; however, this relationship is not well characterized, especially in females, despite their increased risk of these disorders. Social defeat stress is a common model to study stress-induced motivation changes, however, historically this model excluded females due to lack of female-to-female aggression and unreliable male-to-female aggression. Additionally, changes in motivation are often assessed well after stress exposure ends, potentially missing or occluding changes to motivation during stress. Recently, the chronic non-discriminatory social defeat stress (CNSDS) model has demonstrated social defeat of male and female C57BL/6J mice by exposing both mice to an aggressive male CD-1 mouse simultaneously. Here we use this model to directly compare changes in the motivated behavior of male and female mice during and following chronic stress. We hypothesized that motivated behavioral responses would be dysregulated during stress and that the effects would worsen as the stress exposure continued. To monitor motivated behavior, mice had access to a Feeding Experimental Device.3 (FED3), a home cage device for operant responding. Operant responding was monitored prior to, during, and after stress by measuring nose pokes for sucrose pellets on a modified progressive ratio schedule of reinforcement. Our results demonstrated divergent behavioral outcomes between males and female mice in response to stress; where male mice increased motivated behavior during stress only, whereas female mice exhibited a decrease in motivation during and after stress. This study highlights the need to investigate the effects of stress-induced motivation over time, as well as the increased need to understand differences in the stress response in females. HighlightsO_LIOperant behaviors were monitored continuously during and after stress exposure. C_LIO_LIChronic social stress produced opposite effects on motivation in males and females. C_LIO_LISusceptibility to stress only influenced outcomes on female motivated behaviors. C_LI

animal behavior and cognition↗