Behavioral Coping and c-Fos Activation Trends in Hypothyroid mice during Acute Social Defeat

Abstract

Adult onset hypothyroidism, characterized by a decreased level of circulating thyroid hormones, is robustly associated with depressive- and anxiety-like phenotypes/features in both clinical and rodent populations, implicating thyroid hormone signaling as a broad modulator of affective states and behaviors. However, how it contributes to shaping behavioral and neural responses to ethologically relevant stressors, such as social defeat, remains poorly characterized. Here, male C57BL/6J mice with propylthiouracil (PTU)-induced hypothyroidism exposed to acute social defeat stress paradigm enabled comparisons of behavioral coping strategy and whole-brain c-Fos as a neural activity proxy between controls. Manual behavioral scoring for active and passive coping strategies revealed no significant differences in retaliation and fleeing responses, or their compositions and switching dynamics, suggesting appropriate retention of defense under acute social threat. Individual variation in coping strategies correlated with c-Fos activity in most notably hypothalamic and amygdalar nuclei, regardless of condition. Whole-brain iDISCO+ c-Fos mapping identified nominally significant brain region activity differences that partake in social behaviors and stress responses (e.g. periaqueductal gray, basolateral and basomedial amygdalar nuclei, dentate gyrus), though no regions survived FDR correction. Cross-validation of the periaqueductal gray using traditional immunohistochemistry and FIJI-based cell counting elicited a similar weaker neural recruitment trend in PTU mice and partial correlation with individual-based active coping. Together, these findings provide evidence for behaviorally intact but preliminary diverse brain nodes where thyroid hormone status and social stress processing may interact, offering insight for future exploration of hypothyroidism may be shaping stress-circuitry and vulnerability to social adversity.