Prefrontal corticotropin-releasing factor promotes resilience to social stress

Variations in individual coping styles have been linked to either resilience or vulnerability towards stress, thereby influencing the probability of developing stress-related disorders. The involvement of corticotropin-releasing factor (CRF) neurons within the medial prefrontal cortex (mPFC) plays a crucial role in modulating behavioral responses to stressful situations. In this study utilizing a mouse model of social defeat stress (SDS), we demonstrate how coordinated activation and localized release of CRF within the mPFC contribute to promoting adaptive responses under stressful conditions leading to enhanced resilience against subsequent challenges. Specifically, during SDS exposure, heightened activity levels were observed among mPFC CRF neurons coincide with increased local release triggered by active exploration and defensive behaviors, while decreased responses were detected upon exposure to aggression. Interestingly, the CRF neural activity and local release responding to coping behaviors throughout chronic social defeat stress (CSDS) differed between susceptible and resilient mice. Furthermore, activation of CRF receptor 1 (CRFR1) signaling in the mPFC enhanced active coping behaviors and conferred resilience to CSDS, while inhibition of CRF system promoted passive coping behaviors and induced susceptibility to sub-threshold SDS. Additionally, inhibition of CRFR1 in the mPFC nullified the pro-resilience effect elicited by activation of CRF neurons during CSDS. The collective findings provide evidence supporting the crucial role of local endogenous CRF derived from mPFC CRF neurons in maintaining resilience through active coping styles when confronted with social stress. Moreover, these results suggest that targeting the mPFC CRF system could hold promise as a therapeutic approach for managing stress-related disorders.