Functional Role of the Dorsal Raphe Nucleus in Long-Term Social Impairments Following Chronic Stress

Chronic social stress is a key risk factor in the development of psychiatric disorders such as depression and anxiety, where social withdrawal represents a core and persistent symptom. This behavioral phenotype is thought to reflect long-lasting dysregulation of neural circuits involved in emotional regulation and social behavior. The dorsal raphe nucleus (DRN), a key serotonergic structure, plays a well-established role in both stress responses and the encoding of social reward. However, how DRN activity functionally contributes to the long-term consequences of social stress remains poorly understood. In this study, we used the chronic social defeat stress (CSDS) model to investigate how prolonged social stress affects long-term behavior and brain function, and whether modulating DRN activity can prevent the emergence of stress-induced social deficits. We assessed the enduring impact of CSDS at both behavioral and functional levels. Behaviorally, among a battery of tests assessing anxiety- and depression-like phenotypes, CSDS-exposed mice exhibited significant and persistent social avoidance, still evident two weeks after the end of the stress protocol. Functionally, c-Fos mapping across multiple brain regions revealed selective and sustained changes in neuronal activity, with prominent alterations in the DRN, indicating its heightened vulnerability to chronic stress. These changes were further supported by network analysis, which showed disrupted functional connectivity in DRN-associated circuits. Notably, chemogenetic activation of the DRN during CSDS was sufficient to prevent the development of long-term social avoidance, underscoring its role in modulating stress-related behavioral outcomes. These findings highlight the DRN as a critical neural substrate underlying the enduring behavioral consequences of chronic social stress, and support its functional relevance as a promising target for therapeutic strategies aimed at preventing stress-induced social dysfunction.