Distinctive behavioral and neurochemical profile of social stress in male and female adolescent mice

Abstract Background Adolescence is a critical developmental period characterized by increased vulnerability to social stress, closely associated with the emergence of long-term neurobiological alterations. The present study aimed to investigate the short- and long-term effects of social stress during adolescence in mice, using the classical social defeat (SD) model in males and the vicarious social defeat (VSD) model in females, and examining the role of the kynurenine (KYN) pathway in resilience and susceptibility phenotypes. Methods A total of 264 OF1 mice were exposed to SD or VSD between PND 26 and 35. Animals were classified as resilient or susceptible based on their performance in the social interaction test (SIT). Behavioral assessments evaluating anxiety- and depression-like behaviors, as well as locomotor activity, were conducted in both the short term (adolescence) and long term (adulthood). In addition, corticosterone levels and tryptophan metabolites were measured in multiple brain regions. Results Both SD and VSD increased corticosterone levels in both sexes. Depending on the SIT ratio, stressed mice were classified as resilient or susceptible, with females showing a lower proportion of susceptibility than males. In the short term, all defeated male mice exhibited increased locomotor activity, while anxiety-like behaviors were only observed in resilient male animals. Less time spent in back grooming was only observed in defeated adolescent females (both resilient and susceptible). Long-term effects were more limited, with persistent alterations mainly related to anxiety in resilient female mice. Regarding the KYN pathway, females displayed higher kynurenine levels and increased KYN/tryptophan ratios across several brain regions compared with males. Notably, only resilient females showed reduced KYN levels in the striatum. Furthermore, susceptible male mice exhibited an increased serotonin/tryptophan ratio in the cerebellum, limbic forebrain, and striatum compared to control or resilient males. Conclusions Overall, these findings indicate that adolescent social stress induces sex-dependent behavioral and neurochemical responses, with susceptibility/resilience associated with specific sex-dependent alterations in the KYN pathway. These results highlight potential biomarkers underlying adaptive responses to stress and may inform the pathophysiology of stress-related mental disorders.