Adolescent chronic social stress induces sex-specific behavioral alterations with limited persistence into adulthood.

Adolescence is a critical period during which social stress can shape neurobehavioral development, yet how acute stress reactivity relates to behavioral adaptation under repeated threat and to later adult outcomes remains poorly understood. Across two complementary experiments conducted in independent cohorts, we examined acute and repeated social defeat stress in pubertal male and female CD-1 mice to characterize endocrine reactivity, adolescent behavioral adaptation trajectories, and their relationship with adult phenotypes. Acute social defeat elicited robust hypothalamic-pituitary-adrenal axis activation in both sexes, accompanied by a sex-specific progesterone response, with stressed females showing a marked reduction in circulating progesterone. During repeated social defeat, mobility decreased immediately after stress in both sexes, but the accompanying social responses differed: after the first session, males increased body contact and reduced inter-individual distance, whereas females increased inter-individual distance without a detectable change in body contact. Across the 10-day protocol, baseline body contact increased, and inter-individual distance decreased in both sexes, with larger longitudinal changes in females. Principal component analyses confirmed a baseline sex difference driven mainly by greater body contact in females and showed divergent multivariate adaptation trajectories during repeated stress. Adult consequences were selective: previously stressed animals showed reduced open-arm time in the elevated plus maze and lower circulating testosterone, whereas most other adult outcomes were only modestly affected. Associations between adolescent behavioral adaptation and adult outcomes were weak, and none of the developmental-continuity models remained significant after correction for multiple comparisons. These findings suggest that adolescent social stress primarily reorganizes ongoing behavioral strategies, while providing limited evidence for a stable, generalized adult stress phenotype. The results highlight adolescence as a period of considerable behavioral flexibility and identify sex-dependent adaptation trajectories as a central feature of responses to repeated social threat.