Authors: Cecilia Flores�� ��McGill University Abstract: Dopamine (DA) connectivity in the prefrontal cortex (PFC) continues to unfold until early adulthood, with dramatic organizational and functional changes occurring during adolescence. This delayed development involves long-distance axonal growth of midbrain DA neurons across the adolescent period and is mediated by the Netrin-1/DCC guidance cue pathway. We examined whether repeated social stress in adolescence dysregulates the Netrin-1/DCC pathway, disrupting PFC DA innervation and cognitive control in adulthood. We used a modified accelerated social defeat stress (ASD) model and segregated mice into��resilient��(RES) and��susceptible��(SUS) groups by measuring social avoidance in a social interaction test (SIT) 24h after ASD exposure. ASD in adolescence downregulates DCC expression in DA neurons in SUS and RES groups, but its effects on PFC DA development and behavior differ between phenotypes. ASD-induced molecular, cellular and behavioral changes are not observed following ASD exposure in adulthood. While most (~60%) mice exposed to adolescent ASD show RES, most adult mice show stress SUS. Alterations in dopamine development in adolescence may mediate the established link between genetic variance within the Netrin-1/DCC pathway and psychiatric disorders of neurodevelopmental origin.