Unique effects of social defeat stress in adolescent male mice on the Netrin-1/DCC pathway, prefrontal cortex dopamine and cognition (Social stress in adolescent vs. adult male mice)

For some individuals, social stress is a risk factor for psychiatric disorders characterised by adolescent onset, prefrontal cortex (PFC) dysfunction and cognitive impairments. Social stress may be particularly harmful during adolescence when dopamine (DA) axons are still growing to the PFC, rendering them sensitive to environmental influences. The guidance cue Netrin-1 and its receptor, DCC, coordinate to control mesocorticolimbic DA axon targeting and growth during this age. Here we adapted the accelerated social defeat (AcSD) paradigm to expose male mice to social stress in either adolescence or adulthood and categorised them as "resilient" or "susceptible" based on social avoidance behaviour. We examined whether stress would alter the expression of DCC and Netrin-1 in mesolimbic dopamine regions and would have enduring consequences on PFC dopamine connectivity and cognition. While in adolescence the majority of mice are resilient but exhibit risk-taking behaviour, AcSD in adulthood leads to a majority of susceptible mice without altering anxiety-like traits. In adolescent, but not adult mice, AcSD dysregulates DCC and Netrin-1 expression in mesolimbic DA regions. These molecular changes in adolescent mice are accompanied by changes in PFC DA connectivity. Following AcSD in adulthood, cognitive function remains unaffected, but all mice exposed to AcSD in adolescence show deficits in inhibitory control when they reach adulthood. These findings indicate that exposure to AcSD in adolescence vs. adulthood has substantially different effects on brain and behaviour and that stress-induced social avoidance in adolescence does not predict vulnerability to deficits in cognitive performance.Significance statement During adolescence, dopamine circuitries undergo maturational changes which may render them particularly vulnerable to social stress. While social stress can be detrimental to adolescents and adults, it may engage different mechanisms and impact different domains, depending on age. The accelerated social defeat (AcSD) model implemented here allows exposing adolescent and adult male mice to comparable social stress levels. AcSD in adulthood leads to a majority of socially avoidant mice. However, the predominance of AcSD-exposed adolescent mice does not develop social avoidance, and these resilient mice show risk-taking behaviour. Nonetheless, in adolescence only, AcSD dysregulates Netrin-1/DCC expression in mesolimbic dopamine regions, possibly disrupting mesocortical dopamine and cognition. The unique adolescent responsiveness to stress may explain increased psychopathology risk at this age.