The effect of adolescent drug-induced neuroimmune signaling in sex-specific social development and reward learning.

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PROJECT SUMMARY Substance use disorders (SUDs), particularly those involving opioids, have reached epidemic levels. SUDs are hypothesized to be learning and memory disorders: the association of drug ‘reward’ with otherwise neutral stimuli promotes continued or reinstated drug use (relapse) when similar stimuli are re-encountered. Relapse rates are 40-60%, suggesting that previously learned drug associations are a constant risk for those recovering from SUDs. Socially-mediated learning is ubiquitous across species, and social factors also modulate drug use. However, how social factors influence drug-associated learning, and its expression once established, is unclear. The nucleus accumbens (NAc) reward region is critical for both drug associative learning and for social influence over behavior. We determined that microglia, the resident immune cells of the brain, mediate social development via phagocytosis, or “pruning,” of synaptic proteins in the NAc core during early adolescence in male rats, and pre-adolescence in females. Adolescent drug use increases SUD risk and social dysfunction later in life; in fact, even prescription opioid use in adolescence increases opioid misuse later in life. The opioid morphine directly activates a pro-phagocytic receptor on microglia, including on NAc microglia. These data raise the possibility that adolescent opioid use increases SUD risk by changing microglia-mediated NAc and social development, and in turn social influence over reward learning. In this proposal, we will restrict short-term morphine exposure to each sex-specific NAc core pruning period in adolescence to determine (1) how morphine affects ongoing developmental synaptic pruning activity, (2) social development, and (3) socially-mediated reward learning. Our core hypothesis is that adolescent morphine exposure exacerbates microglia-mediated pruning in the NAc core, causing abnormal social development and increased social influence over reward learning. This proposal will be the first to examine a mechanistic relationship between social development in adolescence and reward learning in adulthood, and may identify sex- specific adolescent periods of vulnerability during which lifetime SUD risk and other mental health disorders can be influenced.