Adolescent alcohol consumption differentially alters sexually-divergent behaviors and infralimbic cortex function in mice

Abstract

The cortex is one of the last brain regions to fully mature, making it particularly sensitive to early life drug use. Both human and rodent studies find long-lasting behavioral changes after adolescent alcohol exposure that implicate underlying disruptions in cortical development, including structural abnormalities and altered functional connectivity. Few rodent studies have been conducted across biological scales (from single cell, whole brain network, to behavior) to understand the comprehensive implications of these disruptions. We assessed how adolescent binge-like alcohol consumption in a drinking in the dark (DID) model affected adult alcohol consumption, behavioral exploration, brain-wide functional connectivity, and intrinsic cellular excitability in mice. Only female mice exposed to alcohol during adolescence exhibited aversion-resistant alcohol preference, as well as increased exploration in the elevated plus maze. Resting state neuroimaging revealed broad sex-specific changes in brain-wide networks. Finally, we identify ex vivo intrinsic excitability alterations in key brain regions known to be susceptible to adolescent perturbations identified in neural networks, with greater effects in males, allowing biological and mechanistic targets to be further explored for future study and interventions. Our results show that females may be more vulnerable to lasting addiction-related behavioral and brain connectivity consequences of adolescent alcohol exposure, corroborating human and rodent studies demonstrating that adolescent alcohol use may increase risk for adult alcohol use more strongly in females. We further show that while males do not show identical behavioral changes, they critically show alterations in intrinsic excitability and cellular function, suggesting divergent sex-specific adaptations to adolescent binge drinking.