DESCRIPTION (provided by applicant): The consumption of alcohol during adolescence and young adulthood is a serious public health problem. In this age group, alcohol is often consumed in large quantities in repeated binge-like episodes that result in high levels of intoxication. In addition to legal ramifications and concerns with physical safety, these patterns of alcohol consumption appear to adversely impact continued brain and behavioral maturation during the transition from adolescence to adulthood. The prefrontal cortex (PFC) controls higher-order cognitive functions such as working-memory, behavioral flexibility, and impulse control (collectively referred to as executive cognitive function). Adolescence represents a critical period of refinement of the neurocircuitry of the PFC that supports maturation of executive cognitive functioning. The overarching hypothesis of this research component of the NADIA consortium is that repeated binge-like exposure to alcohol during adolescence produces a neuropathology of the PFC that manifests in the adult as deficits in executive cognitive function and behavioral control. Consistent with this, we have demonstrated that adolescent intermittent ethanol (AIE) exposure results in behavioral deficits in adulthood. Specifically, thes studies reveal that AIE-exposed adult rats exhibit inflexible decision-making that is consistent with prefrontal dysfunction. The studies under this renewal component of the NADIA consortium will build upon these observations through the following four specific aims: 1) Test the hypothesis that AIE-induced deficits in behavioral flexibility in adulthood are associated with circuit-specific alterations of PFC projections to subcortical structures. 2) Test the hypothesis that prelimbic PFC inputs to the RMTg mediate AIE-induced reduction in adult sensitivity to the aversive actions of ethanol. 3) Test the hypothesis that AIE facilitates the development of inflexible habitual ethanol seeking through disruption of PFC-mediated control of response strategy selection. 4) Test the hypothesis that pharmacologic and pharmacogenetic enhancement of cognitive function can restore behavioral flexibility in the AIE-exposed adult. These studies involve an innovative and multidisciplinary set of experiments that utilize state-of-the-art methodologies and procedures. Together, these studies will yield novel and exciting new findings and will significantly advance our understanding of the effect of adolescent alcohol exposure on cognitive function and behavioral control in the adult, and identify novel therapeutic approaches for treatment.

PUBLIC HEALTH RELEVANCE: Binge-like consumption of alcohol during adolescence represents a serious public health concern. Adolescence is a critical period for the development of cortical processes that underlie maturation of behavioral control and decision-making in adulthood. Thus, studies examining how adolescence alcohol consumption results in deficits in these cortical processes that persist well into adulthood are highly significant.