6/8 NADIA U01 Adolescent Alcohol and Prefrontal Cortical Function in the Adult

点击翻译按钮获取中文摘要

PROJECT SUMMARY The consumption and abuse of alcohol during adolescence is a serious public health problem. In this age group, alcohol is often consumed in large quantities within 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 and behavioral flexibility. Adolescence represents a critical period of refinement of PFC neurocircuitry that supports maturation of executive cognitive functioning. This research component of the NADIA consortium will test the overarching hypothesis that AIE-induced deficits in cognitive control in adulthood are associated with alterations in DA neurotransmission in the PFC. This hypothesis is based upon previous studies demonstrating AIE-induced deficits in PFC-mediated behaviors and alterations in expression and function of prefrontal DA. The proposed studies are designed to establish a direct link between AIE-induced altered DA signaling and behavioral impairments, and further test the hypothesis that epigenetic alterations in gene expression are a primary mechanism underlying AIE-induced cognitive deficits. The proposed studies involve the following four specific aims: Aim 1 will test the hypothesis that alterations in activity of DA D1 receptor-expressing neurons in the mPFC contribute to AIE-induced deficits in behavioral flexibility. Aim 2 will test the hypothesis that DNA hypermethylation in the mPFC underlies AIE-induced cognitive deficits. Aim 3 will test the hypothesis that normalization of DNA hypermethylation will reverse AIE-induced alterations in structural plasticity in the mPFC. Aim 4 will test the hypothesis that AIE disrupts the in-growth of VTA-DA axons from the nucleus accumbens to the mPFC. 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.