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

项目摘要 青春期饮酒和滥用酒精是一个严重的公共卫生问题。在这个年龄 在一个群体中，酒精通常在反复的暴饮暴食中大量消耗，导致高水平的 中毒。除了法律的后果和对身体安全的担忧，这些酒精的模式 消费似乎对大脑和行为的持续成熟产生不利影响， 从青春期到成年期前额叶皮层（PFC）控制高级认知功能，如 工作记忆和行为灵活性。青春期是PFC完善的关键时期 支持执行认知功能成熟的神经回路。该研究部分的 NADIA联盟将测试AIE诱导成年期认知控制缺陷的总体假设 与PFC中DA神经传递的改变有关。这一假设是基于以前的研究结果。 研究表明AIE诱导的PFC介导的行为缺陷和表达的改变， 功能的前额叶DA。拟议的研究旨在建立一个直接的联系之间的AIE诱导 改变了DA信号传导和行为障碍，并进一步检验了以下假设： 基因表达是AIE诱导的认知缺陷的主要机制。拟议的研究 涉及以下四个具体目标：目标1将测试DA D1活性的改变 mPFC中的受体表达神经元有助于AIE诱导的行为灵活性缺陷。目标2将 检验mPFC中DNA超甲基化是AIE诱导的认知缺陷的基础这一假设。目标3 将测试DNA超甲基化的正常化将逆转AIE诱导的改变的假设， mPFC的结构可塑性。目的4将检验AIE破坏腹侧被盖区-DA轴突向内生长的假设 从中脑前额叶皮层到中脑前额叶皮层这些研究涉及一套创新和多学科的 利用最先进的方法和程序的实验。总之，这些研究将产生新的 令人兴奋的新发现，并将大大促进我们对青少年酒精影响的理解。 暴露对成人认知功能和行为控制的影响，并确定新的治疗方法 接受治疗

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.