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

项目总结 青春期饮酒和滥用酒精是一个严重的公共卫生问题。在这个时代 在这个群体中，人们经常在反复暴饮式发作中大量饮酒，从而导致高水平的饮酒 喝醉了。除了法律后果和对人身安全的担忧外，这些酒精模式 消费似乎对持续的大脑和行为成熟有负面影响 青春期到成年期。前额叶皮质(PFC)控制着高级认知功能，如 工作记忆和行为灵活性。青春期是PFC精炼的关键时期 支持执行者认知功能成熟的神经回路。这项研究是 NADIA联盟将测试AIE导致成人认知控制缺陷的主要假设 与前额叶DA神经传递的改变有关。这一假设是基于之前的 研究表明，AIE诱导的PFC介导的行为缺陷和表达和 前额多巴胺的功能。拟议的研究旨在建立AIE诱发的 改变DA信号和行为损伤，并进一步检验表观遗传改变在 基因表达是AIE导致认知功能障碍的主要机制。建议进行的研究 涉及以下四个具体目标：目标1将检验DA D1活性变化的假设 MPFC中表达受体的神经元参与了AIE所致的行为灵活性缺陷。目标2将 测试这一假设，即mPFC中的DNA超甲基化是AIE导致的认知障碍的基础。目标3 将检验这样的假设，即DNA超甲基化的正常化将逆转AIE诱导的 MPFC中的结构塑性。Aim 4将验证AIE干扰VTA-DA轴突生长的假设 从伏隔核到mPFC。这些研究涉及一套创新的、多学科的 使用最先进的方法和程序的实验。总而言之，这些研究将产生新的 和令人兴奋的新发现，并将大大促进我们对青少年酒精影响的理解 暴露于成人的认知功能和行为控制，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.