Adolescent Alcohol and Prefrontal Cortical Function in the Adult

 描述（由申请人提供）：在青春期和青年期饮酒是一个严重的公共卫生问题。在这个年龄组，酒精往往是消耗大量的反复暴饮暴食，导致高度中毒。除了法律的后果和对身体安全的担忧外，这些饮酒模式似乎对从青春期向成年期过渡期间大脑和行为的持续成熟产生不利影响。前额叶皮层（PFC）控制高级认知功能，如工作记忆，行为灵活性和冲动控制（统称为执行认知功能）。青少年时期代表了PFC神经回路完善的关键时期，PFC支持执行认知功能的成熟。NADIA联盟的这项研究组成部分的总体假设是，在青春期反复酗酒会产生PFC的神经病理学，在成年后表现为执行认知功能和行为控制的缺陷。与此相一致，我们已经证明，青少年间歇性乙醇（AIE）暴露导致成年后的行为缺陷。具体来说，这些研究表明，暴露于AIE的成年大鼠表现出与前额叶功能障碍一致的不灵活的决策。NADIA联盟的这一更新组成部分下的研究将通过以下四个具体目标建立在这些观察的基础上：1）检验以下假设：AIE诱导的成年期行为灵活性缺陷与PFC投射到皮质下结构的回路特异性改变有关。2)检验这一假设，即前边缘PFC输入RMTg介导AIE诱导的成年人对乙醇的厌恶行为的敏感性降低。3)检验AIE通过破坏PFC介导的反应策略选择控制促进不灵活的习惯性乙醇寻求的发展的假设。4)验证以下假设：药理学和药物遗传学增强认知功能可以恢复AIE暴露成人的行为灵活性。这些研究涉及一系列创新和多学科的实验，利用最先进的方法和程序。总之，这些研究将产生新的和令人兴奋的新发现，并将显着推进我们对青少年酒精暴露对成年人认知功能和行为控制的影响的理解，并确定新的治疗方法。

 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.