Impact of Adolescent Alcohol Exposure on Prefrontal Cortical Function in the Adul

描述（由申请人提供）：青春期和青年期饮酒是一个严重的公共卫生问题。在这个年龄组中，酒精经常在反复的狂饮中大量消耗，导致严重的中毒。除了法律后果和对人身安全的担忧之外，这些饮酒模式似乎对从青春期到成年期的持续神经成熟产生了不利影响。前额叶皮层（PFC）控制着高级认知功能，如工作记忆、行为灵活性和冲动控制（统称为执行认知功能）。青春期是PFC神经回路完善的关键时期，它支持执行认知功能的成熟。执行认知功能的缺陷与注意力和情绪等行为过程的失控以及无保护的性行为和吸毒等危险行为的增加有关。后者包括一旦开始吸毒，停止吸毒的能力下降，导致吸毒升级和失去控制。NADIA联盟的这项研究的主要假设是，青春期反复酗酒会导致PFC神经病变，在成人中表现为执行认知功能和行为控制的缺陷。这一假设将通过一组创新的多学科实验来验证，这些实验利用了最先进的方法和程序，在青少年间歇性乙醇（AIE）暴露的大鼠模型中进行。总体假设将通过四个具体目标进行验证：1)确定AIE暴露对确定的PFC内侧兴奋性锥体和抑制性中间神经元以及腹侧被盖区多巴胺（DA）投射神经元群体的表观遗传修饰（组蛋白乙酰化）的影响；2)确定AIE暴露对DA调节成人内侧PFC兴奋性锥体和抑制性gaba能中间神经元的影响；3)通过评估工作记忆、行为灵活性和冒险行为的任务，确定AIE暴露和成年期再暴露于酒精对执行认知功能的影响；4)评估成年期AIE暴露和再暴露于酒精对认知调节的mPFC神经元群同步活动和组织的影响。总之，这些研究将产生新颖而令人兴奋的新发现，并将显著推进我们对青少年酒精暴露对成人认知功能和行为控制的影响的理解。

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 serve levels of intoxication. In addition to legal ramifications and concerns with physical safety, these patterns of alcohol consumption appear to adversely impact continued neuromaturation 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. Deficits in executive cognitive function are associated with loss of control over behavioral processes such as attention and emotion, and with increased engagement in risky behaviors such as unprotected sex and drug-taking. The latter includes a reduced ability to discontinue drug-taking once initiated resulting in escalation in, and loss of control over, consumption. 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. This hypothesis will be tested by an innovative and multidisciplinary set of experiments that utilize state-of the- art methodologies and procedures in a rat model of adolescent intermittent ethanol (AIE) exposure. The overarching hypothesis will be tested by four specific aims that will: 1) Determine the effects of AIE exposure on epigenetic modifications (histone acetylation) in identified populations of excitatory pyramidal and inhibitory interneurons in the medial PFC and dopamine (DA) projection neurons in the ventral tegmental area; 2) Determine the effects of AIE exposure upon DA modulation of excitatory pyramidal and inhibitory GABAergic interneurons in the adult medial PFC; 3) Determine the effects of AIE exposure and re-exposure to alcohol during adulthood on executive cognitive function using tasks that assess working memory, behavioral flexibility, and risk-taking behavior; and 4) Assess the effects of AIE exposure and reexposure to alcohol during adulthood on cognitively modulated synchronous activity and organization of neuronal ensembles in the mPFC. Together, these studies will yield novel and exciting new finding and will significantly advance our understanding of the effect of adolescent alcohol exposure on cognitive function and behavioral control in the adult.