Effects of Adolescent Alcohol Exposure on Decision Making in Adult Rats

描述(由申请者提供)：这是一份申请导师研究科学家发展奖(K01)的申请书，以支持Heather Tratham-Davidson博士作为酒精研究领域的独立学术研究员的职业发展。应聘者是一名早期研究人员，曾接受过前额叶皮质功能方面的培训，对酒精领域相对较新。提出了一个全面的指导和研究计划，将提供关于青少年酗酒的神经生物学及其对大脑和行为的长期影响的培训。申请者将接受的职业和研究培训将由一个强大的指导团队监督，并得到对候选人职业发展的坚定机构承诺的支持。这项研究是申请人最近在导师的实验室中研究青少年酒精暴露对成年大鼠前额叶皮质(PFC)影响的扩展。拟议的研究计划将充分利用指导团队和环境，使候选人能够开发处于青少年酒精领域前沿的研究计划。PFC是一个与认知功能和抑制控制密切相关的大脑区域，青春期代表着PFC持续发展的关键时期，与这些功能的成熟平行。饮酒通常从青春期开始，那时大量饮酒，像狂欢一样发作，是很常见的。PFC功能的改变与从事危险行为和糟糕决策的可能性增加有关。流行病学证据表明，青少年饮酒可能导致终身行为认知控制缺陷，这可能源于PFC正常发育轨迹的中断。然而，成年人PFC中被青少年酗酒扰乱的特定细胞靶点仍不清楚，将通过本提案中概述的实验加以阐明。最重要的假设是，青少年酒精暴露会产生PFC的神经病理，在成人中表现为预区深层锥体神经元及其向皮质下核团投射的多巴胺调制缺陷。这一假设将使用包括膜片钳切片电生理学和行为研究在内的多学科方法进行验证，这些研究涉及操作任务以评估风险决策。这些研究将确定青少年酒精暴露后持续性认知功能障碍的细胞机制，产生新的和令人兴奋的新发现，并显著促进我们对青少年酒精暴露对成人认知功能影响的细胞机制的理解。这一培训和研究计划将为申请者建立独立的研究计划提供坚实的基础。

DESCRIPTION (provided by applicant): This is an application for a Mentored Research Scientist Development Award (K01) to support the career development of Dr. Heather Trantham-Davidson as an independent academic investigator in alcohol research. The candidate is an early-stage investigator with previous training in the area of prefrontal cortical function and is relatively new to the alcohol field. A comprehensive mentoring and research plan is presented that will provide training in the neurobiology of adolescent alcohol abuse and its long-term effects on brain and behavior. The career and research training the applicant will receive will be overseen by a strong mentoring team and supported by strong institutional commitment to the candidate's career development. The research proposed is an extension of the applicant's recent studies in the mentor's laboratory examining the effects of adolescent alcohol exposure on the prefrontal cortex (PFC) of adult rats. The proposed research plan will take full advantage of the mentoring team and environment to allow the candidate to develop a research program that is at the forefront of the adolescent alcohol field. The PFC is a brain region that is critically involved in cognitive function and inhibitory control, and adolescence represents a critical period of continued PFC development that parallels the maturation of these functions. Alcohol drinking typically begins during adolescence when consumption of large quantities, in binge-like episodic patterns, is common. Alterations in PFC function are associated with increased likelihood to engage in risky behaviors and poor decision-making. Epidemiological evidence suggests that adolescent alcohol exposure may result in life-long deficits in cognitive control of behavior that may stem from disruption of the normal developmental trajectory of the PFC. However, the specific cellular targets in the adult PFC that are disrupted by adolescent alcohol abuse remain unclear and will be elucidated by the experiments outlined in this proposal. The overarching hypothesis is that adolescent alcohol exposure produces a neuropathology of the PFC that manifests in the adult as deficits in dopamine modulation of deep-layer pyramidal neurons of the prelimbic subregion and its projections to subcortical nuclei. This hypothesis will be tested using a multidisciplinary approach that includes patch-clamp slice electrophysiology and behavioral studies involving operant tasks to assess risky decision-making. These studies will determine the cellular mechanisms of persistent cognitive dysfunction following adolescent alcohol exposure, yield novel and exciting new findings, and significantly advance our understanding of the cellular mechanisms mediating the effect of adolescent alcohol exposure on cognitive function in the adult. Together, this training and research plan will provide a solid foundation upon which the applicant can build an independent research program.