Effects of Adolescent Alcohol Exposure on Decision Making in Adult Rats

摘要 这是一个指导研究科学家发展奖（K01）的应用程序，以支持职业生涯 发展石楠博士作为一个独立的学术研究员在酒精研究。 候选人是一个早期的调查员，以前在前额叶皮质功能领域接受过培训， 对酒精行业来说相对较新。提出了一个全面的指导和研究计划， 提供青少年酗酒及其对大脑的长期影响的神经生物学方面的培训， 行为申请人将获得的职业和研究培训将由一个强大的指导监督 我们的工作是建立一个强大的团队，并得到对候选人职业发展的强有力的机构承诺的支持。研究 建议是申请人最近在导师实验室进行的研究的延伸， 青春期酒精暴露对成年大鼠前额叶皮层（PFC）的影响。拟议的研究计划将 充分利用辅导团队和环境，使候选人能够制定研究计划 处于青少年酗酒领域的前沿。前额叶皮层是一个大脑区域， 认知功能和抑制控制，青春期是持续PFC的关键时期 与这些功能的成熟平行的发育。饮酒通常始于 在青春期，以暴饮暴食的模式大量消费是常见的。的改变 PFC功能与参与危险行为和不良决策的可能性增加有关。 流行病学证据表明，青少年酒精暴露可能导致终身认知缺陷， 行为的控制可能源于PFC正常发育轨迹的中断。然而， 成人PFC中被青少年酒精滥用破坏的特定细胞靶点仍不清楚， 将通过本提案中概述的实验来阐明。首要假设是， 青少年酒精暴露产生PFC的神经病理学，在成人中表现为 边缘前亚区深层锥体神经元多巴胺调节的缺陷及其 投射到皮质下核。这一假设将使用多学科方法进行检验， 包括膜片钳切片电生理学和涉及操作性任务的行为研究，以评估风险 决策的这些研究将确定持续性认知功能障碍的细胞机制 在青少年酒精暴露之后，产生了新颖和令人兴奋的新发现，并大大推进了我们的研究。 了解介导青少年酒精暴露对认知功能影响的细胞机制 在成人中的作用。这一培训和研究计划将共同提供一个坚实的基础， 申请人可以建立一个独立的研究计划。

ABSTRACT 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.