Effects of Adolescent Alcohol Exposure on Decision Making in Adult Rats

摘要 这是一份申请导师研究科学家发展奖(K01)以支持职业生涯的申请书 将Heather Tratham-Davidson博士发展为酒精研究领域的独立学术研究员。 候选人是一名早期研究人员，曾在前额叶皮质功能领域接受过培训，并 在酒精领域是相对较新的。提出了一个全面的指导和研究计划，将 提供有关青少年酗酒的神经生物学及其对大脑和 行为。申请人将接受的职业和研究培训将由一个强大的导师监督 团队精神和对候选人职业发展的坚定机构承诺的支持。这项研究 建议延长申请人最近在导师实验室进行的研究，以检验 青春期酒精暴露对成年大鼠前额叶皮质的影响。拟议的研究计划将需要 充分利用指导团队和环境，使应聘者能够制定研究计划 这是青少年饮酒领域的前沿。PFC是一个大脑区域，它关键地参与了 认知功能和抑制控制，青春期是持续PFC的关键时期 与这些功能的成熟相平行的发展。饮酒通常始于 青春期，以狂欢般的间歇性模式大量消费是很常见的。中的更改 PFC功能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认知障碍 对可能源于PFC正常发育轨迹中断的行为的控制。然而， 青少年酗酒扰乱成年前额叶细胞的特定细胞靶点仍不清楚 将通过这项提案中概述的实验加以阐明。最重要的假设是 青少年酒精暴露会导致PFC的神经病理，表现为成人AS 大脑皮层前亚区深层锥体神经元多巴胺调制缺陷及其机制 皮质下核团的投射。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任务的行为研究，以评估风险 决策。这些研究将确定持续性认知功能障碍的细胞机制。 在青少年接触酒精后，产生了新的和令人兴奋的新发现，并显著促进了我们的 青少年酒精暴露对认知影响的细胞机制研究 在成人中起作用。这项培训和研究计划将共同提供坚实的基础 申请者可以建立一个独立的研究项目。

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.