Role of Prefrontal Cortical Projections to the Midbrain in Alcohol-Induced Cognitive Deficits in Mice

项目概要和摘要 酒精使用障碍（AUD）影响了美国1500万以上的美国人， 对受这种疾病影响的人的整体健康和生活质量的后果。尽管如此，只有围绕 7%的AUD患者寻求治疗，但护理选择仍然有限，因此迫切需要 对AUD的发展和治疗进行更多的研究。一个主要的兴趣来源在于什么因素 某些饮酒的人比其他人更容易患上AUD，这可以提供洞察力。 针对这一人群的具体预防和治疗措施。反应认知域缺陷 抑制和认知灵活性被认为是AUD后期发展的危险因素， 更严重的酒精诱导的认知功能障碍的预测因素。内侧前额叶皮层（mPFC）位于 大脑回路的中心，介导已知在AUD中受损的认知功能方面， 研究酒精暴露影响的潜在神经通路一直是研究的主要领域。 领域人类神经影像学研究已经确定了mPFC投射神经元到腹侧被盖区（VTA） 作为一个重要的回路，在奖励处理和启动目标导向的行为，以及酒精的渴望， AUD模型。本提案的目的是利用尖端技术在单细胞体内钙成像 和小鼠的行为任务，以了解这一重要但未充分研究的途径对 既存和酒精诱导的认知功能缺陷。使用复杂的操作性正强化 行为范例来测试小鼠的认知灵活性和反应抑制的领域， 在体单细胞钙离子成像动力学的mPFC → VTA投射作为小鼠完成任务，我将研究 这条通路是如何响应和改变的，因为老鼠在酒精暴露前后学习。我先学习 反应抑制和认知灵活性的认知功能是否存在个体差异， 小鼠在基线与操作性行为任务，之后，我将表征的活动模式， 使用头戴式显微内窥镜捕获真实的时间神经元活动的mPFC → VTA投射神经元 在自由活动的老鼠学习任务时，mPFC中的这些投射。此外，使用纵向 跟踪分析，我将确定是否有小鼠之间的活动模式的个体差异， 基线认知功能的变化以及这些变化在酗酒后如何演变， 两瓶选择任务完成此提案将提供有价值的深入了解电路级的变化 这是个体对酒精诱导的认知缺陷的脆弱性差异的基础， 作为一个未来的独立学术研究者，这对我来说是非常宝贵的训练。

Project Summary and Abstract Alcohol Use Disorder (AUD) impacts upwards of 15 million Americans in the United States and has many consequences on overall health and quality of life for people affected by this disorder. Despite this, only around seven percent of people with AUD seek treatment and options for care remain limited, creating an urgent need for more research into the development and treatment of AUD. A major source of interest lies in what factors predispose certain individuals who consume alcohol over others to develop AUD, which can provide insight into specific preventative and treatment measures for this population. Deficits in cognitive domains of response inhibition and cognitive flexibility have been implicated as risk factors for later development of AUD and are predictors of more severe alcohol induced cognitive dysfunction. The medial prefrontal cortex (mPFC) is at the center of the brain circuitry that mediates aspects of cognitive function known to be impaired in AUD and studying the underlying neural pathways impacted by alcohol exposure has been a major area of study in the field. Human neuroimaging studies have identified mPFC projecting neurons to ventral tegmental area (VTA) as an important circuit in reward processing and initiation of goal directed behavior as well as alcohol craving in AUD models. The aim of this proposal is to utilize cutting edge techniques in single cell in vivo calcium imaging and behavioral tasks in mice to understand the contribution of this important but understudied pathway to preexisting and alcohol-induced deficits in cognitive function. Using complex operant positive reinforcement behavioral paradigms to test domains of cognitive flexibility and response inhibition in mice combined with single cell in vivo calcium imaging dynamics of mPFC→VTA projections as mice complete the task, I will study how this pathway responds to and changes as mice learn before and after alcohol exposure. I will first study whether there are individual differences in cognitive function in response inhibition and cognitive flexibility in mice at baseline with an operant behavioral task, after which I will characterize the activity pattern of mPFC→VTA projecting neurons using head mounted microendoscopes to capture real time neuronal activity of these projections in the mPFC in freely behaving mice as they learn the tasks. Further, using longitudinal tracking analysis, I will determine if there are individual differences in activity patterns between mice with variations in baseline cognitive function and how these changes evolve after binge drinking alcohol exposure in a two-bottle choice task. Completion of this proposal will provide valuable insight into the circuit level changes that underlie individual differences in vulnerability to alcohol induced cognitive deficits and will provide invaluable training for me as a future independent academic researcher.