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

前额皮质投射到中脑在小鼠酒精引起的认知缺陷中的作用

• 批准号: 10751160
• 负责人: Evelyn Kandov
• 金额: $ 3.54万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751160
• 关键词: Address; Affect; Alcohol consumption; Alcohols; American; Area; Behavior; Behavioral; Behavioral Assay; Behavioral Paradigm; Calcium; Caring; Cells; Cognitive; Cognitive deficits; Complex; Corpus striatum structure; Development; Discrimination; Disease; Disease model; Endoscopy; Event; Exhibits; Exposure to; Functional Magnetic Resonance Imaging; Future; Glutamates; Goals; Head; Health; Human; Image; Impaired cognition; Impairment; Implant; Individual; Individual Differences; Internet; Investigation; Knowledge; Learning; Maintenance; Measures; Medial; Mediating; Microscope; Midbrain structure; Morbidity - disease rate; Mus; Neural Pathways; Neurons; Pathway interactions; Pattern; Performance; Persons; Phase; Play; Population; Positive Reinforcements; Predisposing Factor; Predisposition; Prefrontal Cortex; Preventive measure; Quality of life; Research; Research Personnel; Resolution; Reversal Learning; Risk Factors; Role; Running; Signal Transduction; Source; Stimulus; Structure; Techniques; Testing; Time; Training; United States; Variant; Ventral Tegmental Area; Viral; addiction; alcohol abuse therapy; alcohol craving; alcohol exposure; alcohol use disorder; binge drinking; brain circuitry; cognitive change; cognitive control; cognitive function; cognitive performance; design; flexibility; human data; in vivo; in vivo calcium imaging; insight; interest; maladaptive behavior; microendoscope; mortality; neuroimaging; response; reward processing

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.

项目概要和摘要 酒精使用障碍 (AUD) 影响着美国超过 1500 万美国人，并导致许多人 尽管如此，对受这种疾病影响的人的整体健康和生活质量的影响仅在大约范围内。 7% 的 AUD 患者寻求治疗，但护理选择仍然有限，因此需求迫切 对 AUD 的发展和治疗进行更多研究的主要兴趣在于哪些因素。 某些饮酒者比其他人更容易产生 AUD，这可以提供见解 针对该人群认知领域反应缺陷的具体预防和治疗措施。 抑制和认知灵活性已被认为是 AUD 后期发展的危险因素，并且 内侧前额皮质（mPFC）是更严重的酒精引起的认知功能障碍的预测因子。 大脑回路的中心，介导已知在 AUD 和中受损的认知功能的各个方面 研究受酒精暴露影响的潜在神经通路一直是该领域的一个主要研究领域 人类神经影像学研究已确定 mPFC 向腹侧被盖区 (VTA) 投射神经元。 作为奖励处理和目标导向行为的启动以及酒精渴望的重要回路 AUD 模型的目的是利用单细胞体内钙成像的尖端技术。 和小鼠的行为任务，以了解这一重要但尚未充分研究的途径的贡献 使用复杂的操作性积极强化来治疗先前存在的和酒精引起的认知功能缺陷。 测试小鼠认知灵活性和反应抑制领域的行为范式 当小鼠完成任务时，mPFC→VTA预测的单细胞体内钙成像动态，我将研究 我将首先研究小鼠在接触酒精之前和之后学习的反应途径和变化。 反应抑制和灵活性的认知功能是否存在个体差异 小鼠在基线上执行操作行为任务，之后我将描述其活动模式 mPFC→VTA 使用头戴式显微内窥镜投射神经元来捕获实时神经元活动 进一步，使用纵向研究在自由行为的小鼠中进行这些预测。 跟踪分析，我将确定具有以下特征的小鼠之间的活动模式是否存在个体差异 基线认知功能的变化以及这些变化在酗酒后如何演变 完成该提案将为了解电路级别的变化提供宝贵的见解。 这是酒精引起的认知缺陷的个体差异的基础，并将提供 对我作为未来的独立学术研究员来说是非常宝贵的培训。