Dopamine activity patterns in the medial prefrontal cortex underlying compulsive alcohol drinking in mice

小鼠强迫性饮酒背后的内侧前额叶皮层多巴胺活动模式

• 批准号: 10662227
• 负责人: Patrick Robert Melugin
• 金额: $ 3.29万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10662227
• 关键词: Acute; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohols; Animal Model; Animals; Association Learning; Automobile Driving; Behavior; Behavioral; Bilateral; Cannulas; Chronic; Clinical; Complex; Consumption; Corpus striatum structure; Decision Making; Development; Disease; Disparate; Dopamine; Dopamine Receptor; Economic Burden; Female; Fiber; Fiber Optics; Goals; Heavy Drinking; Home; Implant; Individual; Individual Differences; Investigation; Maintenance; Measures; Medial; Mediating; Microdialysis; Modeling; Monitor; Motivation; Mus; Neocortex; Neurons; Norepinephrine; Opsin; Pathway interactions; Patients; Pattern; Periodicity; Photometry; Predisposition; Prefrontal Cortex; Procedures; Prognosis; Protocols documentation; Public Health; Punishment; Quinine; Relapse; Research Personnel; Resistance; Risk Factors; Role; Scanning; Self Administration; Self Assessment; Signal Transduction; Site; Societies; Structure; System; Techniques; Testing; Time; Training; United States; Ventral Tegmental Area; Viral Vector; Virus; Woman; addiction; adverse outcome; alcohol availability; alcohol effect; alcohol exposure; alcohol use disorder; alcohol use initiation; behavior test; behavioral outcome; cell type; disorder risk; dopamine system; drinking; drinking behavior; experience; in vivo; insight; male; men; neocortical; neural circuit; neural correlate; neuroadaptation; novel; optical fiber; optogenetics; photoactivation; pre-clinical; preventable death; real time monitoring; receptor expression; resilience; response; sensor; temporal measurement; theories

Project Summary and Abstract Alcohol use disorder (AUD) is a chronic, relapsing disorder that is profoundly debilitating to those directly affected while placing enormous economic burden onto society. In the United States, a majority of adults consume alcohol on a monthly basis yet only a small subset of these individuals will go on to develop AUD, thus highlighting a critical need to identify risk factors underlying the transition or resilience to problematic drinking behaviors. Continued use of alcohol despite adverse consequences is a distinguishing feature of AUD that is mediated, in part, by the medial prefrontal cortex (mPFC). Activity in the mPFC is robustly modulated by the mesocortical dopamine system, a dopaminergic pathway projecting to the mPFC from the ventral tegmental area that is believed to influence a wide range of behaviors related to decision-making, response inhibition, and motivation. Clinical evidence indicates that both pre-existing and alcohol-induced alterations to the mesocortical dopamine system are critical in the development and maintenance of AUD. However, preclinical investigations of maladaptive drinking behaviors and their neural correlates involving animal models have remained predominantly focused on neuroadaptations at specific time points and as a result, often preclude assessment of pre-existing differences and how these interact with alcohol-induced changes to produce disparate behavioral outcomes. A main goal of this proposal is to longitudinally monitor real-time endogenous dopamine release dynamics within-subjects to ultimately identify dopamine release signatures in the mPFC that are associated with susceptibility to developing AUD-relevant behaviors in mice. To this end, we will use operant alcohol self-administration, punished alcohol self-administration using quinine adulteration, and free-access drinking procedures to assess the development of individual differences over multiple timepoints and drinking experience. Utilizing in vivo fiber photometry in conjunction with a novel dopamine sensor, we will measure real-time dopamine release in the mPFC throughout these behavioral tests. Further, using cell-type and projection-specific optogenetics we will directly test the impact of mPFC dopamine system activity on alcohol self-administration behaviors. Completion of this proposal will provide valuable insight into the role of mesocortical dopamine system in AUD-relevant behaviors and provide technical and conceptual training foundational to pursing my goals as an alcohol researcher.

项目概要和摘要 酒精使用障碍（AUD）是一种慢性复发性疾病，对那些直接 同时给社会带来巨大的经济负担。在美国，大多数成年人 每月饮酒，但只有一小部分人会继续发展AUD， 因此，突出表明迫切需要确定向有问题的环境过渡或恢复能力的风险因素， 饮酒行为。尽管有不良后果，但继续使用酒精是AUD的一个显著特征 这部分是由内侧前额叶皮层（mPFC）介导的。mPFC的活性受到以下因素的强烈调节： 中皮层多巴胺系统，一条从腹侧投射到mPFC的多巴胺能通路 被盖区，被认为影响与决策，反应， 抑制和动机。临床证据表明，既存和酒精诱导的改变， 中皮层多巴胺系统在AUD的发展和维持中起关键作用。然而，在这方面， 涉及动物模型的适应不良饮酒行为及其神经相关因素的临床前研究 仍然主要集中在特定时间点的神经适应上，因此， 排除评估预先存在的差异以及这些差异如何与酒精诱导的变化相互作用， 产生不同的行为结果。该建议的主要目标是纵向监测实时 受试者体内的内源性多巴胺释放动力学，以最终鉴定 mPFC与小鼠发展AUD相关行为的易感性相关。为此目的， 我们将使用操作性酒精自我管理，使用奎宁掺假的惩罚性酒精自我管理， 和自由饮用程序，以评估个体差异的发展， 时间点和饮酒经验。结合新型多巴胺使用体内纤维光度法 传感器，我们将在这些行为测试中测量mPFC中的实时多巴胺释放。此外，本发明还 使用细胞类型和投射特异性光遗传学，我们将直接测试mPFC多巴胺系统的影响。 酒精自我管理行为。完成本建议书将提供宝贵的见解， 中皮层多巴胺系统在听觉诱发障碍相关行为中作用，并提供技术和概念 作为一名酒精研究者，这是我追求目标的基础。