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

项目摘要和摘要 酒精使用障碍(AUD)是一种慢性、复发性障碍，对那些直接 在给社会带来巨大经济负担的同时，也受到了影响。在美国，大多数成年人 每月饮酒，但这些人中只有一小部分人会继续患上AUD， 从而突出了确定向有问题的过渡或恢复能力背后的风险因素的迫切需要 饮酒行为。不顾不良后果继续饮酒是AUD的一个显著特征 这在一定程度上是由内侧前额叶皮质(MPFC)介导的。MPFC中的活动受到以下因素的有力调节 中皮质多巴胺系统，一种从腹侧投射到mPFC的多巴胺能通路 被认为影响与决策、反应相关的广泛行为的被盖区 抑制力和动力。临床证据表明，先前存在的和酒精诱导的改变都是 大脑皮层多巴胺系统在AUD的发生和维持中起关键作用。然而， 不适应性饮酒行为及其神经相关动物模型的临床前研究 仍然主要关注特定时间点的神经适应，因此，通常 排除了对先前存在的差异的评估，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。该提案的一个主要目标是纵向监控实时 内源性多巴胺释放动力学-受试者最终确定多巴胺释放特征 MPFC与小鼠发生AUD相关行为的易感性有关。为此， 我们将使用操纵性酒精自我管理，使用奎宁掺假惩罚酒精自我管理， 和免费饮酒程序，以评估多个个体之间的发展差异 时间点和饮酒经验。体内纤维光度法与新型多巴胺的联合应用 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， 利用细胞类型和投射特异的光遗传学，我们将直接测试mPFC多巴胺系统的影响 酒精自我给药行为的活跃性。该提案的完成将为以下方面提供有价值的见解 中皮质多巴胺系统在AUD相关行为中的作用并提供技术和概念 作为一名酒精研究人员，为了追求我的目标，我接受了基础培训。

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.