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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要和摘要酒精使用障碍（AUD）是一种慢性复发障碍，直接使人衰弱在将巨大的经济负担放在社会上时受到影响。在美国，大多数成年人每月食用酒精，但这些人中只有一小部分会继续发展AUD，因此，强调了确定过渡或韧性有问题的危险因素的关键需求饮酒行为。尽管后果不利，但继续使用酒精是AUD的显着特征这部分由内侧前额叶皮层（MPFC）介导。 MPFC中的活动由中皮层多巴胺系统，这是一种从腹侧投射到MPFC的多巴胺能途径被认为会影响与决策，反应有关的广泛行为的细分区域抑制和动力。临床证据表明，现有和酒精诱导的改变中皮层多巴胺系统对于AUD的开发和维护至关重要。然而，适应不良饮酒行为及其神经相关性的临床前研究涉及动物模型在特定时间点上主要关注神经照顾，因此通常排除先前存在差异的评估以及它们与酒精诱导的变化如何相互作用的评估产生不同的行为结果。该提案的主要目标是纵向监视实时内源性多巴胺释放动力学内部受试者，最终识别多巴胺释放特征与在小鼠中发展相关行为的敏感性相关的MPFC。为此，我们将使用饮酒自我管理，使用奎宁掺假来惩罚酒精自我给药，和自由访问饮酒程序，以评估多个人个体差异的发展时间点和饮酒经验。与新型多巴胺结合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。更远，使用细胞类型和投影特异性光遗传学，我们将直接测试MPFC多巴胺系统的影响酒精自我管理行为的活动。该提案的完成将为您提供宝贵的见识中皮层多巴胺系统在相关的行为中的作用，并提供技术和概念培训基础，以追求我作为酒精研究人员的目标。