Targeting computation in prefrontal cortex to improve decision-making and reduce compulsive drinking in rodent models.

针对前额皮质的计算，以改善啮齿动物模型中的决策并减少强迫性饮酒。

• 批准号: 10675561
• 负责人: CRISTINE L CZACHOWSKI
• 金额: $ 43.2万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675561
• 关键词: Address; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Animal Model; Animals; Behavior; Behavior Control; Behavioral; Biological; Brain; Brain region; Chronic; Computational Technique; Computer Models; Cues; Data; Decision Making; Development; Diagnosis; Electrophysiology (science); Exhibits; Family; Family history of; Functional disorder; Future; Genetic; Goals; Heavy Drinking; Heterogeneity; Human; Impairment; Impulsive Behavior; Impulsivity; Individual; Measures; Meta-Analysis; Modeling; Myopia; Neurons; Neurophysiology - biologic function; Pathology; Pharmacotherapy; Play; Predisposing Factor; Prefrontal Cortex; Prevalence; Procedures; Process; Quinine; Recording of previous events; Research; Rewards; Risk; Risk Factors; Rodent; Rodent Model; Role; Series; Sex Differences; System; Techniques; Testing; Work; addiction; alcohol consequences; alcohol exposure; alcohol use disorder; awake; behavior measurement; behavioral impairment; behavioral phenotyping; cell type; chronic alcohol ingestion; cortical catecholamine; data modeling; design; designer receptors exclusively activated by designer drugs; disorder risk; drinking; experimental study; functional restoration; genetic approach; genetic risk factor; human data; human model; human subject; improved; neural; neural circuit; neural correlate; neural patterning; novel; novel strategies; pre-clinical; preclinical study; programs; psychologic; remediation

Project Summary Impairments in decision-making are both a risk factor for and consequence of an Alcohol Use Disorder (AUD). These impairments are particularly debilitating as there are currently no approved pharmacotherapies designed to improve this aspect of an AUD. Impulsivity is a behavioral phenotype that reflects alterations in the decision-making process and is broadly characterized as the tendency to act without foresight and can be fractionated into several different subtypes. Non-planning impulsivity is a subtype of impulsivity characterized by the tendency to make decisions in a way that is not guided by plans or future goals. In addition, of all impulsivity subtypes a recent meta-analysis indicates that non-planning impulsivity is a strong predictor of alcohol dependence in humans. Therefore, there is a critical need to explore the neural basis of planning and impulsivity to inspire novel treatment approaches capable of addressing this pathology. In addition, previous work from our group in rodents converges with data from human subjects that indicates targeting the prefrontal cortex (PFC) may provide an effective way to reduce addiction-associated behaviors. The overarching hypothesis of this project is that targeting the pathology of the PFC will rescue impairments in decision-making observed in rodent models of AUD. A series of preclinical studies are proposed that will use rigorous and cutting-edge techniques to measure and manipulate neural activity in awake, behaving rodents. Heterogeneity in the animal models used will broaden the impact of the results by making them applicable to those with and without family history/genetic risk factors for problematic alcohol use as well as sex differences. Our previous work and preliminary data indicate that neural and behavioral signatures of planning are disrupted in excessive drinking animals. To explore the neural basis of this disruption and how to fix it, designer receptors exclusively activated by designer drugs (DREADDs) will be used to target and manipulate the activity of PFC neurons during behavior. In addition, large scale neural recordings from the PFC will be performed while animals are engaged in behavioral tasks designed to either measure impulsivity or the decision to consume alcohol. Finally, novel and rigorous statistical procedures and computational modeling approaches will be used to analyze the neural recordings obtained. These approaches will create a generative model of the data and therefore provide a detailed picture of the computations performed by these neurons. In this way, a clear mechanistic picture of the role that PFC neurons play in guiding behavior will be created by establishing causal inference between neural activity and behavior. In summary, the proposed work will identify how decision-making is altered in rodent models of AUD and how to improve it. This work will bring this program of research closer to its long-term goal of inspiring novel targets for treatment that are capable of addressing impaired decision-making in AUD.

项目摘要 决策障碍既是酒精使用障碍(AUD)的危险因素，也是其后果。 这些损伤尤其使人虚弱，因为目前还没有批准的药物疗法 旨在改善澳元的这一方面。冲动是一种行为表型，它反映了 决策过程，被广泛描述为行动没有远见的倾向，可以 分成几个不同的亚型。非计划性冲动是冲动的一个子类型 倾向于以一种不受计划或未来目标指导的方式做出决定。此外，在所有人中， 冲动亚型最近的一项荟萃分析表明，非计划性冲动是 人类对酒精的依赖。因此，迫切需要探索规划和管理的神经基础 激发能够解决这种病理的新的治疗方法的冲动。此外，以前的 我们对啮齿动物的研究与来自人类受试者的数据相一致，表明目标是前额叶 皮质(PFC)可能为减少成瘾相关行为提供了一种有效的方法。最重要的是 该项目的假设是，针对PFC的病理将挽救 在AUD啮齿动物模型中观察到的决策。提出了一系列临床前研究，将 使用严谨和尖端的技术来测量和操纵清醒、行为 啮齿动物。使用的动物模型的异质性将扩大结果的影响，使它们 适用于有或没有家族病史/有问题饮酒的遗传风险因素的人以及 性别差异。我们之前的工作和初步数据表明，神经和行为特征 在过量饮酒的动物身上，计划被打乱。为了探索这种干扰的神经基础以及如何 修复它，由设计师药物(DREADD)独家激活的设计师受体将被用于靶向和 在行为过程中操纵PFC神经元的活动。此外，大规模的神经记录来自 PFC将在动物从事行为任务时进行，这些任务旨在测量冲动或 饮酒的决定。最后，新颖而严谨的统计程序和计算模型 将使用各种方法来分析获得的神经记录。这些方法将创造一个生成性的 数据模型，因此提供了这些神经元执行的计算的详细图像。在……里面 通过这种方式，PFC神经元在引导行为中扮演的角色将产生一幅清晰的机械图景 建立神经活动和行为之间的因果推理。总之，拟议的工作将确定 AUD啮齿动物模型的决策是如何改变的，以及如何改进。这项工作将带来这一点 更接近其长期目标的研究计划，即激发新的治疗靶点，能够 解决澳元决策受损的问题。