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: 10277796
• 负责人: CRISTINE L CZACHOWSKI
• 金额: $ 44.44万
• 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/10277796
• 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 risk factor; human data; human model; human subject; improved; neural circuit; neural correlate; neural patterning; novel; novel strategies; pre-clinical; preclinical study; programs; psychologic; relating to nervous system

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，又是结果。 这些障碍特别令人衰弱，因为目前尚无批准的药物治疗 旨在改善AUD的这一方面。冲动性是一种反映了反映改变的行为表型 决策过程，并且被广泛地描述为无视行动的趋势，可以是 分馏为几种不同的亚型。非计划冲动性是冲动性的亚型 倾向于以不受计划或未来目标指导的方式做出决策。此外， 冲动性亚型最近的荟萃分析表明，非计划的冲动性是强大的预测指标 人类的酒精依赖。因此，迫切需要探索计划的神经基础和 激发能够解决这种病理的新型治疗方法的冲动。另外，以前 我们小组的啮齿动物的工作与来自人类受试者的数据收敛，这些数据表明靶向前额叶 皮层（PFC）可以提供一种有效的方法来减少与成瘾相关的行为。总体 该项目的假设是针对PFC的病理学将挽救障碍 在AUD的啮齿动物模型中观察到决策。提出了一系列临床前研究 使用严格而尖端的技术来衡量和操纵醒着的神经活动 啮齿动物。使用的动物模型中的异质性将通过使结果扩大结果的影响 适用于有或没有家族病史/遗传危险因素的患者，饮酒以及 性别差异。我们以前的工作和初步数据表明，神经和行为签名 在过多的饮用动物中，计划中断。探索这种破坏的神经基础以及如何 修复它，设计器药物（Dreadds）专门激活的设计器受体将用于靶向和 在行为过程中操纵PFC神经元的活性。此外，来自 当动物从事旨在衡量冲动或的行为任务时，将进行PFC 饮酒的决定。最后，新颖而严格的统计程序和计算建模 方法将用于分析获得的神经记录。这些方法将产生生成 数据模型，因此提供了这些神经元执行的计算的详细图片。在 这样，PFC神经元在指导行为中扮演的角色的清晰机械形象将由 在神经活动和行为之间建立因果推断。总而言之，拟议的工作将确定 在AUD的啮齿动物模型以及如何改善它的啮齿动物模型中，如何改变决策。这项工作将带来这个 研究计划更接近其长期目标，即激发能够治疗的新颖目标 解决AUD决策受损。