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

项目摘要 决策障碍既是酒精使用障碍（AUD）的风险因素，也是其后果。 由于目前没有批准的药物治疗，这些损伤特别使人衰弱 旨在改善澳元的这方面。冲动性是一种行为表型，反映了大脑中 决策过程中，广泛的特点是倾向于采取行动没有远见，可以是 分成几种不同的亚型。非计划冲动是冲动的一个亚型， 不以计划或未来目标为指导的决策倾向。此外，在所有 冲动亚型最近的一项荟萃分析表明，非计划性冲动是一个强有力的预测因素， 人类的酒精依赖因此，迫切需要探索计划的神经基础， 冲动，以激发新的治疗方法能够解决这种病理。此外，此前 我们小组在啮齿类动物中的工作与人类受试者的数据一致，表明靶向前额叶 皮质（PFC）可能提供了一种有效的方式来减少成瘾相关的行为。总体 该项目的假设是，靶向PFC的病理学将挽救 在AUD的啮齿动物模型中观察到的决策。提出了一系列临床前研究， 使用严格和尖端的技术来测量和操纵清醒时的神经活动， 啮齿动物所用动物模型的异质性将扩大结果的影响，使它们 适用于有和没有酗酒问题家族史/遗传风险因素的人，以及 性别差异我们以前的工作和初步数据表明， 计划在过度饮酒的动物中被打乱。为了探索这种破坏的神经基础以及如何 修复它，设计师受体专门激活的设计师药物（DREADDs）将用于靶向和 在行为过程中控制PFC神经元的活动。此外，大规模的神经记录，从 PFC将在动物从事行为任务时进行，这些行为任务旨在测量冲动性， 饮酒的决定。最后，新颖而严格的统计程序和计算模型 方法将用于分析所获得的神经记录。这些方法将创建一个生成的 数据的模型，因此提供了这些神经元执行计算的详细情况。在 这样，PFC神经元在引导行为中所起作用的清晰的机制图像将被创建， 在神经活动和行为之间建立因果推理。总而言之，拟议工作将确定 如何在AUD的啮齿动物模型中改变决策以及如何改善它。这项工作将带来 研究计划更接近其长期目标，即激发新的治疗目标， 解决AUD中的决策受损问题。

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.