3/8: INIA Stress and Chronic Alcohol Interactions: Norepinephrine and corticostriatal circuit regulation of cognitive effort after chronic alcohol and stress

项目概要/摘要 长期饮酒会扰乱许多认知功能，包括注意力、记忆力、灵活性和其他功能。 执行控制方面。这是加剧了外源性压力和压力与酒精有关 使用和退出。我们假设，一个关键因素与广泛的认知功能障碍有关， 酒精使用是认知努力，这是维持各种认知功能所必需的，特别是在 需求量大的条件。特别是，我们假设长期饮酒和压力的历史破坏了 发挥认知努力的意愿和能力，相反，酒精前对认知努力的限制 预测未来的酗酒问题。人们对认知努力的神经基础有着浓厚的兴趣，但对我们来说， 尽管我们对酒精的认知程度不高，但没有研究在行为和行为上研究认知努力与酒精之间的关系。 或神经水平。在这里，我们将研究对认知努力至关重要并受压力影响的神经回路， 饮酒这个回路是由蓝斑去甲肾上腺素（LC-NE）系统形成的， 前扣带回皮质（ACC）和ACC的背内侧纹状体（DMS）的投射。独特的这个 建议是1）将这些系统集成到一个统一的电路中，2）在 认知努力、酒精和压力的综合框架。 我们将测量慢性间歇性乙醇（CIE）和/或强迫游泳应激（FSS）对意愿的影响 以及执行两项认知要求高的任务的能力（额外维度的集合转移和认知努力 在持续注意力任务中打折）。我们将在ACC中识别CIE/FSS相关变化 使用RNAscope进行去甲肾上腺素能调节，并用CRISPR介导的NE受体敲除进行探测（Aim 1）。我们将在CIE/FSS（目标2）后的认知表现期间记录该网络中的神经动力学， 使用光遗传学操纵该回路的活动，以可逆地破坏或挽救认知努力（目标3）。 最后，我们将与INIA神经免疫研究人员合作，以确定磷酸二酯酶的影响。 抑制剂阿普斯特对CIE/FSS后认知功能的影响，并表征其在该回路中的作用（目的4）。研究 将整合个体和性别差异，以利用行为的异质性及其与 潜在的神经功能 认知努力是一个新颖而强大的框架，用于研究酒精和压力对认知的影响。 我们的研究有可能将与认知和AUD相关的各种发现结合起来。通过识别变化 在CIE/FSS诱导的认知努力变化的神经回路中， 确定具有广泛影响力的AUD治疗方法，加强认知能力，作为抵御 酒精和压力的综合影响

PROJECT SUMMARY/ABSTRACT Chronic alcohol use disrupts a number of cognitive functions, including attention, memory, flexibility, and other aspects of executive control. This is exacerbated by both exogenous stress and stress associated with alcohol use and withdrawal. We hypothesize that a key factor relating widespread cognitive dysfunction to problematic alcohol use is cognitive effort, which is needed to sustain diverse cognitive functions, particularly under conditions of heavy demand. In particular, we hypothesize that a history of chronic alcohol and stress disrupts the willingness and ability to exert cognitive effort, and conversely, that pre-alcohol limitations in cognitive effort predict future problematic alcohol use. There is strong interest in the neural basis of cognitive effort, but to our knowledge, no studies have examined the relationship between cognitive effort and alcohol at either a behavioral or neural level. Here we will investigate a neural circuit critical for cognitive effort and impacted by stress and alcohol use. This circuit is formed by the locus coeruleus norepinephrine (LC-NE) system, its strong projections to the anterior cingulate cortex (ACC), and ACC projections to the dorsomedial striatum (DMS). Unique to this proposal is 1) the integration of these systems into a unified circuit and 2) the investigation of this circuit in the integrated framework of cognitive effort, alcohol, and stress. We will measure the impact of chronic intermittent ethanol (CIE) and/or forced swim stress (FSS) on willingness and ability to perform two cognitively-demanding tasks (extradimensional set shifting and cognitive effort discounting in a sustained attention task) in mice. We will identify CIE/FSS associated changes in ACC noradrenergic regulation using RNAscope and probe them with CRISPR-mediated NE receptor knockdown (Aim 1). We will record neural dynamics in this network during cognitive performance after CIE/FSS (Aim 2), and manipulate the activity of this circuit using optogenetics to reversibly disrupt or rescue cognitive effort (Aim 3). Finally, we will collaborate with INIA Neuroimmune investigators to identify the impact of the phosphodiesterase inhibitor apremilast on cognitive function after CIE/FSS and characterize its effect in this circuit (Aim 4). Studies will integrate individual and sex differences to capitalize on heterogeneity in behavior and its relationship to underlying neural function. Cognitive effort is a novel and powerful framework for investigating the impact of alcohol and stress on cognition. Our studies have the potential to unite diverse findings related to the cognition and AUD. By identifying changes in neural circuitry underlying CIE/FSS-induced changes in cognitive effort, there is significant potential for identifying broadly-influential treatments for AUD that strengthen cognitive abilities to serve as a bulwark against the combined influences of alcohol and stress.