4/8: INIA Stress and Chronic Alcohol Interactions: Role of corticotropin-releasing factor in cortico- and thalamo-striatal pathways in regulating alcohol-stress interactions

4/8：INIA 压力和慢性酒精相互作用：促肾上腺皮质激素释放因子在皮质纹状体和丘脑纹状体通路中调节酒精压力相互作用的作用

• 批准号: 10412656
• 负责人: Jennifer Anne Rinker
• 金额: $ 45.05万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412656
• 关键词: Alcohol consumption; Alcohol dependence; Alcohols; Anterior; Anxiety; Automobile Driving; Behavior; Behavioral; Brain; CRH gene; Calcium; Cells; Characteristics; Choice Behavior; Chronic; Chronic stress; Cognition; Cognitive; Cognitive deficits; Collaborations; Complex; Computer Analysis; Conflict (Psychology); Corpus striatum structure; Corticotropin-Releasing Hormone; Costs and Benefits; Coupled; Data; Data Set; Decision Making; Dependence; Desire for food; Disease; Electrophysiology (science); Ethanol; Excision; Exposure to; Fiber; Fluorescence-Activated Cell Sorting; Genes; Genetic; Glutamates; Heavy Drinking; Hypothalamic structure; Image; Impaired cognition; Individual; Intervention; Investigation; Knock-out; Lead; Machine Learning; Medial; Mediating; Mental Depression; Modeling; Molecular; Mood Disorders; Motivation; Mus; Neurons; Nucleus Accumbens; Output; Pathway interactions; Phenotype; Photometry; Prefrontal Cortex; Regulation; Relapse; Rewards; Rodent Model; Role; Silicon; Site; Slice; Statistical Data Interpretation; Stress; Structure of paraventricular nucleus of thalamus; Study models; Swimming; Synapses; Synaptic plasticity; Task Performances; Techniques; Testing; Thalamic structure; Ventral Striatum; Work; affective disturbance; alcohol abstinence; alcohol abuse therapy; alcohol exposure; alcohol seeking behavior; alcohol use disorder; anxiety-like behavior; biological adaptation to stress; cognitive control; cognitive performance; comorbidity; density; design; differential expression; effective therapy; experimental study; flexibility; functional plasticity; human model; maladaptive behavior; motivated behavior; negative affect; neural circuit; neurobiological mechanism; neuropsychiatry; prevent; recruit; relating to nervous system; response; therapeutic target; transcriptome sequencing

PROJECT SUMMARY Alcohol use disorder (AUD) is a devastating neuropsychiatric condition that is characterized by chronic and relapsing episodes of excessive, uncontrolled alcohol consumption. AUD is also associated with significant disruption of brain function and behavior, frequently presenting with cognitive deficits and comorbid negative affective disorders (e.g., anxiety and depression). These negative affective and cognitive disturbances that are present during abstinence from alcohol drinking can drive relapse-like behaviors in both humans and rodent models and are often exacerbated by stress. Thus, alcohol and stress may be working synergistically to cause more profound cognitive deficits that lead to decreased cognitive control over alcohol consumption, but the molecular and cellular adaptations and the neurocircuitry underlying these concerted changes are not well understood. The ventral striatum, specifically the nucleus accumbens (NAc), mediates aspects of alcohol taking and seeking, negative affect, and is one of the primary outputs of both the medial prefrontal cortex (mPFC) and the anterior paraventricular thalamus (aPVT). These circuits mediate appetitive and reward-motivated behaviors, are sensitive to stress and alcohol, and are involved decision making and choice behaviors particularly during motivational conflict. Additionally, in both the mPFC and aPVT, pro-stress molecules, like corticotropin-releasing factor (CRF), are recruited and have been implicated in regulating responses to stress and/or alcohol. Thus, this component of the INIAstress Consortium seeks to understand the mechanisms and circuitry involved in the complex interaction between stress and alcohol exposure that engender such high rates of alcohol consumption, cognitive impairments, and negative affective states. We provide evidence that the chronic intermittent ethanol (CIE) exposure model and repeated forced swim stress (FSS) alter reward-choice behaviors under conditions of motivational conflict. We also show that mPFC CRF knockout blocks the escalation of alcohol drinking in the CIE-FSS model. The overarching hypothesis is that CIE-FSS hyper-recruits CRF in the mPFC and aPVT to promote excessive drinking, cognitive deficits, and anxiety-like phenotypes. In Aim 1, we will identify chronic alcohol- and stress-induced changes in synaptic and functional plasticity that occur in a CRF-dependent and independent manner in mPFC®NAc and aPVT®NAc circuitry. Studies in Aim 2 will focus on understanding the influence of CRF on mPFC function and circuitry using high-density silicon Neuropixels probes and fiber photometry. Finally, Aim 3 will identify the role of CRF in the aPVT and its influence on aPVT®NAc projections in the CIE-FSS model. The focus of this new INIAstress Consortium component is to understand the broader implications of CRF modulation of neurocircuitry regulating reward-guided behaviors in chronically stressed, alcohol dependent mice, which is critical to our understanding of the complex interaction between alcohol and stress, and aid in identifying promising therapeutic targets.

项目概要 酒精使用障碍（AUD）是一种破坏性的神经精神疾病，其特点是慢性和 过度、不受控制的饮酒复发也与显着相关。 大脑功能和行为破坏，经常出现认知缺陷和共病阴性 情感障碍（例如焦虑和抑郁）。这些负面情感和认知障碍。 戒酒期间出现的酒精会导致人类和啮齿动物出现类似复发的行为 模型，并且经常因压力而加剧，因此，酒精和压力可能协同作用导致。 更严重的认知缺陷导致对饮酒的认知控制能力下降，但 分子和细胞的适应以及这些协调变化背后的神经回路并不好 据了解，腹侧纹状体，特别是伏隔核（NAc），介导饮酒的各个方面。 和寻求、负面影响，是内侧前额叶皮层 (mPFC) 和 前室旁丘脑（aPVT）这些回路介导食欲和奖励动机行为， 对压力和酒精敏感，并且参与决策和选择行为，尤其是在 此外，在 mPFC 和 aPVT 中，促应激分子，如促肾上腺皮质激素释放。 因子（CRF）被招募并参与调节对压力和/或酒精的反应。 INIAstress 联盟的组成部分旨在了解涉及的机制和电路 压力和酒精暴露之间复杂的相互作用导致如此高的饮酒率， 我们提供的证据表明，慢性间歇性乙醇会导致认知障碍。 （CIE）暴露模型和重复强迫游泳压力（FSS）改变了条件下的奖励选择行为 我们还表明，mPFC CRF 敲除可以阻止饮酒的升级。 CIE-FSS 模型的总体假设是 CIE-FSS 过度招募 mPFC 和 aPVT 中的 CRF。 促进过度饮酒、认知缺陷和焦虑样表型 在目标 1 中，我们将识别慢性症状。 酒精和压力引起的突触和功能可塑性变化发生在 CRF 依赖性和 目标 2 中的研究将侧重于了解 mPFC®NAc 和 aPVT®NAc 电路中的独立方式。 使用高密度硅 Neuropixels 探针和光纤，CRF 对 mPFC 功能和电路的影响 最后，目标 3 将确定 CRF 在 aPVT 中的作用及其对 aPVT®NAc 投影的影响。 在 CIE-FSS 模型中，这个新的 INIAstress 联盟组件的重点是了解更广泛的内容。 CRF 调节神经回路调节长期压力下奖励引导行为的影响， 酒精依赖小鼠，这对于我们理解酒精和酒精之间复杂的相互作用至关重要 压力，并帮助确定有希望的治疗目标。