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

项目摘要 酒精使用障碍（AUD）是一种毁灭性的神经精神疾病，其特征是慢性和慢性的， 反复发作的过度不受控制的饮酒。澳元也与显著的 脑功能和行为中断，经常表现为认知缺陷和共病阴性 情感障碍（例如，焦虑和抑郁）。这些负面的情感和认知障碍 在人类和啮齿类动物中，戒酒期间存在的一种可能会导致类似复发的行为 模型，并往往加剧了压力。因此，酒精和压力可能协同作用， 更深刻的认知缺陷，导致对酒精消费的认知控制能力下降，但 分子和细胞的适应性以及这些协同变化背后的神经回路并不好 明白腹侧纹状体，特别是延髓核（NAc），介导酒精摄入的各个方面 和寻求，负面影响，是内侧前额叶皮层（mPFC）和 前室旁丘脑（aPVT）。这些回路调节食欲和奖励动机行为， 对压力和酒精敏感，特别是在 动机冲突。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， 因子（CRF）被招募，并参与调节对压力和/或酒精的反应。因此， INIastress联盟的一个组成部分试图了解参与的机制和电路， 压力和酒精暴露之间的复杂相互作用导致如此高的酒精消费率， 认知障碍和消极情感状态。我们提供的证据表明，慢性间歇性乙醇 (CIE)暴露模型和重复强迫游泳应激（FSS）改变奖励选择行为的条件下， 动机冲突。我们还表明，mPFC CRF敲除阻断了饮酒的升级， CIE-FSS模型。总体假设是CIE-FSS在mPFC和aPVT中过度募集CRF， 促进过度饮酒、认知缺陷和焦虑样表型。在目标1中，我们将确定慢性 酒精和应激诱导的突触和功能可塑性的变化，发生在CRF依赖性和 在mPFC®NAc和aPVT®NAc电路中，目标2的研究将侧重于了解 应用高密度硅神经元探针和光纤研究CRF对mPFC功能和回路影响 测光法最后，目标3将确定CRF在aPVT中的作用及其对aPVT®NAc预测的影响 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 慢性压力下CRF调节神经回路调节奖励导向行为的意义， 酒精依赖小鼠，这对我们理解酒精和酒精之间复杂的相互作用至关重要。 压力，并帮助确定有前途的治疗目标。

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.