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

项目总结 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 过度、无节制的饮酒反复发作。澳元还与重要的 大脑功能和行为紊乱，经常表现为认知缺陷和共病的消极情绪 情感障碍(如焦虑和抑郁)。这些消极的情感和认知障碍是 戒酒期间出现的酒精会在人类和啮齿类动物中引发复发行为 而且往往会因压力而加剧。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同变化背后的神经回路并不是很好。 明白了。腹侧纹状体，特别是伏隔核(NAC)，调节酒精摄取的各个方面。 和寻求，负性情绪，是内侧前额叶皮质(MPFC)和 前侧室旁丘脑(APVT)。这些回路调节食欲和奖励动机的行为， 对压力和酒精敏感，并参与决策和选择行为，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(CRF)被招募，并参与调节对压力和/或酒精的反应。因此，这一点 INIAStress联合体的组成部分试图了解参与 压力和酒精暴露之间的复杂相互作用导致了如此高的饮酒率， 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)改变了在以下条件下的奖赏选择行为 动机冲突。我们还表明，mPFC CRF基因敲除阻止了饮酒行为的升级 CIE-FSS模型。最重要的假设是CIE-FSS在mPFC和aPVT中过度招募CRF以 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CRF依赖和应激诱导的突触和功能可塑性的变化 在mPFC®NAC和aPVT®NAC电路中采用独立方式。AIM 2的研究将集中于了解 CRF对高密度硅神经素探针和光纤mPFC功能和电路的影响 测光学。最后，目标3将确定CRF在aPVT中的作用及其对aPVT®NAC投射的影响 在CIE-FSS模型中。这个新的INIAStress Consortium组件的重点是了解更广泛的 慢性应激时CRF对调节奖赏行为的神经回路的调节作用 酒精依赖小鼠，这对于我们理解酒精和酒精之间的复杂相互作用至关重要 压力，并帮助确定有希望的治疗靶点。

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.