5/8: INIA Stress and Chronic Alcohol Interactions: Stress-induced Dysregulation of Prefrontal Cortex Circuitry and Plasticity in Alcohol Dependence

项目总结 酒精使用障碍是一个主要的公共健康问题，与大脑应激系统的激活改变有关， 认知缺陷，以及酗酒升级。前额叶皮质(PFC)是参与 执行认知功能和对奖励动机行为的抑制控制。改变的压力 责任感与过度饮酒的发展和维持有关，两者都是慢性的 乙醇和应激对PFC功能有负面影响。酒精使用障碍患者的认知缺陷 被认为阻碍了成功的治疗，并增加了复发的风险。临床前研究表明 慢性酒精暴露会在PFC产生夸大的应激反应，从而调节认知 损伤和不断升级的酒精饮酒。在目前的资助期内，我们确定了慢性乙醇- 小鼠和猴的前额叶核和伏隔核中的敏感蛋白和K+通道基因。我们 还确定了候选K+通道基因与酒精依赖饮酒之间的预测关系 BxD重组近交系小鼠，并经药理验证表明，正向调制a 钾离子通道显著减少应激依赖小鼠的饮酒升级。此外，我们 证明慢性应激只会增加酒精依赖小鼠的饮酒量，并增强 小鼠PFC中长时程增强(LTP)早期成分的大小。除 我们在应激小鼠中观察到的LTP增强，我们的初步数据表明，谷氨酸能信号转导 在长期服用乙醇后，猕猴的PFC有所增强。虽然我们知道慢性病 酒精和应激暴露诱导PFC的非适应性可塑性，其潜在的神经机制和 乙醇-应激相互作用诱导的PFC回路的适应性仍然知之甚少。致信地址 这一认识上的差距，我们提出了三个具体的目标，以检验最重要的假设 PFC回路和可塑性的破坏是过量饮酒和认知障碍产生的基础 由于长期的压力和酒精依赖。目标1的研究将检验慢性乙醇自我调节的假设 酒精依赖和应激之间的给药和相互作用在脑内产生功能适应 猴子和小鼠的PFC。目标2将测试可药物蛋白生成靶点的有效性，以减少升级 应激依赖的雄性和雌性小鼠饮酒。最后，目标3中的研究将检验这一假设 酒精依赖和慢性应激在PFC电路中产生异常信号，导致 不断升级的饮酒和认知障碍。除了确定可用药的目标外，来自 这些研究将提供有关特定电路、功能和形态的时间方面的数据 慢性应激和酒精对小鼠和猴子PFC的适应性。

PROJECT SUMMARY Alcohol use disorder is a major public health issue associated with altered activation of brain stress systems, cognitive deficits, and escalated alcohol drinking. The prefrontal cortex (PFC) is a key structure involved in executive cognitive function and imposing inhibitory control over reward-motivated behaviors. Altered stress responsivity is implicated in the development and maintenance of excessive alcohol drinking, and both chronic ethanol and stress negatively impact PFC function. Cognitive deficits in individuals with alcohol use disorder are thought to hinder successful treatment and contribute to increased risk for relapse. Preclinical studies show that chronic ethanol exposure produces an exaggerated stress response in the PFC that mediates cognitive impairments and escalated ethanol drinking. In the current funding period, we identified chronic ethanol- sensitive proteins and K+ channel genes in the PFC and nucleus accumbens (NAc) of mice and monkeys. We also identified predictive relationships between candidate K+ channel genes and drinking in ethanol-dependent BXD recombinant inbred strains of mice, and pharmacological validation showed that positive modulation of a KCa2 channels significantly reduces escalated drinking in stressed, dependent mice. Moreover, we demonstrated that chronic stress elevates drinking only in ethanol dependent mice and enhances the magnitude of the early component of long-term potentiation (LTP) in the mouse PFC. In addition to the enhanced LTP we observed in the stressed mice, our preliminary data shows that glutamatergic signaling in the PFC is enhanced in macaques following chronic ethanol self-administration. While it is known that chronic ethanol and stress exposure elicit maladaptive plasticity in the PFC, the underlying neural mechanisms and the adaptations in the PFC circuitry induced by ethanol-stress interactions remain poorly understood. To address this gap in our knowledge, we propose three specific aims that will test the overarching hypothesis that disruption of PFC circuitry and plasticity underlies the excessive drinking and cognitive impairments produced by chronic stress and ethanol dependence. Studies in Aim 1 will test the hypothesis that chronic ethanol self- administration and interactions between ethanol dependence and stress produce functional adaptations in the PFC of monkeys and mice. Aim 2 will test the efficacy of drugable proteogenetic targets to reduce escalated drinking in stressed dependent male and female mice. Finally, studies in Aim 3 will test the hypothesis that ethanol dependence and chronic stress produce aberrant signaling in PFC circuitry that contributes to escalated drinking and cognitive impairments. In addition to identifying drugable targets, the findings from these studies will provide data on the temporal aspects of circuit-specific, functional, and morphological adaptations produced by chronic stress and ethanol in the mouse and monkey PFC.