Mechanistic studies of alcohol-sleep interactions

摘要 睡眠失调是酒精使用障碍（AUDs）的标志，睡眠中断可导致 甚至在禁欲数月后复发。尽管睡眠-AUD相互作用已得到公认，但很少有研究表明， 研究了睡眠如何随着过度饮酒的发展而变化，以及 哪些睡眠中断会加剧饮酒和/或复发倾向在很大程度上是未知的。基于几个关键 从已发表的研究和初步工作的结果来看，一种假设是快速眼动睡眠中断会导致 内侧缰核（M）和外侧缰核（LHb）的适应不良变化，反过来又导致 酒精摄入量和促进复发。主要研究结果如下：1.术后2-3周时的特定REM睡眠缺陷 酒精戒断是酒精依赖患者复发的一个强有力的预测因素; 2.慢性、选择性 REM睡眠片段化增强了内侧血红蛋白神经元的紧张性放电和负性情绪; 3.酒精复发 寻找与MHb和LHb神经元的激活增加有关。4.睡眠碎片化 可卡因戒断期间的药物渴望，而选择性巩固快速眼动睡眠减少了渴望。 因此，据预测，长期饮酒和戒酒会导致REM睡眠中断，从而诱导 血红蛋白多动，促进消极的情感状态，驱动酒精和复发的动机。同样，它 据预测，慢性REM睡眠中断可以启动这个周期，导致发展的风险增加， AUD。因此，本提案中的目标1将评估慢性和逐步增加的饮酒的影响， 戒断对睡眠结构和Hb神经活性的影响。拟议的实验将使用间歇性 访问两瓶选择乙醇饮用范式结合慢性EEG/EMG记录和离体 切片电生理学预计基线REM睡眠特征或REM睡眠缺陷 饮酒/戒酒可以预测饮酒量以及Hb神经活性。目标2将 确定慢性快速眼动睡眠片段是否会促进间歇性睡眠中酒精摄入量的增加。 访问模式和/或促进复发的操作性自我管理模式。我们将进一步确定， REM睡眠对酒精摄入/复发的影响部分是由REM睡眠片段诱导的 Hb神经元过度活跃。目标3将测试改善REM睡眠的干预措施的治疗潜力。 利用最近开发的REM睡眠选择性操作，将确定选择性REM睡眠是否 巩固可以减少饮酒和复发，如果这与Hb活性降低有关。 总的来说，拟议中的研究将对快速眼动睡眠的发展潜力进行关键评估。 集中治疗，以防止复发，并提供新的机制洞察的相互作用 在缰核失调的背景下酒精摄入和睡眠稳态之间的关系。因此，这一提议是 与NIAAA RFA-AA-19-006的使命一致，即对慢性酒精使用进行机制研究 睡眠稳态

Abstract Sleep dysregulation is a hallmark of alcohol use disorders (AUDs) and disrupted sleep can contribute to relapse even after months of abstinence. Despite the well-recognized sleep-AUD interactions, few studies have investigated how sleep changes over the development of excessive drinking, and the mechanisms by which sleep disruptions exacerbate drinking and/or relapse liability are largely unknown. Based on several key findings from published studies and preliminary work, one hypothesis is that disrupted REM sleep induces maladaptive changes in the medial (M) and lateral habenula (LHb), which in turn contribute to escalated alcohol intake and promote relapse. The key findings are: 1. Specific REM sleep deficits at 2-3 weeks after alcohol withdrawal are a robust predicting factor for relapse in alcohol dependent patients; 2. Chronic, selective REM sleep fragmentation enhances medial Hb neuron tonic firing and negative affect; 3. Relapse to alcohol seeking is associated with increased activation of MHb and LHb neurons. 4. Sleep fragmentation precipitates drug craving during abstinence from cocaine, while selective consolidation of REM sleep reduces craving. Thus, it is predicted that chronic alcohol drinking and abstinence leads to disrupted REM sleep, which induces Hb hyperactivity, promoting a negative affective state that drives motivation for alcohol and relapse. Likewise, it is predicted that chronic REM sleep disruptions can initiate this cycle, leading to increased risk for developing AUDs. Therefore, aim 1 in this proposal will evaluate the effects of chronic and escalating alcohol drinking and abstinence on sleep architecture and Hb neural activity. The proposed experiments will use the intermittent access two-bottle choice ethanol drinking paradigm combined with chronic EEG/EMG recordings and ex vivo slice electrophysiology. It is expected that the baseline REM sleep features or the REM sleep deficits following alcohol drinking/abstinence may predict the amount of alcohol drinking as well as Hb neural activity. Aim 2 will determine if chronic REM sleep fragmentation promotes the escalation of alcohol intake in the intermittent access model and/or promotes relapse in an operant self-administration model. We will further determine if the REM sleep effects on alcohol intake/relapse are, in part, mediated by REM sleep fragmentation-induced hyperactivity of Hb neurons. Aim 3 will test the treatment potential of interventions that improve REM sleep. Utilizing recently developed REM sleep-selective manipulations, it will be determined if selective REM sleep consolidation can reduce alcohol drinking and relapse, and if this is associated with reduced Hb activity. Overall, the proposed studies will provide a critical assessment of the potential for developing REM sleep- focused therapeutics for preventing relapse, and provide novel mechanistic insight into the interactions between alcohol intake and sleep homeostasis in the context of habenula dysregulation. Thus, this proposal is consistent with the mission of NIAAA RFA-AA-19-006 to perform Mechanistic Studies on Chronic Alcohol Use and Sleep Homeostasis.