Mechanistic studies of alcohol-sleep interactions

摘要 睡眠失调是酒精使用障碍(AUD)的一个标志，睡眠中断可能导致 即使在几个月的禁欲之后也会复发。尽管睡眠与AUD的相互作用是公认的，但很少有研究 研究了睡眠如何在过度饮酒的发展过程中发生变化，以及通过 哪些睡眠中断会加剧饮酒和/或复发，在很大程度上是未知的。基于几个关键字 从已发表的研究和初步工作中发现，一个假说是，快速眼动睡眠中断会导致 内侧缰核(M)和外侧缰核(LHb)的不良适应变化，进而导致升级 饮酒和促进复发。主要发现如下：1.术后2-3周出现特定的快速眼动睡眠缺陷 戒酒是酒精依赖患者复发的有力预测因素；2.慢性的、选择性的 REM睡眠碎片增强内侧Hb神经元紧张性放电和负性效应；3.酒精复吸 寻找与MHb和LHb神经元的激活增加有关。4.睡眠碎片化 在可卡因戒断期间的药物渴望，而选择性巩固的快速眼动睡眠减少渴望。 因此，据预测，长期饮酒和戒酒会导致快速眼动睡眠中断，从而导致 Hb过度活跃，促进一种消极的情感状态，从而推动饮酒和复发的动机。同样，它 据预测，慢性快速眼动睡眠中断会启动这一循环，导致发生疾病的风险增加 AUDS。因此，本提案中的目标1将评估长期和不断升级的饮酒和 戒断睡眠结构和Hb神经活动。拟议的实验将使用间歇性的 结合慢性脑电/肌电记录和体外实验的两瓶选择酒精饮酒范例 切片电生理学。预计基线REM睡眠特征或REM睡眠缺陷如下 饮酒/戒酒可以预测饮酒量和Hb神经活动。目标2将 确定慢性REM睡眠片断是否促进间歇性酒精摄入量的增加 访问模型和/或在可操作的自我管理模型中促进复发。我们将进一步确定是否 REM睡眠对酒精摄取/复发的影响在一定程度上是由REM睡眠碎片诱导的 Hb神经元过度活跃。目标3将测试改善快速眼动睡眠的干预措施的治疗潜力。 利用最近开发的快速眼动睡眠选择性操作，将确定选择性快速眼动睡眠 巩固可以减少饮酒和复发，如果这与减少Hb活动有关。 总体而言，拟议的研究将对发展快速眼动睡眠的潜力进行关键评估-- 预防复发的聚焦疗法，并为相互作用提供新的机制洞察力 缰核失调背景下酒精摄入和睡眠稳态之间的关系。因此，这项建议是 与NIAAA RFA-AA-19-006开展慢性酒精使用机制研究的使命一致 和睡眠稳态。

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.