Mechanistic studies of alcohol-sleep interactions
酒精与睡眠相互作用的机制研究
基本信息
- 批准号:10466827
- 负责人:
- 金额:$ 39.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-17 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AbstinenceAlcohol consumptionAlcohol dependenceAlcohol withdrawal syndromeAlcoholsAnatomyChronicClinical ResearchCocaineDataDevelopmentElectroencephalographyElectrophysiology (science)EthanolFemaleHabenulaHealthHeavy DrinkingHomeostasisHyperactivityHypothalamic structureIncubatedIndividualInterventionLateralLightMeasuresMedialMediatingMethodsMissionModelingMotivationNational Institute on Alcohol Abuse and AlcoholismNeuronsPatientsPersonsPhasePredictive FactorPredispositionPublishingREM SleepRattusRecoveryRelapseRiskRodentSelf AdministrationSignal TransductionSleepSleep ArchitectureSleep DeprivationSleep FragmentationsSleep disturbancesSliceStructureTestingTherapeuticTimeWithdrawalWorkalcohol abstinencealcohol exposurealcohol measurementalcohol relapsealcohol seeking behavioralcohol use disorderanxiety-like behaviorbasecholinergicchronic alcohol ingestioncocaine self-administrationcravingdesigner receptors exclusively activated by designer drugsdrinkingdrug cravingeffective interventionexperimental studyimprovedinsightmalemelanin-concentrating hormonenegative affectneuromechanismneuroregulationnon rapid eye movementnovelpreventreduced alcohol userelating to nervous systemresponserestorationsleep qualitysubstance usetargeted treatment
项目摘要
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.
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,
澳元。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,如果这与血红蛋白活性降低有关。
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
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Yanhua H Huang其他文献
Yanhua H Huang的其他文献
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{{ truncateString('Yanhua H Huang', 18)}}的其他基金
Regulation of nucleus accumbens neurons by sleep and circadian rhythm
睡眠和昼夜节律对伏隔核神经元的调节
- 批准号:
10655471 - 财政年份:2020
- 资助金额:
$ 39.13万 - 项目类别:
Regulation of nucleus accumbens neurons by sleep and circadian rhythm
睡眠和昼夜节律对伏隔核神经元的调节
- 批准号:
10442467 - 财政年份:2020
- 资助金额:
$ 39.13万 - 项目类别:
Regulation of nucleus accumbens neurons by sleep and circadian rhythm
睡眠和昼夜节律对伏隔核神经元的调节
- 批准号:
10217074 - 财政年份:2020
- 资助金额:
$ 39.13万 - 项目类别:
Mechanistic studies of alcohol-sleep interactions
酒精与睡眠相互作用的机制研究
- 批准号:
10687066 - 财政年份:2019
- 资助金额:
$ 39.13万 - 项目类别:
Mechanistic studies of alcohol-sleep interactions
酒精与睡眠相互作用的机制研究
- 批准号:
9912917 - 财政年份:2019
- 资助金额:
$ 39.13万 - 项目类别:
Mechanistic studies of alcohol-sleep interactions
酒精与睡眠相互作用的机制研究
- 批准号:
10019443 - 财政年份:2019
- 资助金额:
$ 39.13万 - 项目类别:
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