Neuronal mechanisms mediating the effects of chronic alcohol consumption on sleep homeostasis.

介导长期饮酒对睡眠稳态影响的神经机制。

• 批准号: 10470383
• 负责人: MAHESH M THAKKAR
• 金额: $ 36.29万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470383
• 关键词: Abstinence; Acute; Adenosine A1 Receptor; Adenosine Kinase; Affect; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Anti-Inflammatory Agents; Attenuated; B-Cell Activation; Brain; Brain Diseases; Cessation of life; Chronic; Coupled; Electrophysiology (science); Enhancers; Enterobacteria phage P1 Cre recombinase; Equilibrative Nucleoside Transporter 1; Etiology; Exposure to; Functional disorder; Gene Expression; Genes; Gliosis; Histone Deacetylase Inhibitor; Histones; Homeostasis; Human; Image; Impairment; Inflammatory; Infusion procedures; Interleukin-1 beta; Interleukins; Internal Ribosome Entry Site; Knock-in; Lesion; Light; MAP Kinase Gene; Mediating; Mediator of activation protein; Microdialysis; Minocycline; Mus; NOS2A gene; National Institute on Alcohol Abuse and Alcoholism; Neurons; Nuclear; Nucleoside Transporter; Patients; Pattern; Pharmacogenetics; Pharmacology; Play; Polysomnography; Relapse; Research; Role; Severities; Signal Transduction; Sleep; Sleep Disorders; Sleep disturbances; Sleeplessness; Symptoms; System; TNF gene; Techniques; Technology; Testing; Time; Toll-like receptors; Transgenic Organisms; Trichostatin A; Up-Regulation; Viral; Wakefulness; alcohol effect; alcohol use disorder; awake; basal forebrain; basal forebrain cholinergic neurons; cholinergic; cholinergic neuron; chronic alcohol ingestion; clinically relevant; cytokine; design; designer receptors exclusively activated by designer drugs; disability; drinking; efficacious treatment; epigenome; improved; in vivo; in vivo calcium imaging; indexing; inhibitor; innovation; kinase inhibitor; multidisciplinary; neuroinflammation; non rapid eye movement; novel; overexpression; premature; prevent; problem drinker; programs; receptor; relapse prediction; sleep quantity; treatment strategy

Alcohol use disorder (AUD), a chronic relapsing brain disorder, characterized by compulsive and excessive alcohol use, is a leading preventable cause of premature disability and death. Insomnia and associated sleep disturbances are amongst the most severe and protracted symptoms of AUD. In fact, subjective and objective indicators of sleep disturbances are predictors of relapse. Thus, while there is a direct relationship between insomnia and AUD, the underlying pathophysiology is not well understood. Evidence suggest that sleep homeostatic mechanism [adenosinergic/cholinergic mechanisms in the basal forebrain (BF)] may play a crucial role in mediating the effects of alcohol on sleep. Hence, we hypothesize that chronic alcohol consumption directly and indirectly, via neuroinflammation, disrupts sleep homeostasis leading to insomnia and sleep disturbances. We will use wild type (C57BL/6J) and transgenic ChAT-cre (expression of Cre-recombinase exclusively in cholinergic neurons) mice and expose them to the common maladaptive pattern of alcohol consumption: chronic intermittent access two-botte choice paradigm (IA2BC). A novel combination of multidisciplinary techniques including in vivo calcium imaging, pharmacogenetics, viral-mediating gene overexpression, microdialysis and local pharmacological manipulations will be used. Three aims are designed to test our hypothesis. In Aim 1, live Ca+2 imaging coupled with electrophysiological monitoring of sleep-wakefulness will be performed to examine the relationship between cholinergic neuronal activity, wakefulness and chronic alcohol intake. We predict that mice exposed to IA2BC will consume alcohol in an escalating pattern and display a positive relationship between cholinergic neuronal activity, disrupted sleep homeostasis and severity of sleep disruptions. While pharmacogenetic silencing of BF cholinergic neurons will attenuate the effects of chronic alcohol and normalize sleep, pharmacogenetic activation will attenuate sleep-promoting effects of acute alcohol. Aim 2 will examine the effects of chronic alcohol consumption on sleep homeostasis. We predict that 1) alcohol will downregulate MAPK signaling cascade and acetylated histones, to reduce the expressions of equilibrative nucleoside transporter 1 (ENT1) and adenosine A1 receptor (A1R) in the BF. 2) Virally mediated overexpression of ENT1 in the BF will attenuate the effects of alcohol on sleep homeostasis and improve the quality and quantity of sleep. 3) Local infusion of trichostatin-A (histone deacetylase inhibitor) will normalize sleep by upregulation of acetylated histones along with the expression of ENT1 and A1R in the BF, without affecting MAPK signaling. Aim 3 will examine chronic alcohol induced neuroinflammation in the BF and its effect on sleep homeostasis. Our predictions are that selective blockade of 1) neuroinflammatory changes by minocycline, 2) Toll-like receptors by TAK-242 and/or c) adenosine kinase by ABT-702, in the BF will attenuate chronic alcohol induced neuroinflammation; reduce gliosis and cytokine levels in the BF and normalize the indices of sleep homeostasis and sleep-wakefulness.

酒精使用障碍（AUD）是一种慢性复发性脑障碍，以强迫性和过度为特征