Hypothalamic Neuronal Activity During Insomnia Induced by Chronic Ethanol Exposure

慢性乙醇暴露引起的失眠期间下丘脑神经元活动

• 批准号: 10363826
• 负责人: Carlos A. Blanco-Centurion
• 金额: $ 46.63万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363826
• 关键词: Abstinence; Affect; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Animal Model; Area; Arousal; Behavior; Biological Assay; Brain; Brain imaging; Cells; Chronic; Chronic Alcoholic Intoxication; Chronic Insomnia; Data; Development; Dopamine; Dose; Electrophysiology (science); FOS gene; Functional Magnetic Resonance Imaging; Histamine; Homeostasis; Hyperactivity; Hypothalamic structure; Image; In Vitro; Knowledge; Label; Link; Maintenance; Measurement; Measures; Modeling; Mus; Neurobiology; Neurons; Neurosciences; Pathologic; Persons; Pharmacogenetics; Phase; Phenotype; Publishing; REM Sleep; Research; Serotonin; Sleep; Sleep disturbances; Sleeplessness; Slice; Synapses; Testing; Time; Withdrawal; alcohol effect; alcohol exposure; alcohol prevention; alcohol relapse; alcohol use disorder; base; chronic alcohol ingestion; designer receptors exclusively activated by designer drugs; drinking; experience; falls; gamma-Aminobutyric Acid; hypnotic; hypocretin; imaging modality; improved; in vivo; innovation; mouse model; non rapid eye movement; preference; problem drinker; receptor; screening; sedative; sex; sleep regulation; tool

Severe insomnia occurs during the withdrawal from chronic use of alcohol. To gain relief from insomnia, alcoholics begin drinking again. Although the cause of the insomnia is unknown, indirect measurements of neuronal activity (c-FOS, fMRI) suggest that during insomnia, more of the arousal- promoting neurons are hyperactive. The status of the sleep-promoting neurons is unknown but are likely to be less active. Our overall hypothesis is that it is the imbalance in activity between wake versus sleep-promoting neurons that is the basis of insomnia during the withdrawal from alcohol. We will directly test this hypothesis in a proven mouse model of chronic ethanol intoxication using newly developed neuroscience tools. Aim 1 will use a miniscope to image Ca2+ influx (as a readout of cell activity) in specific hypothalamic wake-promoting (orexin) or hypothalamic sleep-promoting (GABA) neurons before, during and after chronic intermittent exposure to alcohol (CIE). We will image the neurons during waking, NREM, and REM sleep. We hypothesize that during the CIE-period of insomnia, the orexin neurons are more active while the sleep-promoting GABA neurons are less active. We have robust preliminary data indicating that the GABA neurons have become less active after chronic alcohol exposure. Similarly, our preliminary data reveals that orexin neurons have become more active. The deep-brain Ca2+ imaging method provides descriptive data. Thus Aims 2 and 3 will use pharmacogenetics to mechanistically test the hypothesis that CIE has shifted the excitability thresholds of the GABA and orexin neurons. In-vitro slice electrophysiology studies will confirm the hypothesis. To induce sleep to correct the insomnia, Aim 2 will activate the GABA neurons, while Aim 3 will inhibit the orexin neurons. Aim 4 will test the hypothesis that after CIE, because sleep has improved with our pharmacogenetic manipulations, then the mice will show less preference for drinking alcohol. This aim goes to the core of our hypothesis that improving sleep prevents alcohol relapse. The overall impact of our studies is that, for the first time, hard evidence will mechanistically link insomnia during the withdrawal from chronic ethanol intoxication to changes of activity in specific phenotypes of hypothalamic sleep or wake-promoting neurons. Furthermore, our aims are translational and will aid in the development of appropriate treatments for insomnia. Our aims are integrated and employ cutting-edge tools to understand how chronic ethanol exposure disrupts sleep homeostasis. This project will be conducted jointly by experts in the areas of sleep neurobiology and alcohol addiction.

严重的失眠发生在戒酒期间。从…获得解脱