Alcohol dependence, epigenetic changes and sleep disruptions.

描述(申请人提供)：酒精饮料的摄入量对睡眠有重大影响。非酒精者大量饮酒会促进嗜睡。相比之下，酗酒者在饮酒期间和戒酒期间都会遭受严重的长期失眠和相关的睡眠中断，在戒酒期间会持续几个月。酗酒康复者的失眠和相关的睡眠障碍是再次酗酒的主要危险因素。因此，我们必须了解和治疗戒酒过程中的睡眠障碍。本研究的主要目的是阐明乙醇对睡眠觉醒影响的分子机制，从而为了解和治疗酒精相关的睡眠障碍和酒精中毒提供可靠的基础。我们的假设：在戒酒期间观察到的严重失眠和相关的睡眠中断是促进觉醒的基底前脑区域表观遗传变化的结果。我们预测酒精戒断后促进觉醒的基底前脑区转录因子FosB/Delta FosB的表达将增加。我们进一步预测，在酒精戒断过程中，具有组蛋白乙酰转移酶活性的关键睡眠和昼夜节律调节因子Clock蛋白的表达将在基底前脑中减少。此外，我们预测慢性酒精暴露会减少基底前脑中组蛋白H3和H4的乙酰化。在基底前脑局部和双侧给药组蛋白去乙酰酶抑制剂曲古抑素-A将减轻慢性乙醇引起的失眠和相关的睡眠障碍。 公共卫生相关性：这个研究项目的广泛目标是了解在戒酒过程中导致睡眠中断的分子机制，从而为理解和治疗酒精中毒提供可靠的基础。

DESCRIPTION (provided by applicant): Intake of alcoholic beverages has significant impact on sleep. Acute alcohol intake in non- alcoholics promotes sleepiness. In contrast, alcoholics, both during drinking period as well as during withdrawal suffer from profound and protracted insomnia and associated sleep disruptions that persist for several months during abstinence. Insomnia and associated sleep disturbances in recovering alcoholics are major risk factors for relapse to alcoholism. Thus, it is imperative that we understand and treat sleep disturbances in recovering alcoholics. The broad objective of this program of research is to elucidate the molecular mechanisms mediating the effects of ethanol on sleep-wakefulness and thereby provide a sound basis for the understanding and treatment of ethanol associated sleep disturbances and alcoholism. Our hypothesis: Profound insomnia and associated sleep disruptions observed during alcohol withdrawal are the result of epigenetic changes in the wake-promoting basal forebrain region. We predict that the expression of transcription factor, FosB/delta FosB will be increased in the wake-promoting basal forebrain region during ethanol withdrawal. We further predict that the expression of Clock protein, a key sleep and circadian regulator with histone acetyltransferase activity, will be reduced in the basal forebrain during ethanol withdrawal. Furthermore, we predict that chronic ethanol exposure will decrease acetylation of histones, H3 and H4, in the basal forebrain. Local and bilateral administration of histone deacetylase inhibitor, trichostatin-A, in the basal forebrain will attenuate chronic ethanol induced insomnia and associated sleep disruptions. PUBLIC HEALTH RELEVANCE: The broad objective of this research program is to understand the molecular mechanisms responsible for causing sleep disruptions during alcohol withdrawal and thereby provide a sound basis for the understanding and treatment of alcoholism.