Alcohol dependence, epigenetic changes and sleep disruptions.

描述（由申请人提供）：摄入酒精饮料对睡眠有显著影响。非酗酒者急性饮酒会促进嗜睡。相反，酗酒者，无论是在饮酒期间还是在戒酒期间，都会遭受严重而持久的失眠和相关的睡眠中断，这种失眠在戒酒期间会持续数月。失眠症及相关的睡眠障碍是酒精中毒复发的主要危险因素。因此，我们必须了解并治疗恢复中的酗酒者的睡眠障碍。本研究项目的主要目的是阐明乙醇对睡眠觉醒影响的分子机制，从而为理解和治疗乙醇相关的睡眠障碍和酒精中毒提供坚实的基础。我们的假设是：在酒精戒断期间观察到的深度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，在乙醇戒断期间，转录因子FosB/ δ FosB的表达将在促进尾流的基底前脑区增加。我们进一步预测，在乙醇戒断期间，基底前脑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蛋白的表达将减少。此外，我们预测慢性乙醇暴露会降低基底前脑中组蛋白H3和H4的乙酰化。在基底前脑局部或双侧给予组蛋白去乙酰化酶抑制剂trichostatin-A可减轻慢性乙醇引起的失眠和相关的睡眠中断。

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.