Cellular Mechanisms of Ethanol's Influence on Sleep

描述（由申请人提供）：饮酒使你昏昏欲睡。为 一些失眠症患者，这种影响是睡前饮酒的途径， 最终滥用。睡眠障碍在酗酒患者中很常见， 严重的健康后果。最突出和最好理解的 脑节律的主要部分是与第二阶段睡眠相关的纺锤波， 这种特殊的睡眠形式在急性酒精中毒后会增强 局也许最有希望探索的大脑区域 到目前为止，酒精对睡眠的影响--丘脑--一直被忽视。的 丘脑是睡眠/觉醒周期和大脑节律的主要发生器 这是睡眠分期的标志。雪貂丘脑的切片 产生纺锤波的所有必要电路。的 已知纺锤波产生的机制取决于特定的 丘脑内GABA能回路的突触激活模式， 脑干和皮层的上行和下行控制， 分别GABA能和NMDA能系统（特别是NMDA）是 乙醇的已知靶点，因此突触传递是我们的主要 在这项提案中。乙醇已被证明可增强诱发的GABA a IPSC通过几种已知的机制在许多大脑区域中，包括 增强潜在的GABAa受体介导的通道电导。 已知NMDA的影响会引起丘脑节律。以下具体 目的将确定乙醇对纺锤波电路的影响 丘脑，并将检查GABA a和NMDA介导的突触传递 目标1：我们将研究 乙醇对丘脑内GABA α受体介导的IPSP和IPSC的影响， 细胞内记录技术。我们假设乙醇将 通过突触后机制增强GABAa IPSP和IPSC的幅度 这有利于产生纺锤波，正如我们的初步预测， 建模数据目的2：研究乙醇对NMDA的影响 受体介导的EPSP和丘脑内的EPSC。刺激 皮质丘脑途径特异性激活谷氨酸受体， 突触同步纺锤波。我们假设乙醇将 减弱NMDA受体介导的电位，破坏皮层对 纺锤波与我们的初步数据一致目标3：我们将研究 乙醇对低阈值钙电流的影响， 纺锤体振荡我们的初步数据显示， 在酒精暴露期间，这可能是睡眠纺锤波增加的基础， 乙醇这项研究是一个机会，以工作的机制， 在一项新的，但也是最新的研究中， 良好的特征和可访问的模型系统。这些剧烈的变化可能会使 由于长期滥用睡眠中断的阶段， 远远超过了撤退。因为这里要检查的乙醇的目标是 乙醇在其他系统中的影响的重要联系，我们的研究结果将扩大 乙醇对中枢神经系统的影响的基本机制。

DESCRIPTION (provided by applicant): Drinking alcohol makes you sleepy. For some insomniacs, this effect is the pathway to bedtime alcohol consumption and eventual abuse. Sleep disturbances are common in alcoholic patients, with a number of serious health consequences. The most prominent and best understood of brain rhythms are the spindle waves associated with Stage II sleep, and this specific form of sleep is enhanced in response to acute alcohol administration. Perhaps the most promising brain region in which to explore alcohol influences on sleep - the thalamus- has been so far ignored. The thalamus is a primary generator of sleep/wake cycles and the brain rhythms that are the hallmark of sleep staging. Slices of the ferret thalamus possess all of the necessary circuitry for the generation of spindle waves. The mechanisms underlying spindle wave generation are known to depend on specific synaptic activation patterns of GABAergic circuitry within the thalamus', with both ascending and descending control from the brainstem and cortex, respectively. GABAergic and glutamatergic systems (particularly NMDA) are known targets of ethanol, and synaptic transmission is therefore our primary target in this proposal. Ethanol has been shown to potentiate evoked GABAa IPSCs in a number of brain regions, via several known mechanisms, including enhancement of the underlying GABAa receptor-mediated channel conductance. NMDA influences are known to entrain thalamic rhythms. The following specific aims will determine the influence of ethanol on the spindle wave circuitry of the thalamus, and will examine GABAa, and NMDA mediated synaptic transmission as touchstones of these effects: Aim 1: We will examine the influence of ethanol on GABAa receptor-mediated IPSPs and IPSCs within the thalamus using intracellular recording techniques. We hypothesize that ethanol will potentiate the amplitude of GABAa IPSPs and IPSCs by postsynaptic mechanisms that favor the generation of spindle waves, as predicted by our preliminary modeling data. Aim 2: We will examine the influence of ethanol on NMDA receptor- mediated EPSPs and EPSCs within the thalamus. Stimulation of the corticothalamic pathway specifically activates glutamate receptors and can synaptically synchronize spindle waves. We hypothesize that ethanol will attenuate NMDA receptor-mediated potentials, disrupting cortical control of spindle waves, consistent with our preliminary data. Aim 3: We will examine the effect of ethanol on a low threshold calcium current that is vital to spindle oscillations. Our preliminary data show an enhancement of this current during ethanol exposure, which could underlie increases in sleep spindles by ethanol. This research is an opportunity to work out the mechanisms underlying reported acute perturbations of normal sleep by ethanol in a new, yet well-characterized and accessible model system. These acute changes may set the stage for disruption of sleep due to chronic abuse, disruptions that last well beyond withdrawal. Because the targets of ethanol to be examined here are vital links to ethanol's influence in other systems, our results will extend to basic mechanisms of ethanol effects in the CNS as a whole.