Cellular Mechanisms of Ethanol's Influence on Sleep

描述(申请人提供)：饮酒使人昏昏欲睡。为 一些失眠症患者，这种影响是睡前饮酒和 最终的虐待。睡眠障碍在酗酒患者中很常见， 严重健康后果的数量。最突出和最被理解的 大脑节律的一部分是与第二阶段睡眠相关的纺锤波，以及 这种特殊形式的睡眠在急性酒精刺激下会增强。 行政管理。可能是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。这个 丘脑是睡眠/清醒周期和大脑节律的主要生成器 这些都是睡眠分期的标志。雪貂丘脑的切片 产生纺锤波的所有必要电路。这个 已知纺锤波产生的潜在机制取决于特定的 丘脑内GABA能回路的突触激活模式 从脑干和大脑皮层的上升和下降控制， 分别进行了分析。GABA能和谷氨酸能系统(尤其是NMDA)是 乙醇的已知靶标和突触传递因此是我们的主要 这项提案中的目标。乙醇已被证明可以增强诱发的GABAA IPSCs通过几种已知的机制，包括 增强GABAA受体介导的通道电导。 众所周知，NMDA的影响会影响丘脑的节律。以下是具体的 AIMS将决定乙醇对脑电纺锤波回路的影响 丘脑，并将检测GABAA和NMDA介导的突触传递 作为这些影响的试金石：目标1：我们将检查 乙醇对GABAA受体介导的丘脑IPSP和IPSCs的影响 细胞内记录技术。我们假设乙醇将会 突触后机制增强GABAA IPSP和IPSCs的幅度 这有利于纺锤波的产生，正如我们初步预测的那样 建模数据。目的2：研究乙醇对NMDA的影响 丘脑内受体介导的EPSPS和EPSCs。对人的刺激 皮质丘脑通路特异性激活谷氨酸受体并能 通过突触同步纺锤波。我们假设乙醇将会 减弱NMDA受体介导的电位，扰乱大脑皮质对 纺锤波，与我们的初步数据一致。目标3：我们将检查 乙醇对低阈值钙电流的影响 主轴摆动。我们的初步数据显示，这股洋流有所增强 在酒精暴露期间，这可能是睡眠纺锤波增加的原因 乙醇。这项研究是一个找出潜在机制的机会 据报道，在一项新的研究中，乙醇对正常睡眠造成了急性干扰 具有良好特色和可访问性的模型系统。这些剧烈的变化可能会 由于长期的虐待而导致睡眠中断的阶段， 远远不只是戒毒。因为这里要研究的乙醇的目标是 乙醇在其他系统中的影响至关重要，我们的结果将扩展 乙醇在整个中枢神经系统中的作用的基本机制。

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.