Non-neuronal regulators of sleep

描述（由申请人提供）：睡眠问题，如白天过度嗜睡和失眠在美国很常见。 它们存在于许多精神和神经系统疾病中，并导致注意力、学习和记忆缺陷。使动物困倦并导致困倦动物认知缺陷的细胞机制尚不清楚。 神经胶质和神经元之间的化学信号传导（即胶质传递）可能是这一机制的重要组成部分。胶质星形胶质细胞是电沉默的脑细胞（相对于神经元），几十年来被认为在大脑中起纯粹的支持作用（例如离子缓冲）。最近的研究表明，星形胶质细胞是突触神经传递的重要伙伴。星形胶质细胞包围着突触，并通过分泌自己的化学信使（胶质递质）来对神经递质做出反应，反过来又调节神经元的兴奋性和突触传递。胶质传递在哺乳动物行为中的作用现在才开始被探索。 在哺乳动物中，星形胶质细胞密集地集中在对唤醒、睡眠和高级认知功能至关重要的大脑区域。我们假设这些区域的胶质传递不仅介导嗜睡，还介导与睡眠丧失相关的认知缺陷。我们将测试我们的假设，通过定量测量小鼠的睡眠调节与诱导（条件）突变，抑制星形胶质细胞在体内的gliotransmission。我们将 还利用这些小鼠测试神经胶质传递在睡眠不足引起的学习和注意力缺陷中的作用。 在这个修订后的应用程序中，我们增加了两组新的实验，以回应初步审查。首先，我们现在讨论区域性胶质传递在涉及睡眠调节的脑区（例如，下丘脑的基底前脑和视前区）或记忆（海马）中的作用。 这是通过在体内脑中区域表达转基因来实现的。其次，我们还增加了一个新的认知任务，这是敏感的睡眠不足，但以前从未检查过关于胶质传递（T迷宫参考反转）。 我们现在修改后的应用程序远远超过了我们以前对这些现象的探索。 因此，我们的研究结果将为睡眠需求的细胞基础和动物行为中非神经元细胞的功能提供新的见解。

DESCRIPTION (provided by applicant): Sleep problems such as excessive daytime sleepiness and insomnia are common in the United States. They are found in many psychiatric and neurological disorders and cause deficits in attention, learning and memory. The cellular mechanism that makes animals sleepy and causes cognitive deficits in sleepy animals is unknown. Chemical signaling between glia and neurons (i.e. gliotransmission) may be an important part of this mechanism. Glial astrocytes are brain cells that are electrically silent (relative to neurons) and for many decades were thought to serve purely supportive functions in the brain (e.g. ion buffering). More recent findings indicate that astrocytes are important partner in synaptic neurotransmission. Astrocytes surround synapses and respond to neurotransmitters by secreting their own chemical messengers (gliotransmitters), which in turn regulate neuronal excitability and synaptic transmission. The role of gliotransmission in mammalian behavior is only now beginning to be explored. In mammals astrocytes are densely concentrated in brain regions critical for arousal, sleep and higher cognitive function. We hypothesize that gliotransmission in these regions mediates not only sleepiness, but cognitive deficits associated with sleep loss. We will test our hypothesis by quantitatively measuring sleep regulation in mice with an inducible (conditional) mutation that inhibits astrocytic gliotransmission in vivo. We will also use these mice test the role of gliotransmission in learning and attention deficits caused by sleep loss. In this revised application, we have added two new sets of experiments in response to initial review. First, we now address the role of regional gliotransmission within brain areas implicated in sleep regulation (e.g. the basal forebrain and pre-optic area of the hypothalamus) or memory (hippocampus). This is accomplished by regionally expressing transgenes in the brain in vivo. Second, we also have added a new cognitive task, which is sensitive to sleep loss, but never before examined with respect to gliotransmission (T-maze reference reversal). Our revised application now far exceeds our previous explorations of these phenomena. Our findings will thus provide new insights into the cellular basis of sleep need and the function of non-neuronal cells in animal behavior.