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。它们在许多精神和神经疾病中被发现，并导致注意力、学习和记忆方面的缺陷。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。胶质细胞和神经元之间的化学信号传递（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一种不带电的脑细胞（相对于神经元），几十年来，人们一直认为它在大脑中具有纯粹的支持功能（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。星形胶质细胞包围突触，通过分泌自己的化学信使（胶质递质）对神经递质做出反应，进而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刚刚开始被探索。在哺乳动物中，星形胶质细胞密集地集中在对觉醒、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，还介导与睡眠缺失相关的认知缺陷。我们将通过在体内抑制星形细胞胶质传递的诱导（条件）突变小鼠中定量测量睡眠调节来验证我们的假设。我们将

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.