Astroglia-Neuron Regulation of Sleep

星形胶质细胞神经元对睡眠的调节

• 批准号: 9189564
• 负责人: Priyattam J. Shiromani
• 金额: $ 22.43万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9189564
• 关键词: Accelerometer; Action Potentials; Adenosine; Adenosine A1 Receptor; Area; Arousal; Astrocytes; Behavior; Brain; Brain region; Breathing; Cells; Chemicals; Complex; Corpus striatum structure; Cytoskeletal Proteins; Dendrites; Development; Drug Delivery Systems; Electrophysiology (science); Genetic Engineering; Glial Fibrillary Acidic Protein; Glutamates; Grant; Homeostasis; Human; In Vitro; Lead; Link; Measures; Mediating; Microdialysis; Modeling; Mus; Neuroglia; Neurons; Neurosciences; Pharmacology; Phase; Plasmids; Pontine structure; Posterior Hypothalamus; Proteins; REM Sleep; Recording of previous events; Regulation; Reporter Genes; Role; Site; Sleep; Slice; Source; Specificity; Synapses; Synaptic Transmission; Testing; Time; Wakefulness; Waxes; basal forebrain; base; chemical release; cytokine; extracellular; feeding; in vivo; network models; neurotransmission; new technology; optogenetics; particle; promoter; response; sleep regulation; synaptic function; tool

Current models of sleep-wake regulation are “neuron-centric”. However, there are astrocytes in the brain, and they outnumber neurons. A single astrocyte contacts hundreds of dendrites, and tens of thousands of synapses (Bushong et al., 2002, Halassa et al., 2007). The concept of a tripartite synapse has emerged where astrocytes actively control neuronal activity and synaptic transmission. We provided the first evidence that selectively activating astrocytes in the posterior hypothalamus increases both NREM and REM sleep in mice. This is the first time that optogenetic or DREDD activation of cells other than neurons has been shown to increase sleep. Most importantly, sleep was increased at night, the normal wake period in nocturnal mice. This indicates that astrocytes can impart a load that can induce sleep. What this means is that astrocytes can impart a load on neurons throughout the brain, thus providing for the first time an explanation for the waxing and waning of sleep. This will support the hypothesis of “local use dependent sleep” throughout the brain. We will determine the gliotransmitter that is released, and also monitor the activity of adjacent sleep-wake neurons in response to optogenetic stimulation. Aim 1 will use microdialysis to test the hypothesis that adenosine accumulates in response to optogenetic stimulation of ChR2-positive astroglia. We are focusing on adenosine based on the substantial evidence that it is released from astrocytes and its linkage with sleep. However, the other potential gliotransmitters will also be measured. This aim will also use the adenosine A1 receptor antagonist, CPT, to block the sleep induced by optogenetic stimulation of astrocytes. Aim 2 will test the hypothesis that in response to optogenetic stimulation of ChR2-positive astroglia the arousal neurons in the posterior hypothalamus are inhibited, and this is blocked by the adenosine A1 receptor antagonist. This aim will also determine the site-specificity of the effect in mice by activating the ChR2-containing astrocytes in areas implicated in sleep-wake regulation (VLPO, basal forebrain, and dorsolateral pons). The overall impact of this project is that it mechanistically connects astrocytes, adenosine, A1 receptor, and local neuronal activity with sleep. Inclusion of astrocytes in circuit models will lead to better explanation of sleep homeostasis, which is something that current “neuron-centric” models have failed to do.

当前的睡眠效果调节模型是“以神经元为中心”。但是，有 大脑中的星形胶质细胞和外部数神经元。一个星形胶质细胞接触数百个 树突和成千上万的突触（Bushong等，2002； Halassa等，2007）。 在星形胶质细胞积极控制神经元活动的情况下，出现了三方突触的概念 和突触传输。我们提供了选择性激活星形胶质细胞的第一个证据 在后下丘脑中，小鼠的NREM和REM睡眠增加。这是第一个 神经元以外的细胞的光遗传学或DREDD激活的时间已显示为 增加睡眠。最重要的是，晚上睡眠增加，正常的唤醒期 夜间老鼠。这表明星形胶质细胞可以赋予可以诱发睡眠的负载。什么 这意味着星形胶质细胞可以赋予整个大脑神经元的负载，从而提供 这是第一次解释睡眠和衰落的解释。这将支持 整个大脑中“局部使用依赖性睡眠”的假设。我们将确定 释放的Gliotransmitter，还监测相邻睡眠神经元在 对光遗传学刺激的反应。 AIM 1将使用微透析来检验以下假设。 腺苷对Chr2阳性星形胶质细胞的光遗传学刺激响应。我们 基于大量证据表明它是从星形胶质细胞释放的，重点关注腺苷 及其与睡眠的联系。但是，还将测量其他潜在的闪光灯。 该目标还将使用腺苷A1受体拮抗剂CPT来阻止由 星形胶质细胞的光遗传学刺激。 AIM 2将检验以下假设。 chr2阳性星形胶质细胞的光遗传学刺激后部唤醒神经元 下丘脑受到抑制，这被腺苷A1受体拮抗剂阻止。这 AIM还将通过激活含Chr2的效果来确定小鼠效应的位点特异性 睡眠效果调节中实施的区域的星形胶质细胞（VLPO，基本前脑和背外侧 庞斯）。该项目的总体影响是它可以机械地连接星形胶质细胞， 腺苷，A1受体和局部神经元活性，睡眠。在电路中包含星形胶质细胞 模型将导致更好地解释睡眠体内稳态，这是当前的 “以神经元为中心”的模型未能做到。