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.

目前的睡眠-觉醒调节模式是“以神经元为中心”的。然而，有一些 大脑中的星形胶质细胞，而且它们的数量超过了神经元。一个星形细胞与数百个 树突和数以万计的突触(Bushong等人，2002，Halassa等人，2007)。这个 星形胶质细胞主动控制神经元活动的三部分突触的概念已经出现 和突触传递。我们首次提供了选择性激活星形胶质细胞的证据 在下丘脑后部增加小鼠的NREM和REM睡眠。这是第一次 光遗传或Dredd激活神经元以外的细胞的时间已被证明 增加睡眠。最重要的是，睡眠在夜间增加，正常的清醒时间 夜间活动的老鼠。这表明星形胶质细胞可以提供一种可以诱导睡眠的负荷。什么 这意味着星形胶质细胞可以给整个大脑的神经元带来负担，从而提供 这是第一次对睡眠的起伏做出解释。这将支持 大脑中存在“局部使用依赖睡眠”的假说。我们将确定 释放的神经胶质递质，并监测邻近睡眠-觉醒神经元的活动 对光遗传刺激的反应。目标1将使用微透析来检验这一假设 腺苷的积累是对ChR2阳性星形胶质细胞光遗传刺激的反应。我们 专注于腺苷，因为大量证据表明腺苷是从星形胶质细胞中释放出来的 以及它与睡眠的联系。然而，其他潜在的神经胶质递质也将被测量。 这一目标还将使用腺苷A1受体拮抗剂CPT来阻断由 星形胶质细胞的光遗传刺激。目标2将测试假设，作为对 ChR2阳性星形胶质细胞后部觉醒神经元的光发生刺激 下丘脑受到抑制，这被腺苷A1受体拮抗剂阻断。这 AIM还将通过激活含有ChR2的受体来确定该效应在小鼠中的位置特异性 睡眠-觉醒调节相关区域(VLPO、基底前脑和背外侧)中的星形胶质细胞 Pons)。这个项目的总体影响是，它以机械方式连接星形胶质细胞， 腺苷、A1受体和局部神经元活动与睡眠。星形胶质细胞在环路中的包含 模型将导致对睡眠动态平衡的更好解释，这是目前 “以神经元为中心”的模型未能做到这一点。