Astroglia-Neuron Regulation of Sleep

目前的睡眠-觉醒调节模型是“以神经元为中心”的。但有 星形胶质细胞数量超过神经元单个星形胶质细胞接触数百个 树突和数以万计的突触（Bushong等人，2002年，Halassa等人，2007年）。的 三重突触的概念已经出现，其中星形胶质细胞主动控制神经元活动 和突触传递。我们提供了第一个证据表明选择性激活星形胶质细胞 增加小鼠的NREM和REM睡眠。这是第一 除了神经元以外的细胞的光遗传学或DREDD激活的时间已经被证明是 增加睡眠。最重要的是，睡眠在夜间增加， 夜行鼠这表明星形胶质细胞可以传递可以诱导睡眠的负荷。什么 这意味着星形胶质细胞可以对整个大脑的神经元施加负荷，从而提供 第一次解释了睡眠的盈亏。这将支持 “局部使用依赖性睡眠”的假说。康贝特人将以 神经胶质递质的释放，并监测相邻的睡眠-觉醒神经元的活动， 对光遗传学刺激的反应。目的1将使用微透析来测试假设， 腺苷响应于ChR 2阳性星形胶质细胞的光遗传学刺激而积累。我们 基于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。 该目的还将使用腺苷A1受体拮抗剂CPT来阻断 星形胶质细胞的光遗传学刺激。目标2将检验以下假设： ChR 2阳性星形胶质细胞的光遗传学刺激在后部的唤醒神经元 下丘脑被抑制，并且这被腺苷A1受体拮抗剂阻断。这 目的还将通过激活含有ChR 2的 涉及睡眠-觉醒调节的区域（VLPO、基底前脑和背外侧区）中的星形胶质细胞 脑桥）。这个项目的总体影响是它机械地连接了星形胶质细胞， 腺苷、A1受体和局部神经元活动与睡眠。回路中包含星形胶质细胞 模型将导致更好地解释睡眠稳态，这是目前 “以神经元为中心”的模型已经失败了。

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.