Cortical astrocytes independently regulate sleep depth and duration via separate GPCR pathways.
Cortical astrocytes independently regulate sleep depth and duration via separate GPCR pathways.
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DOI：
10.7554/elife.63329
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发表时间：
2021-03-17
期刊：
影响因子：
7.7
通讯作者：
Poskanzer KE
中科院分区：
文献类型：
--
作者：
Vaidyanathan TV;Collard M;Yokoyama S;Reitman ME;Poskanzer KE
非快速眼动（NREM）睡眠以慢波电生理活动为特征，是包括学习和记忆在内的几个关键功能的基础。然而，非快速眼动睡眠是异质性的，在持续时间、深度和皮层的空间上都有所不同。虽然这些非快速眼动睡眠特征被认为在很大程度上是独立调节的，但也有证据表明它们是机械耦合的。为了研究皮层NREM睡眠特征是如何被控制的，我们检查了星形细胞网络，包括一个影响群体水平神经元活动的全皮层合胞体。我们量化了小鼠在自然睡眠和清醒状态下的内源性星形胶质细胞活性，然后在体内操纵特定的星形胶质细胞g蛋白偶联受体（GPCR）信号通路。我们发现星形细胞Gi-和gq -偶联GPCR信号分别控制NREM睡眠深度和持续时间，星形细胞信号在局部和远端皮层引起不同的变化。这些数据支持一个模型，即皮质星形胶质细胞网络是调节不同的非快速眼动睡眠特征的枢纽。睡眠有很多作用，从增强新记忆到调节情绪和食欲。虽然我们可能本能地认为睡眠是大脑活动减少的一种统一状态，但现实情况要复杂得多。首先，在整个晚上，我们在许多不同的睡眠阶段之间循环，这些阶段反映了不同的睡眠深度。其次，睡眠深度的大小不一定在整个大脑中都有，而是在不同的区域之间有所不同。这些睡眠阶段包括快速眼动（REM）睡眠和非快速眼动（NREM）睡眠。快速眼动睡眠是大多数做梦的时候，而非快速眼动睡眠对学习和记忆特别重要，其持续时间和深度各不相同。在非快速眼动睡眠期间，大量神经元同步放电，产生被称为慢波的有节奏的活动波。活动越同步，睡眠越深。Vaidyanathan等人现在表明，被称为星形胶质细胞的脑细胞有助于调节非快速眼动睡眠。星形胶质细胞不是神经元，而是属于一组被称为胶质细胞的特殊细胞。它们是大脑中最大的神经胶质细胞类型，在其表面显示一系列称为g蛋白偶联受体（gpcr）的蛋白质。这使它们能够感知来自大脑其他部分的睡眠-觉醒信号，并产生自己的信号。事实上，每个星形胶质细胞可以同时与数千个神经元交流。因此，它们在非快速眼动睡眠期间能够很好地协调大脑活动。使用创新工具，Vaidyanathan等人可视化了小鼠醒来或入睡时星形胶质细胞的活动。结果显示，星形胶质细胞在每次睡眠-觉醒转换之前都会改变它们的活动。他们还发现星形胶质细胞通过两种不同类型的GPCR信号控制非快速眼动睡眠的深度和持续时间。增加其中一种信号（Gi-GPCR）会使小鼠睡得更深，但不会改变睡眠时间。降低Gq-GPCR使小鼠睡眠时间延长，但不影响睡眠深度。睡眠问题在生活的某个阶段影响着许多人，并且经常与其他疾病共存，如精神健康障碍。了解大脑如何调节睡眠的不同特征可以帮助我们开发更好的——也许是更具体的——治疗睡眠障碍的方法。例如，目前的研究表明，操纵星形胶质细胞上的gpcr可能会增加睡眠深度。但在开始测试这一想法之前，我们必须首先确定睡眠小鼠的发现是否也适用于人类。
Non-rapid eye movement (NREM) sleep, characterized by slow-wave electrophysiological activity, underlies several critical functions, including learning and memory. However, NREM sleep is heterogeneous, varying in duration, depth, and spatially across the cortex. While these NREM sleep features are thought to be largely independently regulated, there is also evidence that they are mechanistically coupled. To investigate how cortical NREM sleep features are controlled, we examined the astrocytic network, comprising a cortex-wide syncytium that influences population-level neuronal activity. We quantified endogenous astrocyte activity in mice over natural sleep and wake, then manipulated specific astrocytic G-protein-coupled receptor (GPCR) signaling pathways in vivo. We find that astrocytic Gi- and Gq-coupled GPCR signaling separately control NREM sleep depth and duration, respectively, and that astrocytic signaling causes differential changes in local and remote cortex. These data support a model in which the cortical astrocyte network serves as a hub for regulating distinct NREM sleep features. Sleep has many roles, from strengthening new memories to regulating mood and appetite. While we might instinctively think of sleep as a uniform state of reduced brain activity, the reality is more complex. First, over the course of the night, we cycle between a number of different sleep stages, which reflect different levels of sleep depth. Second, the amount of sleep depth is not necessarily even across the brain but can vary between regions. These sleep stages consist of either rapid eye movement (REM) sleep or non-REM (NREM) sleep. REM sleep is when most dreaming occurs, whereas NREM sleep is particularly important for learning and memory and can vary in duration and depth. During NREM sleep, large groups of neurons synchronize their firing to create rhythmic waves of activity known as slow waves. The more synchronous the activity, the deeper the sleep. Vaidyanathan et al. now show that brain cells called astrocytes help regulate NREM sleep. Astrocytes are not neurons but belong to a group of specialized cells called glia. They are the largest glia cell type in the brain and display an array of proteins on their surfaces called G-protein-coupled receptors (GPCRs). These enable them to sense sleep-wake signals from other parts of the brain and to generate their own signals. In fact, each astrocyte can communicate with thousands of neurons at once. They are therefore well-poised to coordinate brain activity during NREM sleep. Using innovative tools, Vaidyanathan et al. visualized astrocyte activity in mice as the animals woke up or fell asleep. The results showed that astrocytes change their activity just before each sleep–wake transition. They also revealed that astrocytes control both the depth and duration of NREM sleep via two different types of GPCR signals. Increasing one of these signals (Gi-GPCR) made the mice sleep more deeply but did not change sleep duration. Decreasing the other (Gq-GPCR) made the mice sleep for longer but did not affect sleep depth. Sleep problems affect many people at some point in their lives, and often co-exist with other conditions such as mental health disorders. Understanding how the brain regulates different features of sleep could help us develop better – and perhaps more specific – treatments for sleep disorders. The current study suggests that manipulating GPCRs on astrocytes might increase sleep depth, for example. But before work to test this idea can begin, we must first determine whether findings from sleeping mice also apply to people.