Brain mechanisms of sleep: top-down or bottom-up?

睡眠的大脑机制：自上而下还是自下而上？

• 批准号: BB/X008711/1
• 负责人: Vladyslav Vyazovskiy
• 金额: $ 76.33万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX008711%2F1
• 关键词: Brain; mechanisms; sleep; top; down

We spend about 1/3 of our life asleep and we still do not know why. The body of new and exciting experimental data is growing, but this does not seem to result in a better understanding of the highly complex process of sleep regulation. There is no universally accepted "theory of sleep" as yet, which could guide our research efforts, and this represents a major barrier for making progress. What is known is that sleep is a strictly regulated process. It is thought that the need for sleep ("sleep pressure") increases gradually during the periods that we are awake, as reflected by us feeling tired. The longer we stay awake, the greater is the urge to sleep, and measuring how long an individual can sustain continuous awake state can inform us about the dynamics of the underlying neurobiological process. Upon sleep onset, the brain starts producing high amplitude, slow frequency oscillations (slow waves), which are proportional to previous wake duration, and are thought to play an important role in restorative functions of sleep. In addition to this, so-called homeostatic process, which maintains the relative constancy in sleep across 24-h, another, equally important process is responsible for initiating and terminating sleep and wake states. These two processes are thought to be separate. In theory, you can fall asleep even when "sleep need" is low, for example, when you are exposed to a monotonous, boring environment. On the other hand, even when sleep drive is high, you can remain awake for many hours or even days, for example when you are experiencing jet lag, when you are hungry, cold or as in the famous Stanford experiment with Randy Gardner who stayed awake for 11 days in a row! How these two processes - the one that keeps track of time spent awake and asleep, and the one that is responsible for sleep-wake switching - interact, remains unclear. The conventional view is that the role of the neocortex - the outermost layered covering of the brain - is to generate state-dependent brain oscillations, such as slow waves. In turn, sleep-wake switching is thought to arise from brain structures deep in the brain, such as the hypothalamus and the brain stem. Contrary to this view, in our recent work we discovered a previously unrecognised role of the cortex in both sleep homeostasis AND sleep-wake control. Cortex is a highly complex structure, both anatomically and functionally, and is therefore difficult to study; and this is why we think its role in sleep control was previously overlooked. When we investigated sleep in genetically modified mice, in which a subset of cortical projection neurons was irreversibly silenced from early postnatal time, we observed that these animals stayed awake for much longer than their wild-type littermates and, strikingly, manifested highly diminished compensatory response to sleep loss, when sleep deprived. It is as if time awake slows down when the cortex is partially silenced, but the fundamental neurobiology behind is still completely unknown. Our findings represent a unique opportunity to make a major progress in understanding the nature of the mysterious process that controls our "sleep need". In this project we set out a comprehensive research programme which aims to investigate the neurobiological substrate, both at the anatomical and functional levels, of cortical sleep control we discovered. We plan to dissect the neural circuitry underlying cortical sleep control, using advanced transgenic tools and will also address the role of circadian clock and key environmental factors, such as light.

我们的一生大约1/3都睡着了，我们仍然不知道为什么。新的令人兴奋的实验数据的身体正在增长，但这似乎并没有更好地了解高度复杂的睡眠调节过程。目前还没有普遍接受的“睡眠理论”，这可以指导我们的研究工作，这代表了取得进步的主要障碍。众所周知，睡眠是一个严格调节的过程。人们认为，在我们醒着的时期，对睡眠的需求（“睡眠压力”）逐渐增加，因为我们感到疲倦。我们保持清醒的时间越长，睡眠的冲动越大，衡量个人可以维持连续的清醒状态的时间可以告知我们基本神经生物学过程的动态。睡眠发作后，大脑开始产生高振幅，缓慢的频率振荡（慢波），与以前的唤醒持续时间成正比，并且被认为在睡眠的恢复功能中起着重要作用。除此之外，所谓的稳态过程，它在24小时内保持睡眠的相对恒定，另一个同样重要的过程负责启动和终止睡眠和唤醒状态。这两个过程被认为是分开的。从理论上讲，即使“睡眠需求”很低，您也可以入睡，例如，当您面临单调，无聊的环境时。另一方面，即使睡眠驱动器很高，您也可以保持醒着数小时甚至几天，例如，当您经历喷气滞后时，当您饿了，寒冷或像著名的斯坦福大学（Stanford）与兰迪·加德纳（Randy Gardner）的实验一样，他连续保持清醒11天！这两个过程如何 - 跟踪醒着和睡着的时间，以及负责睡眠效果开关的过程 - 互动 - 尚不清楚。传统的观点是，新皮层的作用 - 大脑的最外层覆盖 - 是产生依赖状态的大脑振荡，例如慢波。反过来，觉得睡眠转换被认为是由大脑深处的大脑结构引起的，例如下丘脑和脑干。与这一观点相反，在我们最近的工作中，我们发现皮质在睡眠体内稳态和睡眠效果控制中的先前未识别的作用。皮层在解剖学和功能上都是高度复杂的结构，因此很难研究。这就是为什么我们认为其在睡眠控制中的作用以前被忽略了。当我们研究了转基因的小鼠中的睡眠时，从出生后早期开始，一部分皮质投影神经元的子集被不可逆转地沉默时，我们观察到，这些动物的清醒时间比野生型乱立式同意异的静止且出色地表现出对睡眠丧失的高度减少的补偿，而睡眠不足。仿佛在部分沉默的皮质时，时间清醒会减慢，但是背后的基本神经生物学仍然是完全未知的。我们的发现代表了一个独特的机会，可以在理解控制我们“睡眠需求”的神秘过程的本质方面取得重大进展。在这个项目中，我们制定了一项综合研究计划，旨在研究我们发现的皮质睡眠控制控制的神经生物学底物。我们计划使用先进的转基因工具剖析皮质睡眠控制的基础神经回路，还将解决昼夜节律时钟和关键环境因素（例如光）的作用。