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.

我们一生中有三分之一的时间都在睡觉，但我们仍然不知道为什么。新的和令人兴奋的实验数据正在增长，但这似乎并没有导致更好地了解睡眠调节的高度复杂的过程。目前还没有一个普遍接受的“睡眠理论”可以指导我们的研究工作，这是取得进展的主要障碍。众所周知，睡眠是一个受到严格控制的过程。人们认为，睡眠的需要（“睡眠压力”）在我们醒着的时候逐渐增加，这反映在我们感到疲倦。我们保持清醒的时间越长，睡觉的冲动就越大，测量一个人能维持持续清醒状态多久可以告诉我们潜在的神经生物学过程的动态。在睡眠开始时，大脑开始产生高振幅、慢频率的振荡（慢波），其与先前的清醒持续时间成比例，并且被认为在睡眠的恢复功能中起重要作用。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性，另一个同样重要的过程负责启动和终止睡眠和清醒状态。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，例如，当你暴露在单调乏味的环境中时，你也可以入睡。另一方面，即使睡眠动力很高，你也可以保持清醒好几个小时甚至几天，例如当你正在经历时差，当你饿了，冷了，或者像著名的斯坦福大学实验兰迪加德纳谁保持清醒连续11天！这两个过程--一个记录清醒和睡眠时间，另一个负责睡眠-清醒转换--是如何相互作用的，目前还不清楚。传统观点认为，新皮层（大脑的最外层）的作用是产生依赖于状态的脑振荡，如慢波。反过来，睡眠-觉醒转换被认为来自大脑深处的大脑结构，如下丘脑和脑干。与这种观点相反，在我们最近的工作中，我们发现了大脑皮层在睡眠稳态和睡眠-觉醒控制中的一种以前未被认识到的作用。皮层是一个高度复杂的结构，无论是在解剖学上还是在功能上，因此很难研究;这就是为什么我们认为它在睡眠控制中的作用以前被忽视了。当我们研究转基因小鼠的睡眠时，其中一部分皮质投射神经元从出生后早期就不可逆地沉默了，我们观察到这些动物保持清醒的时间比野生型同窝出生的小鼠长得多，并且引人注目的是，当睡眠被剥夺时，表现出对睡眠丧失的补偿反应大大减弱。这就好像当大脑皮层部分沉默时，清醒的时间会变慢，但背后的基本神经生物学仍然完全未知。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，我们制定了一个全面的研究计划，旨在调查我们发现的皮层睡眠控制的神经生物学基础，无论是在解剖学水平还是功能水平。我们计划使用先进的转基因工具来剖析皮层睡眠控制背后的神经回路，并将解决生物钟和关键环境因素（如光线）的作用。