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

我们一生中大约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加，但这似乎并没有导致对高度复杂的睡眠调节过程有更好的理解。到目前为止，还没有一个被普遍接受的“睡眠理论”来指导我们的研究工作，这是取得进展的主要障碍。我们所知道的是，睡眠是一个严格控制的过程。人们认为，在我们醒着的时候，对睡眠的需求(“睡眠压力”)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，测量一个人能够保持持续清醒状态的时间可以让我们了解潜在的神经生物学过程的动态。在睡眠开始时，大脑开始产生高幅度、慢频率的振荡(慢波)，这与之前的觉醒时间成正比，被认为在睡眠的恢复功能中发挥着重要作用。除此之外，另一个同样重要的过程是启动和终止睡眠和觉醒状态，这就是所谓的动态平衡过程。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，你也能入睡。另一方面，即使在睡眠驱动力很高的时候，你也可以保持清醒好几个小时甚至几天，例如，当你经历时差时，当你饥饿、寒冷时，或者像著名的斯坦福大学与兰迪·加德纳的实验一样，他连续11天保持清醒！这两个过程--一个是记录清醒和睡眠时间的过程，另一个是负责睡眠-醒来切换的过程--是如何相互作用的，目前尚不清楚。传统观点认为，新皮质--大脑最外层的覆盖层--的作用是产生依赖于状态的大脑振荡，如慢波。反过来，睡眠-觉醒转换被认为是由大脑深处的结构引起的，比如下丘脑和脑干。与这种观点相反的是，在我们最近的工作中，我们发现大脑皮层在睡眠稳态和睡眠-觉醒控制方面的作用之前并未被认识到。皮质是一种高度复杂的结构，在解剖学和功能上都是如此，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的原因。当我们研究转基因小鼠的睡眠时，其中皮质投射神经元的一个子集从出生后早期就不可逆转地沉默，我们观察到这些动物保持清醒的时间比它们的野生型小鼠长得多，而且令人惊讶的是，当睡眠被剥夺时，这些动物对睡眠丧失的补偿反应高度减弱。这就好像当大脑皮层部分静默时，清醒的时间变慢了，但背后的基本神经生物学仍然完全未知。我们的发现代表着一个独特的机会，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，包括解剖学和功能水平。我们计划使用先进的转基因工具，剖析皮层睡眠控制的神经回路，还将解决生物钟和关键环境因素(如光)的作用。

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.