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

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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.