Award details

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

Reference	BB/X008711/1
Principal Investigator / Supervisor	Professor Vladyslav Vyazovskiy
Co-Investigators / Co-Supervisors	Professor Zoltan Molnar
Institution	University of Oxford
Department	Physiology Anatomy and Genetics
Funding type	Research
Value (£)	599,081
Status	Current
Type	Research Grant
Start date	01/04/2023
End date	31/03/2026
Duration	36 months

Abstract

Sleep need increases during wakefulness and dissipates during sleep. This process is reflected in the levels of EEG slow-wave activity, which is high after sleep deprivation and decreases during subsequent sleep. A typical human has about 4-5 sleep cycles during the night, while a typical mouse in laboratory conditions will go between wake, NREM and REM sleep states more than 100 times every day - for reasons we still do not understand. It is thought that sleep-wake switching is controlled through a mutually antagonistic relationship within a complex subcortical network of sleep-promoting and wake-promoting neurons. Contrary to this widely held view, we recently discovered that selective silencing of a subset of cortical projection neurons - in layer 5 of the neocortex and the dentate gyrus - resulted in a major sleep phenotype, manifested in a marked prolongation of wakefulness and a significantly attenuated homeostatic response to sleep deprivation. Based on these new compelling data, here we will test the hypothesis that the cortex plays an active role in sleep control. To this end, we will start by identifying the role of specific cortical (neocortical or hippocampal) and cortico-subcortical (cortico-cortical striatal or subcerebral) projections, which will be conditionally silenced or acutely manipulated by chemogenetics, investigate changes in circadian clock, motivation and response to light, which are crucially important factors influencing sleep timing and duration, along with measurement of the effects of cortical manipulations on sensory processing. Our team combines expertise in cutting edge techniques, from neuroanatomy and mouse genetics to sleep electrophysiology and circadian neurobiology. The hypothesis tested in our project is paradigm shifting, and will open new perspectives for understanding fundamental mechanisms of sleep regulation, with far-reaching implications for human and animal health.

Summary

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.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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