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Two new papers from the Vyazovskiy Group and both Oxford University and international collaborators have made important progress in bridging the gap between the local and global levels of sleep regulation.

"Flaming June" painting depicts an image of a painting with a woman sleeping. © Frederic Leighton, 1st Baron Leighton / Public domain

Our current understanding of how sleep is regulated is based on the model of sleep homeostasis, which defines a variable called Process S as a measure of sleep need, and a so-called "flip-flop" model of state switching, which builds on a notion of mutually antagonistic relationship between subcortical sleep-promoting and wake-promoting circuits. The neurobiological substrates of the interaction between the sleep switch and Process S remain unknown, and intensive research efforts to address this crucial question over recent decades have led to a long list of putative sleep-wake centers, and factors responsible for the elusive Process S at the molecular, cellular and network levels. As a result, we are currently grappling with a lack of a solid theoretical framework that could address this growing complexity.

One study from the Vyazovskiy Group published in eLife last month uses a combined experimental and mathematical modelling approach to address the dynamics of sleep need. The key conclusion of this paper is that global sleep homeostasis is, in essence, a process arising from a spatial and temporal integration of local neural activities. A conceptually similar approach is demonstrated in a seminal study from Harvard Medical School, which investigated the suprachiasmatic nucleus, or the "master clock" of the brain, and concluded that "circadian period in the whole animal is determined by averaging widely dispersed periods of individual clock cells", leading to important advances in the field. On his eLife paperAssociate Professor Vladyslav Vyazovskiy said: "Based on our data we proposed that Process S, by integrating “sleep-wake histories” or, more accurately, “activity histories” at local levels, provides an intrinsic time-keeping signal that precisely tracks the passage of time in each state of vigilance, thereby generating a signal used to enforce that an exact quota of global sleep is obtained each day. Thus, our study offers a potential solution for how to bridge the gap between global and local aspects of sleep regulation."

While the Vyazovskiy lab team's modelling work describes sleep homeostasis quantitatively at different temporal and spatial scales, the molecular and network mechanisms which "translate" sleep need into the probability of sleep state occurrence remains to be determined. This question has now been tackled in a new Science Advances paper from MRC Harwell and the Nuffield Department of Clinical Neurosciences (NDCN), on which Prof Vyazovskiy co-authored.

This study characterises sleep in a new mouse model, which carries a recessive mutation in the gene of the VAMP2 (synaptobrevin 2, belonging to the SNARE protein family). Using forward genetics and in vivo electrophysiology, the team identified a recessive mouse mutant line characterised by a substantially reduced propensity to transition between wake and sleep states with an especially pronounced deficit in initiating rapid eye movement (REM) sleep episodes. The causative mutation was in the synaptic vesicular protein, VAMP2, which resulted in a markedly diminished probability of vesicular release in mutants, and affected globally the entire brain. Ultimately, the findings highlight how communication in neuronal networks across the brain plays a key role in regulating sleep. According to Prof Vyazovskiy: "The traditional view is that changes in vigilance state transitioning are brought about primarily by changes in synaptic neurotransmission within a limited set of specific brain regions directly involved in sleep-wake control. Our data suggest an entirely novel possibility that sleep state transitions are instead regulated through global shifts in the synaptic efficiency across brain-wide networks."

More information is available in "Scientists uncover the role of neuronal networks in moving between wake and sleep states", on the NDCN website and MRC Harwell Institute website.

Taken together, these two studies give us substantial insights into how sleep might ultimately be regulated. Prof Vyazovskiy summarises: "On the one hand, sleep pressure may first build up locally across many brain regions, in an activity-dependent manner, and through integration across space and time result in the generation of a signal which represents global sleep need. This may in turn influence basic properties of the network function, such as synaptic neurotransmitter release, again across the entire brain. In this scenario, global shifts in excitability are an important prerequisite for relevant changes to occur within local sleep-wake switching areas, which play the key role in sleep-wake switching when the levels of global sleep need are high." 

"Altogether, our studies argue for a more integrative approach, where, at least in mammalian models, investigating both cortical and subcortical dynamics is necessary for making progress in understanding sleep, and highlight the necessity of both experimental work and mathematical modelling."

"These studies also demonstrate power of collaboration, where important advances are made when basic sleep-circadian neurobiology and mathematical modelling meet innovative technologies of transgenic mouse phenotyping and cellular/molecular neuroscience across institutions and countries."

Read more about the publications and collaborators

July 2020 eLife publication "Global sleep homeostasis reflects temporally and spatially integrated local cortical neuronal activity" is first authored by DPhil student Christopher Thomas, and performed in collaboration with Professor Peter Achermann from The KEY Institute for Brain-Mind Research in Zurich, Switzerland.

August 2020 Science Advances publication "Forward genetics identifies a novel sleep mutant with sleep state inertia and REM sleep deficits" is led by Pat Nolan (MRC Harwell) and Stuart Peirson (NDCN), and co-authored by ETH Zurich postdoctoral researcher, former Oxford DPhil student and Vyazovskiy Lab member Dr Mathilde Guillaumin.

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