Scientists Explore the Molecular Mechanics that Drive us to Sleep

Our sleep/wake cycles are driven by a homeostatic mechanism that balances our drive to sleep with the amount of sleep we banked the night before.

Over the years neuroscientists have described how sleep and wake have global effects on brain, from measuring the electrical voltage changes of the brain to explore brain waves during sleep,¹ down to the effects on the single neuron,² to how sleep changes communication between brain cells,³ and the global expression of genes in the brain.^4,5

In this study published in Nature the scientists working in Japan, China and the USA, describe how phosphorylation of just 80 proteins in the brain induce the need to sleep.⁶ What’s more they show that these proteins are typically associated with synapses, the junctions between brain cells where cellular communication takes place. Naming these proteins, ‘sleep-need-index phosphoproteins’ (SNIPPs), they describe how the level of phosphorylation of these SNIPPs forms a molecular signature for the drive to sleep.

They go on to describe how a mutant protein called SLEEPY preferentially associates with SNIPPs. The team found that inhibiting the activity of SLEEPY and its normal variant in mice reduced phosphorylation of SNIPPS and reduced the drive to sleep. This reduction in sleep drive was so powerful it also worked in sleep-deprived mice.

Getting off to sleep in a SNIPP

Taken together, their research suggests that phosphorylating and dephosphorylating SNIPPs presents a major regulatory mechanism by which sleep homeostasis is achieved. Increasing phosphorylation of SNIPPs increases the drive to sleep, and SNIPP dephosphorylation decreases sleep drive.

This could one day mean that modulating SNIPP phosphorylation will be a viable therapeutic angle for treating insomnia or jetlag or mediating the health effects of shift work.

Investigating the mechanisms that regulate circadian rhythms and sleep homeostasis at the level of protein phosphorylation is important. Findings from studies like these will not only inform our understanding of sleep/wake cycles but also shed light on the how brain physiology is affected throughout the 24-hour period, and could greatly influence human health. 

References:

1. Loomis, A. L., Harvey, E. N., & Hobart, G. A. (1937). Cerebral states during sleep, as studied by human brain potentials. Journal of experimental psychology, 21(2), 127.

2. Vyazovskiy, V. V. & Harris, K. D. Sleep and the single neuron: the role of global slow oscillations in individual cell rest. Nat. Rev. Neurosci. 14, 443–451 (2013)

3. Tononi, G. & Cirelli, C. Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron 81

4. Elliott, A. S., Huber, J. D., O’Callaghan, J. P., Rosen, C. L. & Miller, D. B. A review of sleep deprivation studies evaluating the brain transcriptome. Springerplus 3, 728 (2014).

5. Funato, H. et al. Forward-genetics analysis of sleep in randomly mutagenized mice. Nature 539, 378–383 (2016)