This Newly Discovered Process Helps Explain The Molecular Origin Of Sleepiness

Adding a few more pieces to the complex puzzle of circadian rhythms. 24cdesign/Shutterstock

Chronobiology, the field of science dedicated to studying circadian rhythms and the myriad of physical and mental processes that go wrong when they are disrupted, is on a serious upswing. Researchers have released a deluge of recent insights into why we sleep and how to do it better; and the frustrated, sleep-deprived masses (ourselves included) have been gobbling it up with curiosity and gratitude.

The latest illuminating finding comes to us from a team at the International Institute for Integrative Sleep Medicine in Tsukuba, Japan. Their investigation, published in Nature, describes the molecular process that appears to underlie how the brain generates increasing desire for sleep the longer it has been awake, then resets the system after adequate sleep has been achieved – a known phenomenon called sleep pressure or sleep need.


The team discovered that family of 80 proteins present in the brains of mice gain function-altering chemical markers – phosphate groups – in quantities that corresponded to the individual’s degree of sleep pressure. When the animal was given the opportunity to sleep, enzymes chopped the phosphate groups off of the proteins. Think of the molecules, which have been dubbed sleep-need-index phosphoproteins (SNIPPs), as pincushions, and the phosphate groups as pins: as the day goes on, more and more pins get stuck into the cushion, leading to an as-of-yet undescribed physiological alert that gradually gains intensity, leading to increasing signs of fatigue. After a duration of sleep proportionate to the number of pins has been achieved, another unknown mechanism causes them to be pulled out.

“Our results suggest that phosphorylation of SNIPPs accumulates and dissipates in relation to sleep need, and therefore SNIPP phosphorylation is a molecular signature of sleep need,” the authors wrote. (Though this statement assumes that mice and human brains work similarly, many aspects of circadian rhythms are known to be shared across radically different species.)

This breakthrough in teasing out the mechanisms of the sleep-awake cycle – as you can tell, much of it remains quite mysterious – came to be thanks to the group’s earlier investigation into why a particular strain of mutant mice requires much more sleep than normal mice. In the aptly (albeit uncreatively) named Sleepy mice, a hyperactive version of a gene called Sik3 causes these SNIPPs to get phosphorylated to a much higher degree.

Subsequent experiments showed that inhibiting Sik3 in both Sleepy and normal mice reduces SNIPP phosphorylation and reduces sleep pressure, as measured by brainwave patterns captured on electroencephalograms.


Examination of the mouse brains revealed that the SNIPPs occur mostly in neural synapses, a finding that may explain how these proteins become markers for how long we have been awake.

“When we are awake our synapses are actively firing, so synaptic proteins are in the best position to monitor the duration and richness of our waking experience,” senior author Qinghua Liu told New Scientist.

For a more in-depth overview of current sleep science, check out this video from expert Matthew Walker


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