Two years ago, scientists in Japan reported the discovery of a mouse that just could not stay awake. This creature, which had a mutation in a gene called Sik3, slept upwards of 30 percent more than usual: Although it awoke apparently refreshed, it would need to snooze again long before its normal lab mates’ bedtime. It was as if the mouse had a greater need for sleep.

Now, after examining the brain chemistry of sleep-deprived mice and the ones with the Sik3 mutation, a second research group at the International Institute of Integrated Sleep Medicine at the University of Tsukuba has identified tantalizing differences in the state of 80 proteins that well-rested, normal mice do not share. That observation, the scientists suggest, may be the key to understanding at the molecular level both why we need sleep and why we feel sleepy.

Researchers can describe in generalities many things that happen in sleeping brains. The connections between neurons shift. On electroencephalograph recordings, sleep-deprived brains produce slow waves with higher peaks and lower valleys than well-rested brains do. The body produces certain substances that will knock you out, and others that will wake you up. Sleep helps with learning, and, despite the fact that it takes us out of commission for a shockingly large proportion of each day, it’s necessary for survival. If we go without it for too long, it’s likely we will die.

What remains surprisingly murky, however, is what precisely sleep does that’s so important, and how the brain keeps track of how long it’s been awake. Presumably, the mechanism of that internal ledger of sleep need is connected to whatever processes are restored during sleep.

The new results hint that some leads on the problem might emerge from a biochemical approach—specifically, checking out phosphorylation, the attachment of phosphate groups, to those 80 identified proteins (and possibly others). Phosphorylation commonly turns off or otherwise modulates the activity of proteins, so it’s possible that in this case it is altering how some of these proteins function.

Less Sleep, More Phosphorylation

The scientists began their experiments already suspecting that it might be fruitful to look at phosphorylation in mice with the Sik3 mutation, which they aptly call Sleepy mice. Sik3 codes for an enzyme that adds phosphate groups, and the mutation that the Sleepy mice have makes the enzyme overactive—potentially causing it to add more phosphate groups than normal. That sleepiness “indicates there’s something wrong or changed in phosphorylation in these mutant mouse brains,” said Qinghua Liu, a co-author on the paper and a professor at the University of Texas Southwestern and the University of Tsukuba who recently moved to the National Institute of Biological Sciences in Beijing.