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By: Richard Rosenberg, PhD on September 20th, 2018

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A Deep Dive into the Molecular Substrates of Sleep

Sleep Medicine | Research

As a graduate student at the University of Chicago, I had the distinct pleasure to work with Allan Rechtschaffen. He famously said, “If sleep doesn’t serve an absolutely vital function, it is the biggest mistake evolution ever made.” But he was pessimistic that his research in sleep deprivation and the physiology of sleep would ever find that function.

 In 1998, he wrote: “It is doubtful that this function will center on molar activities or physiologic processes; most of these stones have been turned. It seems to us more likely that molecular processes would provide a parsimonious key, but the search for sleep-dependent molecular processes seems to be in an early exploratory phase.”1

Our understanding of the molecular basis of these processes took a giant step forward with the publication of a letter to the journal Nature by Wang and colleagues.2 The study builds on the synaptic homeostasis hypothesis of Tononi and colleagues3 by focusing on synaptic proteins. The research also follows on the two-process model of sleep proposed by Borbely4, which suggests that two processes regulate sleepiness: a circadian rhythm (process C) and a homeostatic sleep drive (process S).

In a paragraph that I am sure would make Rechtschaffen smile, Wang and colleagues set out their research design by defining four criteria for supporting a role for a molecular substrate in sleep need:

“We hypothesize that the molecular substrates of sleep need satisfy four criteria: 1) they should be globally and similarly regulated in most brain cells or regions; 2) they should accumulate gradually during waking and dissipate through sleep; 3) they should change in parallel with sleep need in different contexts; and 4) gain or loss of these functions should cause bidirectional changes of sleep need.”1

The researchers proceed to systematically measure proteins in mutant mice with high sleep need and in wild-type mice subjected to sleep deprivation. They detected 80 mostly synaptic “sleep-need-index phosphoproteins,” or SNIPPs, that meet criteria. The SNIPPs increased with sleep deprivation and were higher in the mutant mice. They were able to “rescue” mutant mice from the molecular changes associated with sleepiness using an inhibitor.

I can’t pretend to understand the details of the studies presented in the paper. I can’t tell the difference between phosphorylation of a brain proteome and a fully activated phaser bank. But I do know that this research is significant. In using slow waves in the EEG as a measure of process S, one is measuring the activity of huge populations of neurons. Wang moves to the level of molecules by shifting the focus to SNIPPs. And the current techniques using intracerebroventricular injection of pan-SIK inhibitors will most likely be seen as a sledgehammer in comparison to methods for blocking individual SNIPPs. Wang and colleagues suspect a “core set of SNIPPs” monitor activity during waking and result in sleepiness. When these have been identified, methods for modifying their actions will surely follow.

Despite the fact that current stimulants and hypnotics have only minimal effects on level of alertness, they are a huge part of the pharmacological industry. When they were developed, drugs to increase or decrease serotonin, norepinephrine and acetylcholine levels were considered magic. But we now know that increasing or decreasing sleepiness was in many ways a side effect of these drugs. Imagine if there were drugs that could specifically target and eliminate SNIPPs that cause sleepiness or turn on the molecular functions of sleep directly.

Perhaps more importantly, these molecular substrates may lead to an understanding of the function of sleep — that elusive, parsimonious explanation for why we spend a third of our lives detached from the environment, lying down with our eyes closed. As Rechtschaffen noted, “who knows what marvelous new, unanticipated biological insights lie behind the doors of sleep function?”1


  1. Rechtschaffen, A. (1998). Current perspectives on the function of sleep. Perspectives in Biology and Medicine, 41(3), 359-390.
  2. Wang, Zhiqiang, Ma, Jing, Miyoshi, Chika, Li, Yuxin, Sato, Makito, Ogawa, Yukino, . . . Liu, Qinghua. (2018). Quantitative phosphoproteomic analysis of the molecular substrates of sleep need. Nature, 558(7710), 435-439.
  3. Tononi, G., & Cirelli, C. (2014). Sleep and the price of plasticity: From synaptic and cellular homeostasis to memory consolidation and integration. Neuron, 81(1), 12-34.
  4. Borbely, A. A. A two process model of sleep regulation. Hum. Neurobiol. 1, 195–204 (1982).