We've all experienced going to bed tired and waking up refreshed, yet how that happens at the molecular level remains a mystery. An international study published in Nature sheds new light on the biochemistry of sleep need in the brain.
The new research reports the first whole-brain, quantitative study of a fundamental molecular process called phosphorylation in the context of sleep need. It features a clever comparison of two different groups of tired mice: sleep-deprived normal mice and Sleepy mutant mice, a variety with a genetic mutation that confers an unusually high sleep need despite increased sleep amount.
"Each animal exhibits a set point of total sleep time. In adult humans, that usually means about 8 out of 24 hours. Everyone has experienced staying up too late and feeling a need to 'make up for lost sleep.' Even simple jellyfish need to rest longer after being forced to remain awake," one of the senior authors said, adding that it has been hypothesized that a substance accumulates in the brain during waking and dissipates during sleep.
"A long-term goal in sleep research is to identify the actual molecular factor or factors involved in sleep need," co-senior author said. Currently, the majority of sleep medicines are mimics of GABA, an inhibitory neurotransmitter that simply shuts off the brain, and they induce nonnatural sleep with many side effects. It would be nice to understand the natural molecules better in order to design improved treatments for sleep problems, he added.
Using immunochemical assays and mass spectrometry, the researchers identified 80 proteins that were hyperphosphorylated in the brains of sleep-deprived and Sleepy mice, meaning that the proteins accumulated more phosphate groups the longer the mice stayed awake. They named these proteins Sleep-Need-Index-Phosphoproteins (SNIPPs). They found that the phosphorylation of SNIPPs increased with sleep need and dissipated, or dephosphorylated, throughout the brain during sleep.
"Previous studies suggested a close link between sleep need and synaptic plasticity (the strengthening and weakening of synaptic connections between neurons that is linked to thinking and learning). Intriguingly, the majority of SNIPPs are synaptic proteins, including many regulators of synaptic plasticity," another author said.
Literature search found that mutations of multiple SNIPPs have been linked to changes in sleep need. "Thus, we propose that SNIPPs constitute the molecular link between synaptic plasticity and regulation of sleep need or, in lay terms, between thinking and sleepiness," co-author said.
"The purpose of sleep-wake balance appears to be to maximize the duration and quality of cognitive (thinking) functions of the brain. While prolonged wakefulness leads to cognitive impairment and sleepiness, sleep refreshes the brain through multiple restorative effects and optimizes cognitive functions for the next waking period," he said. Therefore, the phosphorylation/dephosphorylation cycle of SNIPPs may be an important way for the brain to reset itself every night, restoring both synaptic and sleep-wake balance to maximize clear thinking, co-author added.
https://www.utsouthwestern.edu/newsroom/articles/year-2018/brain-changes-sleep.html
https://www.nature.com/articles/s41586-018-0218-8
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