Reversible changes to neural proteins may explain sleep need

June 13, 2018, University of Tsukuba
By comparing the brains of sleep-deprived mice and Sleepy mutant mice, the phosphorylation of 80 proteins, named SNIPPs (Sleep-Need-Index-Phosphoproteins), was found to be increased along with sleep need. Credit: University of Tsukuba

Long periods of waking can lead to cognitive impairment, and the need to sleep continues to build up. Sleep then refreshes the brain through alterations in molecular biochemistry. These changes impact neuronal plasticity and brain function, but the molecular underpinnings of "sleepiness" are not well understood.

Researchers at the International Institute for Integrative Sleep Medicine (WPI-IIIS) in Japan's University of Tsukuba went looking for the biochemical changes that form the basis of this .

A current theory of the sleep-wake cycle suggests that waking encodes memories, whereas sleep consolidates memories and restores synaptic homeostasis. The researchers suspected the molecular substrate of sleepiness should be seen in all regions, and should accumulate gradually during waking and dissipate through sleep. Their findings, recently published in Nature, revealed that phosphorylation may be the key.

During normal function, cellular proteins may be modified by reversible addition of a chemical phosphoryl group, this is known as phosphorylation. The researchers used techniques for analyzing which proteins are phosphorylated and which are not. This enabled them to identify and quantify the phosphorylation of a wide range of brain proteins in sleep-deprived , and in mice with a single point mutation, named Sleepy, that increases both sleep time and sleep need.

"Protein functions can be switched on or off by site-specific phosphorylation, or modulated by cumulative phosphorylation of multiple sites," says study first author Zhiqiang Wang. "So it seemed likely that phosphorylation patterns may reveal the processes underpinning sleep need."

Immunochemical and mass spectrometry results showed increases in the number of in the whole brains of Sleepy mutant mice and normal sleep-deprived mice. Importantly, the abundance of proteins did not change and the researchers found the pattern of phosphorylation increase in Sleepy mutant mouse brains mimicked that of sleep-deprived mouse brains.

They also found a dose-dependent increase in the number of phosphorylation events in the whole-brain phosphoproteome, which tracked increasing sleep need.

By analyzing the quantity of change in phosphorylation, the researchers identified 80 proteins that are hyper-phosphorylated when the mouse is sleepy, which they termed the Sleep-Need-Index-PhosphoProteins (SNIPPs). The phospho-state of SNIPPs changed along with sleep need. Importantly, the SNIPPs identified were predominantly synaptic proteins.

"By comparing sleep-deprived mice and Sleepy mutant mice, we were able to filter out the effects of prolonged waking, prolonged sleeping and stress," corresponding author Masashi Yanagisawa says. "Our findings show that the phosphorylation/dephosphorylation cycle of SNIPPs may be a major way that the brain regulates sleep-wake homeostasis."

The study provides evidence that prolonged wakefulness causes hyper-, whereas sleep promotes global dephosphorylation of the brain proteome. Given that the sleep-wake cycle impacts cognition, this research could aid in understanding sleep-wake patterns for optimal brain function.

Explore further: A single control center for sleep and wake in the brain

More information: Zhiqiang Wang et al, Quantitative phosphoproteomic analysis of the molecular substrates of sleep need, Nature (2018). DOI: 10.1038/s41586-018-0218-8

Related Stories

A single control center for sleep and wake in the brain

June 12, 2018
Until now, it was thought that multiple brain areas were needed to control sleep and wakefulness. Neuroscientists from Bern have now identified one single control center for the sleep-wake cycle in the brain. The findings ...

A key switch in biological clocks

May 29, 2018
Just as we abide by an external time schedule to eat, sleep, and go to work, our body is similarly dictated by internal clocks. Known as circadian rhythms, these daily cycles keep us on a regular 24-hour day and are involved ...

Sleep and Alzheimer's disease connection

October 17, 2017
How often do you get a good night's sleep? Centers for Disease Control and Prevention guidelines recommend adults get an average of at least seven hours of sleep a night. Dr. Ronald Petersen, a Mayo Clinic neurologist, says ...

Can weekend sleep make up for the detriments of sleep deprivation during the week?

May 23, 2018
In a recent Journal of Sleep Research study, short, but not long, weekend sleep was associated with an increased risk of early death in individuals under 65 years of age. In the same age group, either short sleep or long ...

Why does sleep become disrupted in old age?

March 26, 2018
The brain maintains its ability to generate local neural oscillations during sleep throughout the lifespan, according to a study of young and old mice published in JNeurosci. The research indicates that age-related disruptions ...

Recommended for you

New technique helps uncover changes in ALS neurons

June 22, 2018
Northwestern Medicine scientists have discovered that some neurons affected by amyotrophic lateral sclerosis (ALS) display hypo-excitability, using a new method to measure electrical activity in cells, according to a study ...

Broken shuttle may interfere with learning in major brain disorders

June 22, 2018
Unable to carry signals based on sights and sounds to the genes that record memories, a broken shuttle protein may hinder learning in patients with intellectual disability, schizophrenia, and autism.

Watching stem cells repair spinal cord in real time

June 22, 2018
Monash University researchers have restored movement and regenerated nerves using stem cells in zebra fish where the spinal cord is severely damaged.

Scientists discover fundamental rule of brain plasticity

June 21, 2018
Our brains are famously flexible, or "plastic," because neurons can do new things by forging new or stronger connections with other neurons. But if some connections strengthen, neuroscientists have reasoned, neurons must ...

Waking up is hard to do: Prefrontal cortex implicated in consciousness

June 21, 2018
Philosophers have pondered the nature of consciousness for thousands of years. In the 21st century, the debate over how the brain gives rise to our everyday experience continues to puzzle scientists. To help, researchers ...

Researchers find mechanism behind choosing alcohol over healthy rewards

June 21, 2018
A new study links molecular changes in the brain to behaviours that are central in addiction, such as choosing a drug over alternative rewards. The researchers have developed a method in which rats learn to get an alcohol ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.