Sleep clears brain of toxic metabolites

Anthony Komaroff writes in New England Journal of Medicine Journal Watch:

We all know that without enough sleep, mood and cognition are impaired. Certain central nervous system conditions, including migraines and seizures, become more frequent and severe with a lack of sleep. When animals are kept from sleeping, they ultimately die.

Clearly, we need to sleep. But why? In a study in the October 18, 2013, issue of Science (http://dx.doi.org/10.1126/science.1241224), researchers report on a technique they developed for measuring the interstitial space in the brains of living mice. That space is bathed by cerebrospinal fluid that is produced by the choroid plexus and pumped back into the blood in the meninges. The researchers found that, during sleep and anesthesia, the interstitial space increased by 60%. The functional result of this expansion is that many metabolites of neurons and glial cells that spill into the interstitial space are cleared from the space much more rapidly, enter the blood, and are detoxified by the liver. These molecules include β‐amyloid and tau, which build up in the brains of patients with Alzheimer disease. When sleeping animals are aroused, the clearance of toxic metabolites slows markedly.

The researchers speculate that, at least in mice, the buildup of toxic metabolites in the interstitial space in the brain is a trigger for sleep, and that a key purpose of sleep is to clear these metabolites. Maybe the reason we feel restored after a good night’s sleep is because the brain has freed itself of toxins. This hypothesis is arresting in its simplicity and could prove to be profoundly important in human biology (http://dx.doi.org/10.1126/science.1245798).

Emily Underwood comments:

Scientists have long speculated that one of the functions of sleep is to restore and repair the brain, but whether this is a “core” purpose of sleep remains controversial. Now, a paper published in Science this week on page 373 provides direct experimental evidence that the mouse brain cleans itself during sleep, by expanding channels between neurons that allow an influx of cerebrospinal fluid. The fluid flushes out detritus such as amyloid proteins, which accumulate as plaques in Alzheimer's disease, twice as fast when mice are sleeping as when they are awake.

Suzana Herculano-Houzel comments:

We know from personal experience that sleep is not just another brain state but a basic requirement for normal brain function while we are awake. Mental fatigue, poor decision-making, impaired learning, and a heightened risk of migraine and epileptic attacks ensue when we are sleep deprived — and chronic and complete insomnia ultimately lead to death in humans, rats, and flies alike. Why does normal brain function deteriorate with prolonged waking and require sleep to be restored? On page 373 in this issue, Xie et al. report that during sleep, waste products of brain metabolism are removed from the interstitial space among brain cells where they accumulate. Sleep, therefore, might be required for potentially toxic metabolites — the very results of a working brain — to be cleared from the tissue.

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