Sleep allows brain to wash out junk

Discovery could lead to better treatments for Alzheimer’s disease

WIDE ASLEEP  Colored tracers penetrate more deeply into a mouse’s brain when it’s asleep (left, red tracer) than awake (right, green tracer). The finding indicates that channels between brain cells open up during sleep and allow cerebrospinal fluid to wash debris out of the brain. Blood vessels are shown in blue.

L. Xie, H. Kang and M. Nedergaard

Sleep hoses garbage out of the brain, a study of mice finds.

The trash, including pieces of proteins that cause Alzheimer’s disease, piles up while the rodents are awake. Sleep opens spigots that bathe the brain in fluids and wash away the potentially toxic buildup, researchers report in the Oct. 18 Science.

The discovery may finally reveal why sleep seems mandatory for every animal. It may also shed new light on the causes of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases.

“It’s really an eye-opening and intriguing finding,” says Chiara Cirelli, a sleep researcher at the University of Wisconsin–Madison. The results have already led her and other sleep scientists to rethink some of their own findings.

Although sleep requirements vary from individual to individual and across species, a complete lack of it is deadly. But no one knows why.

One popular idea is that sleep severs weak connections between brain cells and strengthens more robust connections to solidify memories (SN Online: 4/2/09; SN Online: 6/23/11).

But a good memory is not a biological imperative. “You don’t die from forgetting what you learned yesterday,” says Maiken Nedergaard, a neuroscientist at the University of Rochester Medical Center in New York who led the study.

Researchers in Nedergaard’s lab stumbled upon sleep’s role in garbage clearance while studying a brain drainage system they described last year (SN: 9/22/12, p. 15). This service, called the glymphatic system, flushes fluid from the brain and spinal cord into the space between brain cells. Ultimately, the fluid and any debris it carries washes into the liver for disposal.

Studying fluid flow in the brain isn’t easy. Lulu Xie in Nedergaard’s lab trained mice to sit quietly on a microscope stage while researchers probed their brains. The mice were so relaxed that they sometimes fell asleep.

When that happened, Nedergaard says, “it was almost like you opened a faucet.” While the mice slept, cerebrospinal fluid rushed into the brain’s interstitial space and washed away debris. When the mice woke up, the faucet dried up and only a trickle of fluid left the brain.

Further experiments revealed that brain cells known as glial cells swell and shrink to control fluid flow. When mice are awake, glial cells expand, reducing the space between brain cells and shutting off fluid flow. During sleep, the cells contract and the faucet opens. The interstitial space changes in volume by at least 60 percent between wake and sleep, the researchers found.

The fluid flow’s on-off switch comes as a surprise because scientists have paid little attention to the area between cells, says Suzana Herculano-Houzel, a neuroscientist at the Federal University of Rio de Janeiro. “It’s usually disregarded. It’s considered just space.”

Researchers including Randall Bateman, a neurologist and neuroscientist at Washington University in St. Louis, have previously found that some substances build up in the brain during waking hours. He and others have evidence that brain cells just keep pumping out more and more of the stuff the longer a person or animal is awake, and scientists thought that was the reason garbage piled up. One substance that follows this pattern is amyloid-beta, or A-beta, a protein fragment that forms plaques in the brains of people with Alzheimer’s disease.

Levels of A-beta decrease with sleep, but researchers thought that was mostly due to enzymes and brain cells eating away the gunk, and that too little sleep meant the brain’s clean-up crew doesn’t have time to clear away all the mess. Scientists never considered that brain tissue could expand and contract enough to open flood gates and flush away toxic by-products, Bateman says. Now he’s rethinking some of his experiments.

“I’d be a fool not to pay attention to this,” he says. If the results are confirmed in people, it could mean that doctors should time Alzheimer’s treatment to when patients sleep.

Increasing the brain’s ability to rinse itself off may also combat Alzheimer’s and similar diseases, he suggests. But flushing away muck probably won’t eliminate the need for sleep altogether, he says. Even if garbage disposal is sleep’s primary task, he says, “sleep has become such an integral part of life on this planet that it serves additional functions besides clearing substances out of the brain.”

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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