Nightly fix for a dirty mind

Researchers are starting to understand what happens in the brain after its work day ends. James Mitchell Crow reports.

Sleep takes up a third of our lives. It is clearly vital, and going without rapidly takes its toll, as any new parent will attest. We know it’s involved in everything from memory consolidation to rejuvenating tired muscles. But exactly what goes on in the brain during sleep has been hard for researchers to nail down.

Maiken Nedergaard and her colleagues at the University of Rochester in New York might just have figured it out. In studies of mice, the team has shown that the sleeping brain switches into an alternate state. Like a busy office after 6 pm, it surrenders itself for cleaning. And at the end of a long day’s cerebration, there’s a lot to clean up.

As our neurons process information, they generate toxic waste such as the proteins amyloid beta and tau, which are both associated with Alzheimer’s disease. Until recently, the brain was thought to deal with its waste mainly by recycling it inside its own cells. But in mid-2012, Nedergaard’s team found an alternative disposal route: a network of microscopic drainage channels for flushing away toxic waste. They dubbed it the “glymphatic system”, because it is analogous to the lymphatic system that washes waste fluids from other body tissue, and because the glial cells of the brain (long-known to have a role in maintaining the “thinking” cells) formed part of the wall of the channel. Just as with the lymphatic system, the waste-filled glymphatic fluid ultimately drains into the bloodstream.

In their latest work, published in October in Science, Nedergaard’s team reported a surprise. They discovered this system speeds up dramatically during sleep. The glial cells shrink, expanding the drainage channels by 60%. When they injected amyloid beta into the brains of sleeping mice, they found that it was cleared twice as fast as when they were awake.

Mouse brains and human brains are largely built the same way, and so Nedergaard is convinced something similar is going on in humans. “The restorative nature of sleep appears to be the result of the active clearance of the by-products of neural activity that accumulate during wakefulness,” she wrote.

It might seem strange that this system has only just been discovered, but the drainage channels are far from obvious. Unlike the clearly visible vessels of the lymphatic system, the brain glymphatic system is simply a space between cells. Nedergaard picked it up using a recently developed technique to study fluid flowing between cells inside a living brain. It involves infusing a fluorescent tracer compound into the brain, and using sophisticated lasers to light it up inside living tissue.

The team identified the waste disposal system, and spotted that it flows much faster during sleep. The extent to which these drainage channels open up is “staggering”, says Brett Garner, a researcher at the Illawarra Health and Medical Research Institute in Wollongong, New South Wales, who researches Alzheimer’s and other neurodegenerative diseases.

Garner cautions that Nedergaard’s mouse studies only measured the flow of single molecules of amyloid beta, whereas in humans it is small clusters of amyloid beta molecules that are believed to cause Alzheimer’s disease. Since these clusters are larger they might not be pumped out of the brain at the same rate. But if the results do hold up in humans then the study has promising clinical implications for Alzheimer’s disease, he says.

Why doesn’t the brain keep its cleaning system at maximum flow all the times? Energy, Nedergaard says. All that pumping is hard work.

“The brain only has limited energy at its disposal and it appears that it must choose between two different functional states – awake and aware or asleep and cleaning up,” she says. “You can think of it like having a house party. You can either entertain the guests or clean up the house, but you can’t really do both at the same time.”

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