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Does sleep really clean the brain?

A mouse study challenges popular “glymphatic” theory, but its methodology is drawing criticism.

We all need sleep, but no one really knows why. For the past 10 years, a prevailing theory has been that a key function of sleep is to wash waste products and toxins from the brain via a series of tiny channels called the glymphatic system. Sleep problems can disrupt this process, the theory’s proponents say, perhaps raising the risk of Alzheimer’s disease and other brain disorders.

ciscenje-mozgaMouse experiments seem to support the idea. But in recent years, several groups of scientists have challenged some aspects of the theory. Now, a new study has found that the mouse brain clears small dye molecules more efficiently while the animal is awake than when it is asleep or under anesthesia. A glymphatic system might still cleanse the brain, the researchers say, but sleep actually slows this cleansing down.

Other researchers are stumped as to how to explain the opposing results, and several declined to comment on the record for fear of entering a heated debate. A few see the new findings as a serious blow to the sleep clearance theory, but others say the new paper’s methods are too different from those of the earlier work to credibly challenge it. “When you criticize a concept that has been there for some time, then your design should be even better,” says Per Kristian Eide of the University of Oslo.

In the original mouse experiments, neuroscientist Maiken Nedergaard at the University of Rochester and her team injected a dye into the cisterna magna, a fluid-filled pocket at the back of the neck, which sits just outside the brain and supplies it with cerebrospinal fluid (CSF). They used a two-photon microscope to measure the influx of the dye to the brain and its spread through the organ. The influx increased when mice were asleep or under anesthesia compared with when they were awake, allowing the dye to penetrate through the brain. That led the researchers to conclude that more fluid was flowing through the brain and draining into blood or lymphatic vessels. Nedergaard proposed that this efflux relied on the pumping of fluid through tiny glymphatic vessels between neurons, which her team had identified in an earlier study.

Nicholas Franks, an anesthesia researcher at Imperial College London and senior author of the new paper, didn’t set out to disprove this popular hypothesis. “I really liked this sort of theory of sleep,” he says, “as a basic housekeeping mechanism that keeps the brain healthy and fully functional.” But he questioned whether the influx of dye was a reliable proxy for efflux, which he says would be impossible to measure directly by tracking every blood or lymphatic vessel or potential exit point from the brain.

He likens the brain to a leaky bucket, where the water level is the amount of dye that penetrates it. That level will rise when water is poured into the bucket faster—if the brain pulls more CSF in during sleep. But it will also rise if the hole at the bottom shrinks—if efflux slows. And it’s difficult to distinguish the two.

Franks’s team used a different technique, also indirect, to infer flow. They injected dye directly into mice’s brains via portals through their skulls and measured its concentration with a sensor in another part of the brain away from the injection site. The sensor revealed far less dye when the mice were awake than when they were asleep or anesthetized, suggesting the molecules were leaving the brain more quickly, the team reported on 13 May in Nature Neuroscience.

“I think they did a very good job,” says Erik Bakker, a circulation expert at Amsterdam University Medical Center. Steven Proulx, a vascular expert at the University of Bern, calls the new study’s approach “very clever.”

Proulx found something similar in 2018, when he and colleagues injected tracer dyes into the cisterna magna and found they entered the systemic blood more quickly in awake mice than anesthetized ones.

But Nedergaard says the new study doesn’t seriously challenge her results. “You can’t just come in and do something that’s completely different and say all the old data is wrong,” she says. “I’m actually shocked that this paper was published.” Nedergaard is writing a letter to Nature Neuroscience detailing her many concerns. One is that the dye was pumped in at the same rate during wake and sleep, which she argues could lead to spurious results. Her research has found neurons shrink during sleep—a claim others have challenged—which could lower pressure in the brain and affect how quickly dye flows through it.

Her main concern, shared by others, is that inserting the dye portal damaged the brain—the glymphatic system is delicate and could easily collapse. (Franks’s team waited a week after surgery before injecting dye to allow potential injuries to heal, he notes.) Eide adds that the team didn’t measure dye in the cortex, which is where most glymphatic clearance occurs.

Bakker says it’s possible the brain has multiple waste clearing mechanisms. Small molecules such as dyes might exit the brain through different means from large ones such as the Alzheimer’s-linked protein beta amyloid.

Nedergaard’s group is working on a rodent model that produces waste products that can be precisely traced as they leave the brain. Meanwhile, Franks’s team plans to investigate how different-size molecules behave in the brain and mechanisms that might pump waste-bearing fluid through the organ in the first place.

Challenging a popular theory about something as basic as sleep is difficult, he says. “It’s got such a firm rooting in the zeitgeist.”

doi: 10.1126/science.zfoly9p

Source: Science