Scientists uncover how the brain washes itself during sleep
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Pulsating blood vessels push fluid into and out of the brains of slumbering mice
- 8 Jan 2025
- 11:00 AM ET
- ByMitch Leslie
“This is excellent science,” says neuroscientist Suzana Herculano-Houzel of Vanderbilt University, who wasn’t connected to the study. “They put a number of pieces of evidence together that tell a pretty compelling story.”
The scientists also found that the sleep drug zolpidem, better known as Ambien, impedes the blood vessel oscillations and the fluid flow they promote, implying it could hamper cleansing. The finding could help researchers create new sleep aids that preserve this brain-scrubbing function.
The brain lacks the lymphatic vessels that collect and move fluid in other parts of the body. But in 2012, neuroscientist Maiken Nedergaard of the University of Rochester Medical Center and colleagues identified an alternative drainage system in which cerebrospinal fluid, the liquid bathing the brain, seeps through the organ via tiny passages alongside blood vessels, sweeping away metabolic refuse and other unwanted molecules. Fluid flow through this so-called glymphatic system ramps up during sleep, they also reported. Studies from Nedergaard’s group and others suggest vigorous glymphatic clearance is beneficial: Circulation falters in Alzheimer’s disease and other neurodegenerative illnesses. Some researchers have challenged parts of this picture, however; a 2024 study, for example, suggested waste clearance is actually faster during waking than during sleep.
In the new research, Nedergaard and her team wanted to pin down what keeps cerebrospinal fluid moving through the brain. But studying the mouse glymphatic system often involves anesthetizing the rodents, she says, which is very different from natural sleep. To avoid this problem, the scientists surgically implanted mice with electrodes and fiber optic filaments. Although the rodents are tethered to a set of cables, they can fall asleep normally while researchers track blood volume, electrical activity, and chemical levels and use light transmitted through the fiber optic lines to activate certain groups of neurons.
Previous work showed that levels of the neurotransmitter norepinephrine, which is chemically almost identical to adrenaline and spurs blood vessels to contract, fluctuate rhythmically in the mouse brain, peaking about every 50 seconds. Nedergaard and colleagues found that when mice were in the sleep stage known as non-REM sleep, during which the body’s tissues undergo renewal, blood volume in the brain also oscillated, tracking—with more than a half-second delay—the changes in norepinephrine. The connection between the two measures wasn’t as tight when the animals were awake or in the other main sleep phase, REM sleep, when memories are consolidated.
By injecting the animals with a fluorescent molecule that can trace the flow of cerebrospinal fluid, the researchers found that its levels, too, varied with norepinephrine levels during non-REM sleep. To gauge whether the blood vessel pulsations propel glymphatic flow, the researchers stimulated the area of the mouse brain that produces the neurotransmitter, artificially speeding up the pulses from every 50 seconds to every 10. They then followed labeled cerebrospinal fluid to show it penetrated deeper into regions near the site of norepinephrine production.
Because the brain is boxed in by the skull, the contraction and relaxation of blood vessels creates a pump that circulates the cerebrospinal fluid, Nedergaard explains. When the vessels clench after a pulse of norepinephrine, cerebrospinal fluid moves in to fill the gap. And when the blood vessels relax, they push the cerebrospinal fluid along.
Norepinephrine may not be the only player, but “we have identified maybe the most important driver of glymphatic flow in non-REM sleep,” Nedergaard says. Recent research suggests humans, like mice, show oscillations in norepinephrine release and blood vessel pulsations during sleep, so the same pumping mechanism could be operating in our brains, she notes.
“I do think it’s an important advance,” says neuroscientist Laura Lewis of the Massachusetts Institute of Technology, who wasn’t connected to the study. “It’s one of the first insights into a neural circuit that can regulate this process.”
Zolpidem could disrupt the mechanism. Other research had shown the drug may alter brain activity during sleep and modify the lengths of different sleep phases, so Nedergaard and her team decided to test the drug’s effects in the mice. It diminished the norepinephrine oscillations and reduced penetration of cerebrospinal fluid into the brain.
Zolpidem is a widely used sleep aid, but Nedergaard, Herculano-Houzel, and Lewis agree that the study shouldn’t prompt people to stop taking it. Instead, Lewis says, “It should be a priority to look at this medication in human studies” to determine whether the side effects on brain clearance are the same.