‘Body clock’ rhythms, not sleep, control brain waste disposal


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A study in mice suggests that the “glymphatic system,” which removes the brain’s toxic waste during sleep, may not operate efficiently in shift workers who sleep during the day. This may explain their increased risk of brain disorders, such as Alzheimer’s disease.

body clock concept illustration
New research in mice finds that disruption to an individual’s circadian rhythms is likely to interfere with the clearing of ‘brain waste.’
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In 2012, researchers at the University of Rochester Medical Center (URMC), NY, discovered a previously unknown waste disposal system in the brain.

They dubbed it the glymphatic system because nerve cells called glial cells manage its operation, which fulfills a similar role for the brain that the lymphatic system does for the rest of the body.

The following year, the same team found that the glymphatic system is most active during sleep.

In their latest experiments, the researchers reveal that it is the body’s circadian rhythms, the “master clock” regulating the sleep-wake cycle of roughly 24 hours, that governs this system.

“These findings show that glymphatic system function is not solely based on sleep or wakefulness, but by the daily rhythms dictated by our biological clock,” says neuroscientist Dr. Maiken Nedergaard, co-director of the Center for Translational Neuromedicine at URMC and senior author of the study.

The findings appear in the journal Nature Communications.

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Toxic waste products

One of the processes that occur during sleep is the clearance of toxic products of metabolism that accumulate in the brain during wakefulness. One such waste product is the protein beta-amyloid, which — if not removed — forms the plaques associated with Alzheimer’s disease.

An ongoing failure to remove waste products such as beta-amyloid may partly explain why chronic sleep disruption is an early sign of neurodegenerative disorders such as Alzheimer’s.

In their early work, Dr. Nedergaard and her colleagues showed that the glymphatic system is a network of channels adjoining blood vessels in the brain. 

The channels comprise projections, or “endfeet,” from a type of glial cell known as astrocytes. The endfeet effectively enclose the blood vessels in a hollow sheath.

During sleep, the glymphatic system pumps cerebrospinal fluid around the brain in time with the pulsing of arteries. This liquid washes away soluble waste products before draining into the lymphatic system. 

But the new research reveals the activity of the glymphatic system is governed by the body’s biological clock, rather than sleep.

In humans, circadian rhythm regulates our physiology cycle between wakefulness during the day and sleep at night.

“Because this timing also influences the glymphatic system, these findings suggest that people who rely on cat naps during the day to catch up on sleep, or work the night shift, may be at risk for developing neurological disorders,” says Lauren Hablitz, Ph.D., a research assistant professor in Nedergaard’s lab and the first author of the paper. 

“In fact, clinical research shows that individuals who rely on sleeping during daytime hours are at much greater risk for Alzheimer’s and dementia, along with other health problems,” she adds.

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Fluorescent tracer

The researchers made their discovery in mice, which are nocturnal — their sleep-wake cycle is the reverse of that characteristic in humans.

To monitor cerebrospinal fluid movement through the animals’ brains, they injected a fluorescent tracer that they could see through the animals’ skulls. 

This revealed that the flow of fluid into the brain was around 53% higher during the day while the animals were asleep, compared with the night when they were active.

Crucially, this cycle of activity in their glymphatic system persisted even when the researchers anesthetized the mice throughout the day and night. 

It also continued when they kept the rodents in constant light for 10 days.

This strongly suggests that circadian rhythms govern this system and therefore may not operate efficiently during daytime sleep in humans.

Finally, the researchers show that the circadian regulation of cerebrospinal fluid through the brain depends on a water channel called aquaporin-4 in the membrane of the endfeet.

In mice genetically engineered to lack this channel, the usual tidal flow of fluid across the day and night was completely absent.

Disrupted daily rhythms

The authors note that while much research is needed, their work suggests disrupting circadian rhythms may prevent the efficient removal of the brain’s toxic byproducts. 

This may lead to the chronic inflammation that characterizes neurodegenerative disorders such as Alzheimer’s.

They conclude:

“Although glymphatic function has yet to be studied in models of circadian disruption, such as in shiftwork, it has been established that shift workers are at increased risk for neurodegenerative disorders […] Understanding how these rhythms, all with different timing and biological functions, interact to affect glymphatic function and lymphatic drainage may help prevent morbidity associated with circadian misalignment.”

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