How deep sleep clears the mind — literally

Study in Cell reveals that a common sleep aid disrupts healthy sleep in mice

By Tiffany Chen

A good night’s sleep does more than just help you feel rested — it might literally clear your mind. A new study published Wednesday in the Cell Press journal Cell shows how deep sleep may wash away waste buildup in the brain during waking hours, an essential process for maintaining brain health. The findings also offer insights into how sleep aids may disrupt the “brainwashing” system, potentially affecting cognitive function in the long run.

Scientists have known that the brain has a built-in waste removal system, called the glymphatic system, which circulates fluid in the brain and spinal cord to clear out waste. This process helps remove toxic proteins that form sticky plaques linked to neurological disorders. However, what drives this system has remained unclear — until now.

Danish neuroscientists found that a molecule called norepinephrine plays a key role in the brain’s cleaning in mice. During deep sleep, the brainstem releases tiny waves of norepinephrine about once every 50 seconds. Norepinephrine triggers blood vessels to contract, generating slow pulsations that create a rhythmic flow in the surrounding fluid to carry waste away.

"It's like turning on the dishwasher before you go to bed and waking up with a clean brain," says senior author Dr Maiken Nedergaard, a neuroscience researcher at the University of Rochester and the University of Copenhagen, Denmark. "We're essentially asking what drives this process and trying to define restorative sleep based on glymphatic clearance."

"It's like turning on the dishwasher before you go to bed and waking up with a clean brain."

Illustration above illustrates norepinephrine-mediated slow vasomotion driving glymphatic clearance (Credit: Nadia Alzoubi and Natalie Hauglund with sleeping mouse from graphical abstract)

To find clues, Dr Nedergaard and her team looked into what happens in mice when the brain sleeps. Specifically, they focused on the relationship between norepinephrine and blood flow during deep slumber. They found that norepinephrine waves correlate to variations in brain blood volume, suggesting norepinephrine triggers a rhythmic pulsation in the blood vessels.

The team then compared the changes in blood volume to brain fluid flow. They found that the brain fluid flow fluctuates in correspondence to blood volume changes, suggesting that the vessels act as pumps to propel the surrounding brain fluid to flush out waste.

You can view norepinephrine as this conductor of an orchestra," says lead author Dr Natalie Hauglund, a researcher in neuromedicine at the University of Copenhagen and the University of Oxford, UK. "There's a harmony in the constriction and dilation of the arteries, which then drives the cerebrospinal fluid through the brain to remove the waste products."

Do sleep aids help or hinder this process?

Dr Hauglund then had another question: Is all sleep created equal?

To find out, the researchers gave mice zolpidem, a common drug to aid sleep. They found that the norepinephrine waves during deep sleep was 50% lower in zolpidem-treated mice than in naturally sleeping mice. Although the zolpidem-treated mice fell asleep faster, fluid transport into the brain dropped more than 30%. The findings suggest that the sleeping aid may disrupt the norepinephrine-driven waste clearance during sleep. As Dr Hauglund explains:

"More and more people are using sleep medication, and it's really important to know if that's healthy sleep. If people aren't getting the full benefits of sleep, they should be aware of that so they can make informed decisions."

Implications for humans

The team says that the findings likely apply to humans, who also have a glymphatic system, although this needs further testing. Researchers have observed similar norepinephrine waves, blood flow patterns, and brain fluid flux in humans. Their findings may offer insights into how poor sleep may contribute to neurological disorders like Alzheimer's disease.

"Now we know norepinephrine is driving the cleaning of the brain, we may figure out how to get people a long and restorative sleep," says Dr Nedergaard.