How Deep Sleep Clears the Mind and Protects the Brain

A good night’s sleep doesn’t just help you feel refreshed – it might actually clear your brain.

A new study, led by researchers from the University of Copenhagen and the University of Oxford, reveals how norepinephrine drives the brain’s waste removal system during deep sleep, in mice. The research, published in Cell, highlights the essential role of quality sleep in maintaining brain health.

What is the glymphatic system?

The brain has a unique way of keeping itself clean – a specialized waste clearance system known as the glymphatic system. Discovered in mice in 2013 by Dr. Maiken Nedergaard, this network of fluid channels works by circulating cerebrospinal fluid (CSF) around the brain to remove metabolic waste products, including toxic proteins like beta-amyloid. The glymphatic system is vital for maintaining brain health, but for years, scientists have been puzzled about what drives its activity.

"It's like turning on the dishwasher before you go to bed and waking up with a clean brain. We're essentially asking what drives this process and trying to define restorative sleep based on glymphatic clearance," said Nedergaard, a professor in the departments of neuroscience and neurology at the University of Rochester Medical Center and the University of Copenhagen.

One key insight from Nedergaard’s original study was that the glymphatic system operates most effectively during sleep. Research shows that during deep, non-rapid eye movement (REM) sleep, the brain’s interstitial spaces expand, allowing CSF to flow more freely and flush out accumulated waste. Conversely, poor or disrupted sleep hampers this process, potentially contributing to the development of cognitive disorders and conditions like Alzheimer’s disease.

Alzheimer’s is characterized by the buildup of beta-amyloid plaques and tau tangles in the brain – substances that the glymphatic system is designed to clear away. When this system is impaired due to poor sleep, it can lead to the accumulation of these harmful proteins, accelerating the progression of neurodegeneration and cognitive decline.

Understanding what drives the glymphatic system could aid the development of treatment strategies for when this mechanism goes wrong.

Norepinephrine drives the glymphatic system

In the latest study, Nedergaard and the team explored the glymphatic system’s activity by focusing on the role of norepinephrine. Using advanced tools, the team studied mice during their natural sleep cycles, observing how norepinephrine influences blood flow and fluid movement in the brain.

Fluorescent tracers were introduced into the brain to track the flow of CSF as it moved through the glymphatic system. The team also used a technique called optogenetics to control the release of norepinephrine from specific brain regions. Sensitive tools for monitoring brain activity allowed the team to see how the release of norepinephrine affected the rhythm of blood vessel contractions and the flow of CSF.

The study found that during deep, non-REM sleep, norepinephrine is released in small, regular pulses about once every 50 seconds. These pulses act like a rhythm that causes blood vessels in the brain to contract and relax in waves. This motion creates a gentle pumping effect that moves CSF through the brain’s network, flushing out waste products.

"You can view norepinephrine as this conductor of an orchestra. 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," said lead author Dr. Natalie Hauglund, a Novo Nordisk Foundation postdoctoral fellow at the University of Oxford.

Is all sleep equal?

The researchers also investigated the impact of zolpidem, a widely used sleep aid. While zolpidem helped mice fall asleep faster, it significantly disrupted norepinephrine waves, reducing their frequency by 50%. Consequently, the pulsating motion of blood vessels was impaired, and CSF flow decreased by more than 30%. This suggests that zolpidem-induced sleep might not provide the same restorative benefits as natural sleep.

"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," said Hauglund.

Quality, not quantity, is important when regarding sleep

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

By identifying norepinephrine as the key driver of the glymphatic system, this study helps clarify why deep, uninterrupted sleep is essential for cognitive function and overall well-being.

The findings also highlight the potential dangers of sleep aids like zolpidem, which, while they promote faster sleep onset, can disrupt the natural rhythm of norepinephrine waves. By compromising the glymphatic system’s ability to clear waste, this raises concerns about the long-term use of such medications.

Looking ahead, therapies aimed at enhancing norepinephrine’s activity during sleep could hold promise. Such approaches might improve glymphatic clearance and reduce the risk of neurodegenerative diseases like Alzheimer’s.

The study emphasizes that sleep is far more than a state of rest, it is a complex and dynamic process essential for the brain’s maintenance and longevity. Raising awareness about the quality of sleep – not just its quantity – can encourage individuals to make informed decisions about their sleep habits and health choices.

Reference: Hauglund NL, Andersen M, Tokarska K, et al. Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep. Cell. 2025. doi: 10.1016/j.cell.2024.11.027

This article is a rework of a press release issued by Cell. Material has been edited for length and content.