Scientists have discovered how deep sleep drives the brain’s waste clearance – or glymphatic – system through rhythmic releases of norepinephrine, offering new insights into restorative sleep and potential implications for neurodegenerative diseases.
Danish researchers have made a groundbreaking discovery about how the brain cleans itself during deep sleep, revealing that a molecule called norepinephrine orchestrates a rhythmic “pumping” system that flushes out waste products. The study, published in Cell on January 8, demonstrates how this essential housekeeping process could be disrupted by common sleep medications.
The research team, led by Professor Maiken Nedergaard from the University of Copenhagen and University of Rochester, found that during deep sleep, the brainstem releases tiny waves of norepinephrine approximately every 50 seconds. This triggers blood vessels to contract and generate slow pulsations that create a rhythmic flow in the surrounding fluid, effectively washing away toxic waste products.
“It’s like turning on the dishwasher before you go to bed and waking up with a clean brain,” said Nedergaard. “We’re essentially asking what drives this process and trying to define restorative sleep based on glymphatic clearance.”
Impact of sleep medication on brain cleaning
In a concerning finding, the researchers discovered that the commonly prescribed sleep aid zolpidem (Ambien) significantly impairs this cleaning process. When mice were given zolpidem, the norepinephrine waves during deep sleep were 50% lower than in naturally sleeping mice. Although the medicated mice fell asleep faster, fluid transport into the brain dropped by more than 30%.
Lead author Natalie Hauglund of the University of Copenhagen and University of Oxford emphasised the implications: “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.”
The science behind brain cleaning
The study reveals that the brain’s waste removal system, known as the glymphatic system, relies on the precise timing of norepinephrine release to function effectively. During deep sleep, blood vessels contract and relax in a coordinated manner, creating a pumping effect that propels cerebrospinal fluid through brain tissue to remove accumulated waste products.
The researchers note in their discussion that this process is particularly important as the brain lacks conventional lymphatic vessels found elsewhere in the body. The newly discovered mechanism explains how the brain compensates for this absence through the coordinated action of blood vessels and fluid dynamics.
Clinical implications
The findings have significant implications for understanding how poor sleep may contribute to neurological disorders like Alzheimer’s disease. The authors suggest that the arterial “pumping” of cerebrospinal fluid likely functions optimally when cerebral vessels retain high elasticity. Stiffening of the vascular wall, whether due to chronic hypertension or vascular amyloidosis, would reduce the amplitude of vascular volume changes, thereby decreasing glymphatic clearance.
This research also raises important questions about the long-term use of sleep medications that might interfere with the brain’s natural cleaning mechanism. The authors emphasise that while zolpidem reduces the latency to sleep, it interferes with normal sleep architecture and suppresses glymphatic flow in mice.
The team believes these findings likely apply to humans, who also possess a glymphatic system, though this requires further testing. Similar norepinephrine waves, blood flow patterns, and brain fluid movements have been observed in human studies.
“Now we know norepinephrine is driving the cleaning of the brain, we may figure out how to get people a long and restorative sleep,” concluded Nedergaard.
Reference:
Hauglund, N. L., Andersen, M., Tokarska, K., et. al. Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep. Cell, 188, 1-17. January 8, 2025. https://doi.org/10.1016/j.cell.2024.11.027
