A common sleep aid may leave behind a dirty brain, according to new research.

Getting a good night’s sleep is a critical part of our daily biological cycle and is associated with improved brain function, a stronger immune system, and a healthier heart.

Conversely, sleep disorders like insomnia and sleep apnea can significantly impact health and quality of life. Poor sleep often precedes the onset of neurodegenerative diseases and is a predictor of early dementia.

The new research in the journal Cell describes for the first time the tightly synchronized oscillations in the neurotransmitter norepinephrine, cerebral blood, and cerebrospinal fluid (CSF) that combine during non-rapid eye movement (non-REM) sleep in mice.

These oscillations power the glymphatic system—a brain-wide network responsible for removing protein waste, including amyloid and tau, associated with neurodegenerative diseases.

“As the brain transitions from wakefulness to sleep, processing of external information diminishes while processes such as glymphatic removal of waste products are activated,” says Maiken Nedergaard, codirector of the University of Rochester Center for Translational Neuromedicine and lead author of the study.

“The motivation for this research was to better understand what drives glymphatic flow during sleep, and the insights from this study have broad implications for understanding the components of restorative sleep.”

The study also holds a warning for people who use the commonly prescribed sleep aid zolpidem. The drug suppressed the glymphatic system, potentially setting the stage for neurological disorders like Alzheimer’s, which are the result of the toxic accumulation of proteins in the brain.

Finding the ‘missing link’

The research, conducted by a team at the University of Rochester and the University of Copenhagen, employed an optic technique called flow fiber photometry combined with electroencephalogram and electromyography monitors.

Unlike previous research techniques, which immobilized the mice and used anesthesia to induce sleep, the new approach allowed researchers to record brain activity during long, uninterrupted periods of wakefulness and sleep while allowing mice to move freely during recordings.

The research highlights the critical role of norepinephrine, a neurotransmitter associated with arousal, attention, and the body’s response to stress. The team observed that slow synchronized waves of norepinephrine, cerebral blood volume, and CSF flow characterized non-REM sleep. The norepinephrine triggered “micro-arousals,” causing vasomotion, the rhythmic constriction of blood vessels independent of the heartbeat. This oscillation, in turn, generates the pumping action necessary to move CSF in the glymphatic system during sleep.

“These findings, combined with what we know about the glymphatic system, paint the whole picture of the dynamics inside the brain, and these slow waves, micro-arousals, and the norepinephrine were the missing link,” says Natalie Hauglund, first author of the study and currently a postdoctoral fellow at the University of Oxford.

Sleep aids’ hidden risks

The study also explored whether sleep aids replicate the natural oscillations necessary for glymphatic function. The team focused on zolpidem, a sedative marketed under the name Ambien, which is frequently prescribed to treat insomnia.

While zolpidem effectively induced sleep in the mice, it also suppressed norepinephrine oscillations, disrupting the glymphatic system and impeding the brain’s waste-clearing processes, a finding that raises concerns about its long-term use.

Scientists now have a new tool and potential target to improve sleep. “The research provides a mechanistic link between norepinephrine dynamics, vascular activity, and glymphatic clearance, advancing understanding of sleep’s restorative functions,” says Nedergaard.

“It also calls attention to the potentially detrimental effects of certain pharmacological sleep aids on brain health, highlighting the necessity of preserving natural sleep architecture for optimal brain function.”

Additional coauthors are from the University of Copenhagen.

Support for the research came from the Novo Nordisk Foundation, the National Institutes of Health, the US Army Research Office, the Human Frontier Science Program, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Simons Foundation, and the Cure Alzheimer Fund.

Source: University of Rochester