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.
New research appearing 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," said Maiken Nedergaard, MD, DMSc, co-director 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.
The "missing link" in the glymphatic system
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," said Natalie Hauglund, PhD, first author of the study and currently a postdoctoral fellow at the University of Oxford.
The hidden risks of sleep aids
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," said 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 co-authors include Mie Andersen, Klaudia Torkarska, Tessa Radivanovic, Celia Kjaerby, Frederikke Sorensen, Zuzanna Bojarowska, Verena Untiet, Sheyla Ballestero, Mie Kolmos, Pia Weikop, and Hajime Hirase with the University of Copenhagen. The research was supported with funding 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.
