Summary: During wakeful periods, the glymphatic system diverts cerebrospinal fluid to lymph nodes in the neck. The CSF may act as a “fluid clock” that helps initiate the body’s infection-fighting capabilities during the day. Astrocytes in the suprachiasmatic nucleus may serve to control CSF through the central nervous system. Communication between astrocytes in different brain regions may optimize the glymphatic system’s function as we sleep.
Source: University of Rochester Medical Center
New research details how the complex set of molecular and fluid dynamics that comprise the glymphatic system – the brain’s unique process of waste removal – are synchronized with the master internal clock that regulates the sleep-wake cycle. These findings suggest that people who rely on sleeping during daytime hours are at greater risk for developing neurological disorders.
“These findings show that glymphatic system function is not solely based on sleep or wakefulness, but by the daily rhythms dictated by our biological clock,” said neuroscientist Maiken Nedergaard, M.D., D.M.Sc., co-director of the Center for Translational Neuromedicine at the University of Rochester Medical Center (URMC) and senior author of the study, which appears in the journal Nature Communications.
The findings add to a growing understanding of the operation and function of glymphatic system, the brain’s self-contained waste removal process which was first discovered in 2012 by researchers in the Nedergaard’s lab. The system consists of a network of plumbing that follows the path of blood vessels and pumps cerebrospinal fluid (CSF) through brain tissue, washing away waste. Research a few years later showed that the glymphatic system primarily functions while we sleep.
Since those initial discoveries, Nedergaard’s lab and others have shown the role that blood pressure, heart rate, circadian timing, and depth of sleep play in the glymphatic system’s function and the chemical signaling that occurs in the brain to turn the system on and off. They have also shown how disrupted sleep or trauma can cause the system to break down and allow toxic proteins to accumulate in the brain, potentially giving rise to a number of neurodegenerative diseases, such as Alzheimer’s.
The link between circadian rhythms and the glymphatic system is the subject of the new paper. Circadian rhythms – a 24-hour internal clock that regulates several important functions, including the sleep-wake cycle – are maintained in a small area of the brain called the suprachiasmatic nucleus.
The new study, which was conducted in mice, the researchers showed that when the animals were anesthetized all day long, their glymphatic system still only functioned during their typical rest period – mice are nocturnal, so their sleep-wake cycle is the opposite of humans.
“Circadian rhythms in humans are tuned to a day-wake, night-sleep cycle,” said Lauren Hablitz, Ph.D., first author of the new study and a research assistant professor in the URMC Center for Translational Neuromedicine. “Because this timing also influences the glymphatic system, these findings suggest that people who rely on cat naps during the day to catch up on sleep or work the night shift may be at risk for developing neurological disorders. In fact, clinical research shows that individuals who rely on sleeping during daytime hours are at much greater risk for Alzheimer’s and dementia along with other health problems.”
The study singles out cells called astrocytes that play multiple functions in the brain. It is believed that astrocytes in the suprachiasmatic nucleus help regulate circadian rhythms. Astrocytes also serve as gatekeepers that control the flow of CSF throughout the central nervous system. The results of the study suggest that communication between astrocytes in different parts of the brain may share the common goal of optimizing the glymphatic system’s function during sleep.
The researchers also found that during wakefulness, the glymphatic system diverts CSF to lymph nodes in the neck. Because the lymph nodes are key waystations in the regulation of the immune system, the research suggests that CSF may represent a “fluid clock” that helps wake up the body’s infection fighting capabilities during the day.
“Establishing a role for communication between astrocytes and the significant impacts of circadian timing on glymphatic clearance dynamics represent a major step in understanding the fundamental process of waste clearance regulation in the brain,” said Frederick Gregory, Ph.D., program manager for the Army Research Office, which helped fund the research and is an element of the U.S. Army Combat Capabilities Development Command’s Army Research Laboratory. “This knowledge is crucial to developing future countermeasures that offset the deleterious effects of sleep deprivation and addresses future multi-domain military operation requirements for Soldiers to sustain performance over longer periods without the ability to rest.”
Additional co-authors of the study include Virginia Pla, Michael Giannetto, Hanna Vinitsky, Tanner Metcalfe, Rebecca Nguyen, and Abdellatif Benrais with URMC and Filip Staeger with the University of Copenhagen. The Center for Translational Neuromedicine maintains labs at both Rochester and Copenhagen.
Funding: The study was supported with funding from the Army Research Office, the National Institute of Neurological Disorders and Stroke, the National Institute of Aging, and the Novo Nordisk and Lundbeck Foundations.
Circadian control of brain glymphatic and lymphatic fluid flow
The glymphatic system is a network of perivascular spaces that promotes movement of cerebrospinal fluid (CSF) into the brain and clearance of metabolic waste. This fluid transport system is supported by the water channel aquaporin-4 (AQP4) localized to vascular endfeet of astrocytes. The glymphatic system is more effective during sleep, but whether sleep timing promotes glymphatic function remains unknown. We here show glymphatic influx and clearance exhibit endogenous, circadian rhythms peaking during the mid-rest phase of mice. Drainage of CSF from the cisterna magna to the lymph nodes exhibits daily variation opposite to glymphatic influx, suggesting distribution of CSF throughout the animal depends on time-of-day. The perivascular polarization of AQP4 is highest during the rest phase and loss of AQP4 eliminates the day-night difference in both glymphatic influx and drainage to the lymph nodes. We conclude that CSF distribution is under circadian control and that AQP4 supports this rhythm.