Circadian rhythms help guide waste from brain
September 2, 2020
Science Daily/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."
https://www.sciencedaily.com/releases/2020/09/200902082326.htm
Not all sleep is equal when it comes to cleaning the brain
February 27, 2019
Science Daily/University of Rochester Medical Center
New research shows how the depth of sleep can impact our brain's ability to efficiently wash away waste and toxic proteins. Because sleep often becomes increasingly lighter and more disrupted as we become older, the study reinforces and potentially explains the links between aging, sleep deprivation, and heightened risk for Alzheimer's disease.
"Sleep is critical to the function of the brain's waste removal system and this study shows that the deeper the sleep the better," said Maiken Nedergaard, M.D., D.M.Sc., co-director of the Center for Translational Neuromedicine at the University of Rochester Medical Center (URMC) and lead author of the study. "These findings also add to the increasingly clear evidence that quality of sleep or sleep deprivation can predict the onset of Alzheimer's and dementia."
The study, which appears in the journal Science Advances, indicates that the slow and steady brain and cardiopulmonary activity associated with deep non-REM sleep are optimal for the function of the glymphatic system, the brain's unique process of removing waste. The findings may also explain why some forms of anesthesia can lead to cognitive impairment in older adults.
The previously unknown glymphatic system was first described by Nedergaard and her colleagues in 2012. Prior to that point, scientists did not fully understand how the brain, which maintains its own closed ecosystem, removed waste. The study revealed a system of plumbing which piggybacks on blood vessels and pumps cerebral spinal fluid (CSF) through brain tissue to wash away waste. A subsequent study showed that this system primarily works while we sleep.
Because the accumulation of toxic proteins such as beta amyloid and tau in the brain are associated with Alzheimer's disease, researchers have speculated that impairment of the glymphatic system due to disrupted sleep could be a driver of the disease. This squares with clinical observations which show an association between sleep deprivation and heightened risk for Alzheimer's.
In the current study, researchers conducted experiments with mice that were anesthetized with six different anesthetic regimens. While the animals were under anesthesia, the researchers tracked brain electrical activity, cardiovascular activity, and the cleansing flow of CSF through the brain. The team observed that a combination of the drugs ketamine and xylazine (K/X) most closely replicated the slow and steady electrical activity in the brain and slow heart rate associated with deep non-REM sleep. Furthermore, the electrical activity in the brains of mice administered K/X appeared to be optimal for function of the glymphatic system.
"The synchronized waves of neural activity during deep slow-wave sleep, specifically firing patterns that move from front of the brain to the back, coincide with what we know about the flow of CSF in the glymphatic system," said Lauren Hablitz, Ph.D., a postdoctoral associate in Nedergaard's lab and first author of the study. "It appears that the chemicals involved in the firing of neurons, namely ions, drive a process of osmosis which helps pull the fluid through brain tissue."
The study raises several important clinical questions. It further bolsters the link between sleep, aging, and Alzheimer's disease. It is known that as we age it becomes more difficult to consistently achieve deep non-REM sleep, and the study reinforces the importance of deep sleep to the proper function of the glymphatic system. The study also demonstrates that the glymphatic system can be manipulated by enhancing sleep, a finding that may point to potential clinical approaches, such as sleep therapy or other methods to boost the quality of sleep, for at-risk populations.
Furthermore, because several of the compounds used in the study were analogous to anesthetics used in clinical settings, the study also sheds light on the cognitive difficulties that older patients often experience after surgery and suggests classes of drugs that could be used to avoid this phenomenon. Mice in the study that were exposed to anesthetics that did not induce slow brain activity saw diminished glymphatic activity.
"Cognitive impairment after anesthesia and surgery is a major problem," said Tuomas Lilius, M.D., Ph.D., with the Center for Translational Neuromedicine at the University of Copenhagen in Denmark and co-author of the study. "A significant percentage of elderly patients that undergo surgery experience a postoperative period of delirium or have a new or worsened cognitive impairment at discharge."
https://www.sciencedaily.com/releases/2019/02/190227173111.htm