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
Stress hormone helps control the circadian rhythm of brain cells
November 8, 2019
Science Daily/University of Copenhagen The Faculty of Health and Medical Sciences
Researchers have shown how the brain's circadian rhythm in rats is, among other things, controlled by the stress hormone corticosterone -- in humans called cortisol. This has been shown by means of a completely new method in the form of implanted micropumps.
As day turns into night, and night turns into day, the vast majority of living organisms follow a fixed circadian rhythm that controls everything from sleep needs to body temperature.
This internal clock is found in everything from bacteria to humans and is controlled by some very distinct hereditary genes, known as clock genes.
In the brain, clock genes are particularly active in the so-called suprachiasmatic nucleus. It sits just above the point where the optic nerves cross and sends signals to the brain about the surrounding light level. From here, the suprachiasmatic nucleus regulates the rhythm of a number of other areas of the body, including the cerebellum and the cerebral cortex.
However, these three areas of the brain are not directly linked by neurons, and this made researchers at the University of Copenhagen curious. Using test rats, they have now demonstrated that the circadian rhythm is controlled by means of signalling agents in the blood, such as the stress hormone corticosterone.
'In humans, the hormone is known as cortisol, and although the sleep rhythm in rats is the opposite of ours, we basically have the same hormonal system', says Associate Professor Martin Fredensborg Rath of the Department of Neuroscience.
He explains that recent years have seen an increasing, scientific focus on research on clock genes, one reason being that previous research on clock genes have found a correlation between depression and irregularities in the body's circadian rhythms.
New Method with Medical Micropumps
In the study with the stress hormone corticosterone, the researchers removed the suprachiasmatic nucleus in a number of rats. As expected, this removed the circadian rhythm of the animals.
Among other things, the body temperature and activity level of the rats went from circadian oscillations to a more constant state. The same was true of the otherwise rhythmic hormone production.
However, the circadian rhythm of the cerebellum was restored when the rats were subsequently implanted with a special programmable micropump, normally used to dose medication in specific quantities.
In this case, however, the researchers used the pump to emit carefully metered doses of corticosterone at different times of the day and night, similar to the animals' natural rhythm.
'Nobody has used these pumps for anything like this before. So technically, we were onto something completely new', says Martin Fredensborg Rath.
For that reason, the researchers spent the best part of a year carrying out a large number of control tests to ensure that the new method was valid.
Interaction Between Neurons and Hormones
As mentioned, the new method paid off. With the artificial corticosterone supplement, researchers were again able to read a rhythmic activity of clock genes in the cerebellum of the rats, even though their suprachiasmatic nucleus had been removed.
'This is hugely interesting from a scientific point of view, because it means that we have two systems -- the nervous system and the hormonal system -- that communicate perfectly and influence one another. All in the course of a reasonably tight 24-hour programme', says Martin Fredensborg Rath.
With the test results and the new method in the toolbox, the researchers' next step is to study other rhythmic hormones in a similar manner, including hormones from the thyroid gland.
https://www.sciencedaily.com/releases/2019/11/191108102850.htm
Newly discovered neural pathway processes acute light to affect sleep
Different pathways process long-term circadian rhythms and short-term exposure to light
July 19, 2019
Science Daily/Northwestern University
Either to check the time or waste time, people often look at their smartphones after waking in the middle of the night.
While this acute burst of light does make it more difficult to fall back to sleep, a new Northwestern University study reports that it won't interfere with the body's overall circadian rhythms.
For the first time, researchers directly tested how short pulses of light are processed by the brain to affect sleep. They discovered that separate areas of the brain are responsible for short pulses versus long-term exposure to light. This finding challenges the widely accepted, long-held belief that all light information is relayed through the brain's suprachiasmatic nucleus (SCN), which synchronizes the body's sleep/wake cycles.
"Prior to the widespread use of electricity, our exposure to light and darkness occurred in a very predictable pattern," said Northwestern's Tiffany Schmidt, who led the study. "But light has become very cheap. We all have smartphones, and their screens are very bright. We're all getting exposed to light at the wrong times of day. It's becoming more important to understand how these different types of light information are relayed to the brain."
The paper will publish July 23 in the journal eLife. Schmidt is an assistant professor of neurobiology in Northwestern's Weinberg College of Arts and Sciences. The study was carried out in collaboration with the laboratories of Fred Turek, the Charles and Emma Morrison Professor of Neurobiology in Weinberg, and Samer Hattar, section leader at the National Institute of Mental Health.
After light enters the eye, specialized neurons called intrinsically photosensitive retinal ganglion cells (ipRGCs) carry the light information to the brain. Before Northwestern's study, researchers widely believed that all light information went through the SCN, a densely packed area in the hypothalamus known as the body's "circadian pacemaker."
"Light information comes into the SCN, and that's what synchronizes all of the body's clocks to the light/dark cycle," Schmidt said. "This one master pacemaker makes sure everything is in sync."
To conduct the study, Schmidt and her team used a genetically modified mouse model that only had ipRGCs projecting to the SCN -- but no other brain regions. Because mice are nocturnal, they fall asleep when exposed to light. The mice in the experiment, however, stayed awake when exposed to short pulses of light at night. The mice's body temperature, which also correlates to sleep, also did not respond to the short-term light.
The mice maintained a normal sleep/wake cycle and normal rhythms in their body temperature, suggesting that their overall circadian rhythms remained intact. This helps explain why one night of restless sleep and smartphone gazing might make a person feel tired the following day but does not have a long-term effect on the body.
"If these two effects -- acute and long-term light exposure -- were driven through the same pathway, then every minor light exposure would run the risk of completely shifting our body's circadian rhythms," Schmidt said.
Now that researchers know that the light-response system follows multiple pathways, Schmidt said more work is needed to map these pathways. For one, it is still unknown what area of the brain is responsible for processing acute light.
After more is known, then researchers might understand how to optimize light exposure to increase alertness in those who need it, such as nurses, shift workers and emergency personnel, while mitigating the harmful effects of a wholesale shift in circadian rhythms.
"Light at the wrong time of day is now recognized as a carcinogen," Schmidt said. "We want people to feel alert while they are exposed to light without getting the health risks that are associated with shifted circadian rhythms, such as diabetes, depression and even cancer."
https://www.sciencedaily.com/releases/2019/07/190719135543.htm