Posts tagged circadian clock
Articles and news from the latest research reports.
A hormone that governs sleep and jet lag in humans may also drive the mass migration of plankton in the ocean, scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have found. The molecule in question, melatonin, is essential to maintain our daily rhythm, and the European scientists have now discovered that it governs the nightly migration of a plankton species from the surface to deeper waters. The findings, published online today in Cell, indicate that melatonin’s role in controlling daily rhythms probably evolved early in the history of animals, and hold hints to how our sleep patterns may have evolved.
In vertebrates, melatonin is known to play a key role in controlling daily activity patterns – patterns which get thrown out of synch when we fly across time zones, leading to jet lag. But virtually all animals have melatonin. What is its role in other species, and how did it evolve the task of promoting sleep? To find out, Detlev Arendt’s lab at EMBL turned to the marine ragworm Platynereis dumerilii. This worm’s larvae take part in what has been described as the planet’s biggest migration, in terms of biomass: the daily vertical movement of plankton in the ocean. By beating a set of microscopic ‘flippers’ – cilia – arranged in a belt around its midline, the worm larvae are able to migrate toward the sea’s surface every day. They reach the surface at dusk, and then throughout the night they settle back down to deeper waters, where they are sheltered from damaging UV rays at the height of day.
“We found that a group of multitasking cells in the brains of these larvae that sense light also run an internal clock and make melatonin at night.” says Detlev Arendt, who led the research. “So we think that melatonin is the message these cells produce at night to regulate the activity of other neurons that ultimately drive day-night rhythmic behaviour.”
Maria Antonietta Tosches, a postdoc in Arendt’s lab, discovered a group of specialised motor neurons that respond to melatonin. Using modern molecular sensors, she was able to visualise the activity of these neurons in the larva’s brain, and found that it changes radically from day to night. The night-time production of melatonin drives changes in these neurons’ activity, which in turn cause the larva’s cilia to take long pauses from beating. Thanks to these extended pauses, the larva slowly sinks down. During the day, no melatonin is produced, the cilia pause less, and the larva swims upwards.
“When we exposed the larvae to melatonin during the day, they switched towards night-time behaviour,” says Tosches, “it’s as if they were jet lagged.”
The work strongly suggests that the light-sensing, melatonin-producing cells at the heart of this larva’s nightly migration have evolutionary relatives in the human brain. This implies that the cells that control our rhythms of sleep and wakefulness may have first evolved in the ocean, hundreds of millions of years ago, in response to pressure to move away from the sun.
“Step by step we can elucidate the evolutionary origin of key functions of our brain. The fascinating picture emerges that human biology finds its roots in some deeply conserved, fundamental aspects of ocean ecology that dominated life on Earth since ancient evolutionary times,” Arendt concludes.
Fruitfly Study Identifies Brain Circuit that Drives Daily Cycles of Rest, Activity
Amita Sehgal, PhD, a professor of Neuroscience at the Perelman School of Medicine, University of Pennsylvania, describes in Cell a circuit in the brain of fruit flies that controls their daily, rhythmic behavior of rest and activity. The new study also found that the fly version of the human brain protein known as corticotrophin releasing factor (CRF) is a major coordinating molecule in this circuit. Fly CRF, called DH44, is required for rest/activity cycles and is produced in cells that receive input from the clock cells in the fly brain. In mammals, CRF is secreted rhythmically and it drives the expression of glucocorticoids such as cortisol and is associated with stress and anxiety.
Animal models like flies are helping to fill gaps in current knowledge about how the brain works, notes Sehgal. Indeed, she says, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN), initiative, a project of the National Institutes of Health, includes the study of simple animal models, which are expected to provide more detailed insight into brain function.
Though much is known about the cellular and molecular components of the clock, the connections that link clock cells to overt behaviors, such as rest/activity behavior, have not been identified. “This study is essentially a map-of-the-circuitry experiment,” says Sehgal, who is also an investigator with the Howard Hughes Medical Institute (HHMI). Like humans, flies are active during the day — walking, flying, feeding and mating — and spend most of the night asleep.
“We conducted a screen for circadian-relevant neurons in the flybrain and found that cells of the pars intercerebralis — the fly version of the mammalian hypothalamus — comprise an important component of the circadian output pathway for rest/activity rhythms in flies,” Sehgal says. The mammalian hypothalamus is a neuroendocrine structure that regulates sleep, circadian rhythms, feeding and, metabolism.
The Penn team did a random targeting of cells, activating neuronal firing with a transgene designed for this purpose, to see which cells are important in the rest/active behavior. They found that cells in the pars intercerebralis (PI) are essential for rhythmic behavior, and PI cells are connected to the clock cells through a circuit of at least two synapses.
Molecular profiling of PI cells identified the fly version of DH44 as a circadian molecule that is specifically expressed by PI neurons and required for normal rest/activity rhythms in flies. And, when the scientists selectively activated or removed just six PI cells positive for DH44, the fly’s activity cycles became irregular. In other words, the flies no longer restricted their sleep to the dark and their activity to the light, but instead showed more random distribution of these behaviors
Chrono, the last piece of the circadian clock puzzle?
In an article published today in PLOS Biology, researchers from the RIKEN Brain Science Institute in Japan report the identification of Chrono, a gene involved in the regulation of the body clock in mammals and that might be a key component of the body’s response to stress.
All organisms, from mammals to fungi, have daily cycles controlled by a tightly regulated internal clock, called the circadian clock. The whole-body circadian clock, influenced by the exposure to light, dictates the wake-sleep cycle. At the cellular level, the clock is controlled by a complex network of genes and proteins that switch each other on and off based on cues from their environment.
Most genes involved in the regulation of the circadian clock have been characterized, but Akihiro Goriki, Toru Takumi and their colleagues from RIKEN and Hiroshima University in Japan and University of Michigan in the United States knew that a key component was missing and sough to uncover it in mammals.
In the study, the team performed a genome-wide chromatin immunoprecipitation analysis for genes that were the target of BMAL1, a core clock component that binds to many other clock genes, regulating their transcription.
The authors characterize a new circadian gene that they name Chrono. They show that CHRONO functions as a transcriptional repressor of the negative feedback loop in the mammalian clock: the protein CHRONO binds to the regulatory region of clock genes, with its repressor function oscillating in a circadian manner. The expression of core clock genes is altered in mice lacking the Chrono gene, and the mice have longer circadian cycles.
"These results suggest that Chrono functions as a core clock repressor,” conclude the authors.
In addition, they demonstrate that the repression mechanism of Chrono is under epigenetic control and links, via a glucocorticoid receptor, to metabolic pathways triggered by behavioral stress.
These findings are confirmed by another study by the University of Pennsylvania, also published in PLOS Biology today. In the study, John Hogenesch and his team prove the existence of Chrono using a computer-based analysis.
Scientists find mechanism to reset body clock
Researchers from The University of Manchester have discovered a new mechanism that governs how body clocks react to changes in the environment.
And the discovery, which is being published in Current Biology, could provide a solution for alleviating the detrimental effects of chronic shift work and jet-lag.
The team’s findings reveal that the enzyme casein kinase 1epsilon (CK1epsilon) controls how easily the body’s clockwork can be adjusted or reset by environmental cues such as light and temperature.
Internal biological timers (circadian clocks) are found in almost every species on the planet. In mammals including humans, circadian clocks are found in most cells and tissues of the body, and orchestrate daily rhythms in our physiology, including our sleep/wake patterns and metabolism.
Dr David Bechtold, who led The University of Manchester’s research team, said: “At the heart of these clocks are a complex set of molecules whose interaction provides robust and precise 24 hour timing. Importantly, our clocks are kept in synchrony with the environment by being responsive to light and dark information.”
This work, funded by the Biotechnology and Biological Sciences Research Council, was undertaken by a team from The University of Manchester in collaboration with scientists from Pfizer led by Dr Travis Wager.
The research identifies a new mechanism through which our clocks respond to these light inputs. During the study, mice lacking CK1epsilon, a component of the clock, were able to shift to a new light-dark environment (much like the experience in shift work or long-haul air travel) much faster than normal.
The research team went on to show that drugs that inhibit CK1epsilon were able to speed up shift responses of normal mice, and critically, that faster adaption to the new environment minimised metabolic disturbances caused by the time shift.
Dr Bechtold said: “We already know that modern society poses many challenges to our health and wellbeing - things that are viewed as commonplace, such as shift-work, sleep deprivation, and jet lag disrupt our body’s clocks. It is now becoming clear that clock disruption is increasing the incidence and severity of diseases including obesity and diabetes.
“We are not genetically pre-disposed to quickly adapt to shift-work or long-haul flights, and as so our bodies’ clocks are built to resist such rapid changes. Unfortunately, we must deal with these issues today, and there is very clear evidence that disruption of our body clocks has real and negative consequences for our health.”
He continues: “As this work progresses in clinical terms, we may be able to enhance the clock’s ability to deal with shift work, and importantly understand how maladaptation of the clock contributes to diseases such as diabetes and chronic inflammation.”
(Source: manchester.ac.uk)
Broken cellular ‘clock’ linked to brain damage
A new discovery may help explain the surprisingly strong connections between sleep problems and neurodegenerative conditions such as Alzheimer’s disease. Sleep loss increases the risk of Alzheimer’s disease, and disrupted sleeping patterns are among the first signs of this devastating disorder.
Scientists at Washington University School of Medicine in St. Louis and the University of Pennsylvania have shown that brain cell damage similar to that seen in Alzheimer’s disease and other disorders results when a gene that controls the sleep-wake cycle and other bodily rhythms is disabled.
The researchers found evidence that disabling a circadian clock gene that controls the daily rhythms of many bodily processes blocks a part of the brain’s housekeeping cycle that neutralizes dangerous chemicals known as free radicals.
“Normally in the hours leading up to midday, the brain increases its production of certain antioxidant enzymes, which help clean up free radicals,” said first author Erik Musiek, MD, PhD, assistant professor of neurology at the School of Medicine. “When clock genes are disabled, though, this surge no longer occurs, and the free radicals may linger in the brain and cause more damage.”
Musiek conducted the research in the labs of Garret FitzGerald, MD, chairman of pharmacology at the University of Pennsylvania, and of David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology at Washington University School of Medicine, who are co-senior authors.
The study appears Nov. 25 in The Journal of Clinical Investigation.
Musiek studied mice lacking a master clock gene called Bmal1. Without this gene, activities that normally occur at particular times of day are disrupted.
“For example, mice normally are active at night and asleep during the day, but when Bmal1 is missing, they sleep equally in the day and in the night, with no circadian rhythm,” Musiek said. “They get the same amount of sleep, but it’s spread over the whole day. Rhythms in the way genes are expressed are lost.”
FitzGerald uses mice lacking Bmal1 to study whether clock cells have links to diabetes and heart disease. He has shown that clock genes influence blood pressure, blood sugar and lipid levels.
Several years ago, Musiek, who at the time was a neurology resident at the University of Pennsylvania, and FitzGerald decided to investigate how knocking out Bmal1 affects the brain. Holtzman, who has published pioneering work on sleep and Alzheimer’s disease, encouraged Musiek to continue and expand these studies when he came to Washington University as a postdoctoral fellow.
In the new study, Musiek found that as the mice aged, many of their brain cells became damaged and did not function normally. The patterns of damage were similar to those seen in Alzheimer’s disease and other neurodegenerative disorders.
“Brain cell injury in these mice far exceeded that normally seen in aging mice,” Musiek said. “Many of the injuries appear to be caused by free radicals, which are byproducts of metabolism. If free radicals come into contact with brain cells or other tissue, they can cause damaging chemical reactions.”
This led Musiek to examine the production of key antioxidant enzymes, which usually neutralize and help clear free radicals from the brain, thereby limiting damage. He found levels of several antioxidant proteins peak in the middle of the day in healthy mice. However, this surge is absent in mice lacking Bmal1. Without the surge, free radicals may remain in the brain longer, contributing to the damage Musiek observed.
“We’re trying to identify more specifics about how problems in clock genes contribute to neurodegeneration, both with and without influencing sleep,” Musiek said. “That’s a challenging distinction to make, but it needs to be made because clock genes appear to control many other functions in the brain in addition to sleeping and waking.”
(Source: news.wustl.edu)
Researchers find hormone vasopressin involved in jet lag
A team of researchers from several research centers in Japan has together found what appears to be a connection between the hormone vasopressin and jet-lag. In their paper published in the journal Science, the team describes experiments they conducted with test mice that indicate that repressing neural connections that respond to vasopressin reduced the time it took for them to readjust their circadian clock.
Adjustments to the circadian clock can be more than a nuisance for long distance flyers, research over the years has shown that it can cause stressed induced medical problems for those that work odd hours. For that reason, scientists have been looking for a way to reset the circadian clock much quicker than happens naturally. In this new effort the researchers looked at a part of the brain called the suprachiasmatic nucleus—it’s believed to be the main region involved in monitoring the passage of time and hence the circadian clock. Upon closer scrutiny, they found that many of the neurons in that part of the brain had receptors that were sensitive to vasopressin.
To find out why, they genetically altered test mice to inhibit such receptors and then artificially altered their day/night schedule. They found that without the receptors the mice were able to adjust to a radically altered time schedule in just one day, as opposed to the week or more it took unaltered mice. Next, they tried giving test mice a chemical that is known to block the same receptors, but only in the brain (neurons with vasopressin sensitive receptors are found throughout the nervous system) and found the mice were able to readjust their internal clocks in three days, much faster than normal, but still not as fast as those without the receptors.
The findings by the team suggest that a cure for jet-lag may be on the way. The chemical given to the mice has not been tested yet to see if it has other side-effects, most particularly, whether it causes problems with the kidneys—vasopressin is known to play a role in causing the kidneys to retain water to help regulate salt levels throughout the body.
Circadian Clock is Key to Firing Up Cell’s Furnace
Clock’s rhythm ensures steady energy supply to cells during times of fasting
Each of our cells has an energy furnace, and it is called a mitochondrion. A Northwestern University-led research team now has identified a new mode of timekeeping that involves priming the cell’s furnace to properly use stored fuel when we are not eating.
The interdisciplinary team has identified the “match” and “flint” responsible for lighting this tiny furnace. And the match is only available when the circadian clock says so, underscoring the importance of the biological timing system to metabolism.
“Circadian clocks are with us on Earth because they have everything to do with energy,” said Joe Bass, M.D., who led the research. “If an organism burns its energy efficiently, it has a better chance of survival. Our results tell us how the circadian clock triggers the cell’s energy-burning process. Cells are most capable of using fuel when the clock is working properly.”
Bass is the Charles F. Kettering Professor and chief of the division of endocrinology, metabolism and molecular medicine at Northwestern University Feinberg School of Medicine and an endocrinologist at Northwestern Memorial Hospital.
Mitochondria regulate the supply of energy to cells when we are at rest, with no glucose available from food. In a study of mice, the researchers found that the circadian clock supplies the match to light the furnace and on the match tip is a critical compound called NAD+. It combines with an enzyme in mitochondria called Sirtuin 3, which acts as the flint, to light the furnace. When the clock in an animal isn’t working, the animal can’t metabolize stored energy and the process doesn’t ignite.
This pathway through which the body clock controls activities within the mitochondria shows how energy generation is tied tightly to the light-dark/activity-rest cycle each day.
The findings, which could be useful in the development of therapies to treat metabolic disorders related to circadian disruption, is published today (Sept. 19) by the journal Science.
The results demonstrate that the circadian clock, a genetic timekeeper that evolved to enable organisms to track the daily transition from light to darkness early in evolution, generates oscillations in mitochondrial energy capacity through rhythmic regulation of NAD+ biosynthesis.
The clock facilitates oxidative rhythms that anticipate an animal’s fasting/feeding cycle that occurs during the transition from light to darkness and wakefulness to sleep each day, and, in so doing, prevents the cell from “starving” during the night.
To understand how mitochondria are affected by circadian clock disorder, the researchers genetically removed the clocks in laboratory mice and compared them to controls. Both groups of mice were studied in a state of fasting; this “stress” test enabled the researchers to pinpoint just how the clock maintains “energy reserves” (akin to stress testing of a bank).
Bass and his research group worked together with Navdeep S. Chandel, a colleague of Bass’ at Feinberg, and John M. Denu, at the University of Wisconsin-Madison. They found the mice lacking clocks had defects in their mitochondria: the mitochondria could not metabolize stored energy and had no reserve to prevent depletion of the main currency, ATP. (Adenosine triphosphate is an energy-bearing molecule found in all living cells.)
Working with Northwestern colleague Milan Mrksich, they went on to show that removal of the clock depletes the necessary ingredient to turn on an enzyme within mitochondria, Sirtuin 3, which activates energy burning during fasting.
The researchers also showed that when the circadian clock was disrupted, resulting in a lack of NAD+, they could provide NAD+ supplements and restore function to the mitochondrion.
The findings expand the understanding of the molecular pathways linking the circadian clock with metabolism and show that the clock provides an essential buffer to stabilize the cell as organisms transition between eating and fasting each day. This knowledge has implications for disease intervention and prevention, including of diabetes, and potentially for states of increased cell demand for metabolism (including inflammation and cancer).
“We have established the chain of events that couples the clock’s control switch with the machinery of the mitochondria,” said Bass, who also is a member of the department of neurobiology at the Weinberg College of Arts and Sciences. “We now have identified an additional link in the supply chain that provides energy to the cell at different phases of our daily sleep-wake cycle. These findings establish a key role for the NAD+ biosynthetic cycle in this process.”
Major senior authors from Northwestern include Chandel, a professor in medicine-pulmonary and cell and molecular biology at Feinberg, and Mrksich, the Henry Wade Rogers Professor of Biomedical Engineering, Chemistry and Cell and Molecular Biology at Feinberg, Weinberg and the McCormick School of Engineering and Applied Science. Chandel and Mrksich are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
The co-first authors are Clara Bien Peek, a postdoctoral fellow, and Alison H. Affinati, an M.D./Ph.D. candidate, both working in Bass’ lab. They have literally worked around the clock on the research, which builds on the earlier work of co-author Kathryn Moynihan Ramsey. In 2009, she and colleagues reported in Science that the compound NAD, together with the enzyme SIRT1, functions as a molecular “switch” to coordinate the internal clock with metabolic systems.
The current research team combined Northwestern expertise in basic circadian clock research, chemistry and physiology with outside collaborators who were able to verify the Northwestern findings.
Co-author Eric Goetzman, from the University of Pittsburgh School of Medicine, an expert in the rare children’s disease called metabolic myopathy, was able to confirm that the pattern the researchers observed in mice was the same as that seen in these children. Fasting can be life-threatening for children with this disorder because they can’t metabolize stored energy due to defects in their mitochondria.
Analyses by co-author Christopher B. Newgard at Duke University Medical Center identified a signature profile of the metabolic myopathy in mice with altered circadian clock genes.
(Source: northwestern.edu)
Gene Involved in Neurodegeneration Keeps Clock Running
Northwestern University scientists have shown a gene involved in neurodegenerative disease also plays a critical role in the proper function of the circadian clock.
In a study of the common fruit fly, the researchers found the gene, called Ataxin-2, keeps the clock responsible for sleeping and waking on a 24-hour rhythm. Without the gene, the rhythm of the fruit fly’s sleep-wake cycle is disturbed, making waking up on a regular schedule difficult for the fly.
The discovery is particularly interesting because mutations in the human Ataxin-2 gene are known to cause a rare disorder called spinocerebellar ataxia (SCA) and also contribute to amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. People with SCA suffer from sleep abnormalities before other symptoms of the disease appear.
This study linking the Ataxin-2 gene with abnormalities in the sleep-wake cycle could help pinpoint what is causing these neurodegenerative diseases as well as provide a deeper understanding of the human sleep-wake cycle.
The findings will be published May 17 in the journal Science. Ravi Allada, M.D., professor of neurobiology in the Weinberg College of Arts and Sciences, and Chunghun Lim, a postdoctoral fellow in his lab, are authors of the paper.
Period (per) is a well-studied gene in fruit flies that encodes a protein, called PER, which regulates circadian rhythm. Allada and Lim discovered that Ataxin-2 helps activate translation of PER RNA into PER protein, a key step in making the circadian clock run properly.
“It’s possible that Ataxin-2’s function as an activator of protein translation may be central to understanding how, when you mutate the gene and disrupt its function, it may be causing or contributing to diseases such as ALS or spinocerebellar ataxia,” Allada said.
The fruit fly Drosophila melanogaster is a model organism for scientists studying the sleep-wake cycle because the fly’s genes are highly conserved with the genes of humans.
“I like to say that flies sleep similarly to humans, except flies don’t use pillows,” said Allada, who also is associate director for Northwestern’s Center for Sleep and Circadian Biology. The biological timing mechanism for all animals comes from a common ancestor hundreds of millions of years ago.
Ataxin-2 is the second gene in a little more than two years that Northwestern researchers have identified as a core gear of the circadian clock, and the two genes play similar roles.
Allada, Lim and colleagues in 2011 reported their discovery of a gene, which they dubbed “twenty-four,” that plays a role in translating the PER protein, keeping the sleep-wake cycle on a 24-hour rhythm.
Allada and Lim wanted to better understand how twenty-four works, so they looked at proteins that associate with twenty-four. They found the twenty-four protein sticking to ATAXIN-2 and decided to investigate further. In their experiments, reported in Science, Allada and Lim discovered the Ataxin-2 and twenty-four genes appear to be partners in PER protein translation.
“We’ve really started to define a pathway that regulates the circadian clock and seems to be especially important in a specific group of neurons that governs the fly’s morning wake-up,” Allada said. “We saw that the molecular and behavioral consequences of losing Ataxin-2 are nearly the same as losing twenty-four.”
As is the case in a mutation of the twenty-four gene, when the Ataxin-2 gene is not present, very little PER protein is found in the circadian pacemaker neurons of the brain, and the fly’s sleep-wake rhythm is disturbed.
Circadian clock linked to obesity, diabetes and heart attacks
Disruption in the body’s circadian rhythm can lead not only to obesity, but can also increase the risk of diabetes and heart disease.
That is the conclusion of the first study to show definitively that insulin activity is controlled by the body’s circadian biological clock. The study, which was published on Feb. 21 in the journal Current Biology, helps explain why not only what you eat, but when you eat, matters.
The research was conducted by a team of Vanderbilt scientists directed by Professor of Biological Sciences Carl Johnson and Professors of Molecular Physiology and Biophysics Owen McGuinness and David Wasserman.
“Our study confirms that it is not only what you eat and how much you eat that is important for a healthy lifestyle, but when you eat is also very important,” said postdoctoral fellow Shu-qun Shi, who performed the experiment with research assistant Tasneem Ansari in the Vanderbilt University Medical Center’s Mouse Metabolic Phenotyping Center.
In recent years, a number of studies in both mice and men have found a variety of links between the operation of the body’s biological clock and various aspects of its metabolism, the physical and chemical processes that provide energy and produce, maintain and destroy tissue. It was generally assumed that these variations were caused in response to insulin, which is one of the most potent metabolic hormones. However, no one had actually determined that insulin action follows a 24-hour cycle or what happens when the body’s circadian clock is disrupted.
Because they are nocturnal, mice have a circadian rhythm that is the mirror image of that of humans: They are active during the night and sleep during the day. Otherwise, scientists have found that the internal timekeeping system of the two species operate in nearly the same way at the molecular level. Most types of cells contain their own molecular clocks, all of which are controlled by a master circadian clock in the suprachiasmatic nucleus in the brain.
“People have suspected that our cells’ response to insulin had a circadian cycle, but we are the first to have actually measured it,” said McGuinness. “The master clock in the central nervous system drives the cycle and insulin response follows.”
Rhythmic Changes in Gene Activation Power the Circadian Clock
Rhythms underlie the daily functions of mammals, from sleep-wake cycles to metabolic processes in the liver. The circadian clock has evolved in response to daily changes in temperature and light in the environment. At the root of circadian rhythms are daily fluctuations in gene expression, which occur in part through the process of transcription—the creation of RNA from sequences of DNA. Although past studies have uncovered how changes in transcription states relate to irreversible processes, for example when cells become more specialized, much less is known about how transcription fluctuates in synch with recurring cycles.