Posts tagged jet lag
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.
(Image caption: A peptide responsible for cell communication in the brain, Vip (green) is reduced in the brains of mice that have little or no Lhx1 (right). Credit: Salk Institute for Biological Studies)
Scientists at the Salk Institute for Biological Studies have identified a gene that regulates sleep and wake rhythms.
The discovery of the role of this gene, called Lhx1, provides scientists with a potential therapeutic target to help night-shift workers or jet lagged travelers adjust to time differences more quickly. The results, published in eLife, can point to treatment strategies for sleep problems caused by a variety of disorders.
“It’s possible that the severity of many dementias comes from sleep disturbances,” says Satchidananda Panda, a Salk associate professor who led the research team. “If we can restore normal sleep, we can address half of the problem.”
Every cell in the body has a “clock” – an abundance of proteins that dip or rise rhythmically over approximately 24 hours. The master clock responsible for establishing these cyclic circadian rhythms and keeping all the body’s cells in sync is the suprachiasmatic nucleus (SCN), a small, densely packed region of about 20,000 neurons housed in the brain’s hypothalamus.
More so than in other areas of the brain, the SCN’s neurons are in close and constant communication with one another. This close interaction, combined with exposure to light and darkness through vision circuits, keeps this master clock in sync and allows people to stay on essentially the same schedule every day. The tight coupling of these cells also helps make them collectively resistant to change. Exposure to light resets less than half of the SCN cells, resulting in long periods of jet lag.
In the new study, researchers disrupted the light-dark cycles in mice and compared changes in the expression of thousands of genes in the SCN with other mouse tissues. They identified 213 gene expression changes that were unique to the SCN and narrowed in on 13 of these that coded for molecules that turn on and off other genes. Of those, only one was suppressed in response to light: Lhx1.
“No one had ever imagined that Lhx1 might be so intricately involved in SCN function,” says Shubhroz Gill, a postdoctoral researcher and co-first author of the paper. Lhx1 is known for its role in neural development: it’s so important, that mice without the gene do not survive. But this is the first time it has been identified as a master regulator of light-dark cycle genes.
By recording electrical activity in the SCN of animals with reduced amounts of the Lhx1 protein, the researchers saw that the SCN neurons weren’t in sync with one another, despite appearing rhythmic individually.
“It was all about communication–the neurons were not talking to each other without this molecule,” says Ludovic Mure, a postdoctoral researcher and an author on the paper. A next step in the work will be to understand exactly how Lhx1 affects the expression of genes that creates this synchronicity.
Studying a mouse version of jet lag–an 8-hour shift in their day-night cycle–the scientists found that those with little or no Lhx1 readjusted much faster to the shift than normal mice. This suggests that because these neurons are less in sync with one another, they are more easily able to shift to a new schedule, though it is difficult for them to maintain that schedule, Panda says.
These mice also exhibited reduced activity of certain genes, including one that creates vasoactive intestinal peptide or Vip, a molecule that has important roles in development and as a hormone in the intestine and blood. In the brain, Vip affects cell communication, but nobody had known that Lhx1 regulated it until now, Panda says. Interestingly, the team also found that adding Vip restored cell synchrony in the SCN.
“This approach helped us to close that knowledge gap and show that Vip is a very important protein, at least for SCN,” Panda says. “It can compensate for the loss of Lhx1.”
On the other hand, cutting back on Vip could be another way to treat jet lag. Vip could be an even easier drug target compared with Lhx1 because Vip is secreted from cells rather than inside cells, Panda says. “If we find a drug that will block the Vip receptor or somehow break down Vip, then maybe that will help us reset the clock much faster,” he adds.
The new results take the group a step closer to their goal of creating cell regenerative therapies that restore the SCN and ameliorate sleep problems. The scientists have made their gene expression data available through a searchable web interface at http://scn.salk.edu, giving other researchers a handy way to explore the effect of light and dark in genes in the SCN and other tissues.
A brain chemical that desynchronizes the cells in the biological clock helps the clock adjust more quickly to abrupt shifts in daily light/dark schedules such as those that plague modern life.
A small molecule called VIP, known to synchronize time-keeping neurons in the brain’s biological clock, has the startling effect of desynchronizing them at higher dosages, said a research team at Washington University in St. Louis.
Far from being catastrophic, the temporary loss of synchronization actually might be useful.
Neurons knocked for a loop by a burst of VIP are better able to re-synchronize to abrupt shifts in the light-dark cycle such as those that make jet lag or shift work so miserable. It takes tumbling cells only half as long as undisturbed cells to entrain to the new schedule, the scientists say in the Oct. 28 online early edition of the Proceedings of the National Academy of Sciences.
Resynching by jarring is familiar to everyone who has whacked a flickering analog TV to get it to sync or hit the ceiling near a fluorescent light in the hope that its ballast starts buzzing.
The scientists hope to find a way to coax the brain into releasing its own stores of VIP or to find other ways to deliberately cause tumbling so the body’s clock will reset to a new time. Such a treatment might help travelers, shift works and others who overtax the biological clock’s ability to entrain to environmental cues.
The finding is the latest to emerge from the lab of Erik Herzog, PhD, who has studied the body’s time-keeping mechanisms for 13 years at Washington University in St. Louis. His focus is on understanding the clock, but because most of us live against our biological clocks and research shows this leads to health problems ranging from obesity to depression, his work is likely to have practical payoffs.
Timing is everything
The master circadian clock in mammals is a knot of 20,000 nerve cells roughly the size of a quarter of a grain of rice called the suprachiasmatic nucleus (SCN). Each neuron in the SCN keeps time, but because they’re different cells, they have slightly different rhythms. Some run a bit fast and others a bit slow.
“They’re like a society where each cell has its own opinion on what time of day it is,” said Herzog, a profesor of biology in Arts & Sciences. “They need to agree on the time of day in order to coordinate daily rhythms in alertness and metabolism.”
The cells talk to one another through a molecule called VIP (vasoactive intestinal polypeptide), a small string of amino acids that they release and receive. It’s through VIP that cells tell one another what time they think it is, Herzog said. If you get rid of VIP or the receptor for VIP, the cells lose synchrony.
“We were trying to understand exactly when VIP is released and how it synchronized the cells,” Herzog said, “and Sungwon An, then a graduate student in my lab, discovered that when there was extra VIP around, the cells lost synchrony.
“That was really surprising for us,” he said. “We did a lot of experiments just to make sure the VIP we had bought wasn’t contaminated in some way.”
It turned out the effect was real. Above a critical level, the more VIP was released, the more desynchronized the cells became. “It’s almost as if at higher doses the cells become blind to the information from their neighbors,” Herzog said.
“Then we thought: ‘Well, if the cell rhythms are messed up and out of phase, the system may be more sensitive to environmental cues than it would be if all the cells were in sync.’” If it was more sensitive, it might be better able to adjust to the abrupt schedule shifts that characterize modern life.
They were encouraged in this line of thinking by a simulation of the SCN created by Linda Petzold, Kirsten Meeker, Rich Harang and Frank Doyle, all chemical engineers at the University of California, Santa Barbara. The numerical model predicted that increasing VIP would lead to phase tumbling (less synchrony) and accelerated entrainment.
Rapid entrainment to environmental cues is important, Herzog explained. The master clock has evolved to adjust to slow seasonal changes in light/dark schedules, but not to abrupt ones that are built into the fabric of modern life. Even the seemingly benign one-hour shift for daylight savings time increases the risk of fatal car crashes and of heart attacks.
“We were curious to see whether adding extra VIP would improve the ability of biological clocks to make big adjustments,” Herzog said. An, together with graduate student Cristina Mazuski and research scientist Daniel Granados-Fuentes, showed that a shot of VIP did in fact accelerate entrainment to a new light schedule.
“We found that in mice we could cut ‘jet lag’ in half by giving them a shot of VIP the day before we ‘flew them to a new time zone,’ by shifting their light schedule,” Herzog said.
“That’s really exciting, “ Herzog said. “This is the first demonstration that giving a bit more of a substance the brain already makes actually improves the way the circadian system functions. “
“We’re taking the system the brain uses to entrain to changes in the seasons and goosing it a bit so that it can adjust to bigger shifts in the light schedule,” he said.
“We’re hoping we’ll be able to find a way to coax the brain into releasing its own stores of VIP or a light trigger or other signal that mimics the effects of VIP,” Herzog said.
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.
Gene discovered that could cure jet lag
A gene has been discovered which stops our body clock from resetting, paving the way for new drugs to combat jet lag
The gene slows our body’s adaptation to new time zones, the team from the University of Oxford found, acting as a safety mechanism to prevent our internal clock from getting out of synch, a process which is linked to chronic diseases.
However, turning the gene off could prevent the symptoms jet lag, tests on mice indicated.
Our bodies, like those of most life forms on earth, operate to the circadian clock, a natural 24 cycle which tells us when to sleep or wake up.
This responds to natural light - but when we rapidly move to a different time zone, such as on a long haul flight, it is thrown into disarray.
The circadian clock is governed by an area of the brain called the suprachiasmatic nuclei (SCN), which in turn receives information from a specialised system in the eyes which detects environmental light, according to the report in the journal Cell.
This allows the body to synchronise with the night and day cycle. However, scientists were unable to explain why it took so long for the body clock to ‘reset’ to different time zones - sometimes as long as a day for each hour the actual clock shifted.
Now a team from the University of Oxford have identified a gene in mice which appears to stop the body clock from adjusting too quickly.
This is because it can take some days for the brain to be convinced the new data about the night/day cycle is reliable, they say.
Dr Stuart Peirson said: “We’ve identified a system that actively prevents the body clock from re-adjusting.
"If you think about, it makes sense to have a buffering mechanism in place to provide some stability to the clock. The clock needs to be sure that it is getting a reliable signal, and if the signal occurs at the same time over several days it probably has biological relevance.
"But it is this same buffering mechanism that slows down our ability to adjust to a new time zone and causes jet lag."
They studied gene expression in the SCN in mice, who were exposed to light and darkness.
They identified around 100 genes that were switched on in response to light, revealing a sequence of events that act to retune the circadian clock.
Amongst these, they identified one molecule, SIK1, that terminates this response, acting as a brake to limit the effects of light on the clock.
When they blocked the activity of SIK1, the mice adjusted faster to changes in light cycle.
Dr Russell Foster said that we were still a long way off from a jet lag cure, but added it was a step towards developing drugs for interrupted sleep cycles.
Disruptions in the circadian system have been linked to chronic diseases including cancer, diabetes, and heart disease, as well as weakened immunity to infections and impaired cognition.
More recently, researchers are uncovering that circadian disturbances are a common feature of several mental illnesses, including schizophrenia and bipolar disorder.
Dr Foster said: “We’re still several years away from a cure for jet-lag but understanding the mechanisms that generate and regulate our circadian clock gives us targets to develop drugs to help bring our bodies in tune with the solar cycle.
"Such drugs could potentially have broader therapeutic value for people with mental health issues."