Posts tagged suprachiasmatic nucleus
Articles and news from the latest research reports.
(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.
Researchers Pinpoint Protein Crucial For Development Of Biological Rhythms In Mice
Johns Hopkins researchers report that they have identified a protein essential to the formation of the tiny brain region in mice that coordinates sleep-wake cycles and other so-called circadian rhythms.
(Image caption: An illustration of the activity patterns of normal mice (left). An illustration of the activity patterns mice whose “master clock,” or SCN, has been disrupted (right). Credit: Cell Reports, Bedont et al.)
By disabling the gene for that key protein in test animals, the scientists were able to home in on the mechanism by which that brain region, known as the suprachiasmatic nucleus or SCN, becomes the body’s master clock while the embryo is developing.
The results of their experiments, reported in the tk issue of Cell Reports, are an important step toward understanding how to better manage the disruptive effects experienced by shift workers, as well as treatment of people with sleep disorders, the researchers say.
“Shift workers tend to have higher rates of diabetes, obesity, depression and cancer. Many researchers think that’s somehow connected to their irregular circadian rhythms, and thus to the SCN,” says Seth Blackshaw, Ph.D., an associate professor in the Department of Neuroscience and the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. “Our new research will help us and other researchers isolate the specific impacts of the SCN on mammalian health.”
Blackshaw explains that every cell in the body has its own “clock” that regulates aspects such as its rate of energy use. The SCN is the master clock that synchronizes these individual timekeepers so that, for example, people feel sleepy at night and alert during the day, are hungry at mealtimes, and are prepared for the energy influx that hits fat cells after eating. “A unique property of the SCN is that if its cells are grown in a dish, they quickly synchronize their clocks with each another,” Blackshaw says.
But while evidence like this gave researchers an idea of the SCN’s importance, they hadn’t completely teased its role apart from that of the body’s other clocks, or from other parts of the brain.
The Johns Hopkins team looked for ways to knock down SCN function by targeting and disabling certain genes that disrupt only the formation of the SCN clock. They analyzed which genes were active in different areas of developing mouse brains to identify those that were “turned on” only in the SCN. One of the “hits” was Lhx1, a member of a family of genes whose protein products affect development by controlling the activity of other genes. When the researchers turned off Lhx1 in the SCN of mouse embryos, the grown mice lacked distinctive biochemical signatures seen in the SCN of normal mice.
The genetically modified mice behaved differently, too. Some fell into a pattern of two to three separate cycles of sleep and activity per day, in contrast to the single daily cycle found in normal mice, while others’ rhythms were completely disorganized, Blackshaw says. Though an SCN is present in mutant mice, it communicates poorly with clocks elsewhere in the body.
Blackshaw says he expects that the mutant mice will prove a useful tool in finding whether disrupted signaling from the SCN actually leads to the health problems that shift workers experience, and if so, how this might happen. Although mouse models do not correlate fully to human disease, their biochemical and genetic makeup is closely aligned.
Blackshaw’s team also plans to continue studying the biochemical chain of events surrounding the Lhx1 protein to determine which proteins turn the Lhx1 gene on and which genes it, in turn, directly switches on or off. Those genes could be at the root of inherited sleep disorders, Blackshaw says, and the proteins they make could prove useful as starting points for the development of new drugs to treat insomnia and even jet lag.
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)
Researchers Identify Gene That Helps Fruit Flies Go to Sleep
A novel protein may explain how biological clocks regulate human sleep cycles
In a series of experiments sparked by fruit flies that couldn’t sleep, Johns Hopkins researchers say they have identified a mutant gene — dubbed “Wide Awake” — that sabotages how the biological clock sets the timing for sleep. The finding also led them to the protein made by a normal copy of the gene that promotes sleep early in the night and properly regulates sleep cycles.
Because genes and the proteins they code for are often highly conserved across species, the researchers suspect their discoveries — boosted by preliminary studies in mice — could lead to new treatments for people whose insomnia or off-hours work schedules keep them awake long after their heads hit the pillow.
“We know that the timing of sleep is regulated by the body’s internal biological clock, but just how this occurs has been a mystery,” says study leader Mark N. Wu, M.D., Ph.D., an assistant professor of neurology, medicine, genetic medicine and neuroscience at the Johns Hopkins University School of Medicine. “We have now found the first protein ever identified that translates timing information from the body’s circadian clock and uses it to regulate sleep.”
A report on the work was published online March 13 in the journal Neuron.
In their hunt for the molecular roots of sleep regulation, Wu and his colleagues studied thousands of fruit fly colonies, each with a different set of genetic mutations, and analyzed their sleep patterns. They found that one group of flies, with a mutation in the gene they would later call Wide Awake (or Wake for short), had trouble falling asleep at night, a malady that looked a lot like sleep-onset insomnia in humans. The investigators say Wake appears to be the messenger from the circadian clock to the brain, telling it that it’s time to shut down and sleep.
After isolating the gene, Wu’s team determined that when working properly, Wake helps shut down clock neurons of the brain that control arousal by making them more responsive to signals from the inhibitory neurotransmitter called GABA. Wake does this specifically in the early evening, thus promoting sleep at the right time. Levels of Wake cycle during the day, peaking near dusk in good sleepers.
Flies with a mutated Wake gene that couldn’t get to sleep were not getting enough GABA signal to quiet their arousal circuits at night, keeping the flies agitated.
The researchers found the same gene in every animal they studied: humans, mice, rabbits, chickens, even worms.
Importantly, when Wu’s team looked to see where Wake was located in the mouse brain, they found that it was expressed in the suprachiasmatic nucleus (SCN), the master clock in mammals. Wu says the fact that the Wake protein was expressed in high concentrations in the SCN of mice is significant.
“Sometimes we discover things in flies that have no direct relevance in higher order animals,” Wu says. “In this case, because we found the protein in a location where it likely plays a role in circadian rhythms and sleep, we are encouraged that this protein may do the same thing in mice and people.”
The hope is that someday, by manipulating Wake, possibly with a medication, shift workers, military personnel and sleep-onset insomniacs could sleep better.
“This novel pathway may be a place where we can intervene,” Wu says.
(Source: hopkinsmedicine.org)
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.
The link between circadian rhythms and aging
Human sleeping and waking patterns are largely governed by an internal circadian clock that corresponds closely with the 24-hour cycle of light and darkness. This circadian clock also controls other body functions, such as metabolism and temperature regulation.
Studies in animals have found that when that rhythm gets thrown off, health problems including obesity and metabolic disorders such as diabetes can arise. Studies of people who work night shifts have also revealed an increased susceptibility to diabetes.
A new study from MIT shows that a gene called SIRT1, previously shown to protect against diseases of aging, plays a key role in controlling these circadian rhythms. The researchers found that circadian function decays with aging in normal mice, and that boosting their SIRT1 levels in the brain could prevent this decay. Conversely, loss of SIRT1 function impairs circadian control in young mice, mimicking what happens in normal aging.
Since the SIRT1 protein itself was found to decline with aging in the normal mice, the findings suggest that drugs that enhance SIRT1 activity in humans could have widespread health benefits, says Leonard Guarente, the Novartis Professor of Biology at MIT and senior author of a paper describing the findings in the June 20 issue of Cell.
“If we could keep SIRT1 as active as possible as we get older, then we’d be able to retard aging in the central clock in the brain, and health benefits would radiate from that,” Guarente says.
Staying on schedule
In humans and animals, circadian patterns follow a roughly 24-hour cycle, directed by the circadian control center of the brain, called the suprachiasmatic nucleus (SCN), located in the hypothalamus.
“Just about everything that takes place physiologically is really staged along the circadian cycle,” Guarente says. “What’s now emerging is the idea that maintaining the circadian cycle is quite important in health maintenance, and if it gets broken, there’s a penalty to be paid in health and perhaps in aging.”
Last year, Guarente found that a robust circadian period correlated with longer lifespan in mice. That got him wondering what role SIRT1, which has been shown to prolong lifespan in many animals, might play in that phenomenon. SIRT1, which Guarente first linked with aging more than 15 years ago, is a master regulator of cell responses to stress, coordinating a variety of hormone networks, proteins and genes to help keep cells alive and healthy.
To investigate SIRT1’s role in circadian control, Guarente and his colleagues created genetically engineered mice that produce different amounts of SIRT1 in the brain. One group of mice had normal SIRT1 levels, another had no SIRT1, and two groups had extra SIRT1 — either twice or 10 times as much as normal.
Mice lacking SIRT1 had slightly longer circadian cycles (23.9 hours) than normal mice (23.6 hours), and mice with a 10-fold increase in SIRT1 had shorter cycles (23.1 hours).
In mice with normal SIRT1 levels, the researchers confirmed previous findings that when the 12-hour light/dark cycle is interrupted, younger mice readjust their circadian cycles much more easily than older ones. However, they showed for the first time that mice with extra SIRT1 do not suffer the same decline in circadian control as they age.
The researchers also found that SIRT1 exerts this control by regulating the genes BMAL and CLOCK, the two major keepers of the central circadian clock.
Enhancing circadian function
A growing body of evidence suggests that being able to respond to large or small disruptions of the light/dark cycle is important to maintaining healthy metabolic function, Guarente says.
“Essentially we experience a mini jet lag every day because the light cycle is constantly changing. The critical thing for us is to be able to adapt smoothly to these jolts,” Guarente says. “Many studies in mice say that while young mice do this perfectly well, it’s the old mice that have the problem. So that could well be true in humans.”
If so, it could be possible to treat or prevent diseases of aging by enhancing circadian function — either by delivering SIRT1 activators in the brain or developing drugs that enhance another part of the circadian control system, Guarente says.
“I think we should look at every aspect of the machinery of the circadian clock in the brain, and any intervention that can maintain that machinery with aging ought to be good,” he says. “One entry point would be SIRT1, because we’ve shown in mice that genetic maintenance of SIRT1 helps maintain circadian function.”
Some SIRT1 activators are now being tested against diabetes, inflammation and other diseases, but they are not designed to cross the blood-brain barrier and would likely not be able to reach the SCN. However, Guarente believes it could be possible to design SIRT1 activators that can get into the brain.
Roman Kondratov, an associate professor of biology at Cleveland State University, says the study raises several exciting questions regarding the potential to delay or reverse age-related changes in the brain through rejuvenation of the circadian clock with SIRT1 enhancement.
“The importance of this study is that it has both basic and potentially translational applications, taking into account the fact that pharmacological modulators of SIRT1 are currently under active study,” Kondratov says.
Researchers in Guarente’s lab are now investigating the relationship between health, circadian function and diet. They suspect that high-fat diets might throw the circadian clock out of whack, which could be counteracted by increased SIRT1 activation.
(Image: Wikimedia Commons)
Scientists map the wiring of the biological clock
The World Health Organization lists shift work as a potential carcinogen, says Erik Herzog, PhD, Professor of Biology in Arts & Sciences at Washington University in St. Louis. And that’s just one example among many of the troubles we cause ourselves when we override the biological clocks in our brains and pay attention instead to the mechanical clocks on our wrists.
In the June 5 issue of Neuron, Herzog and his colleagues report the discovery of a crucial part of the biological clock: the wiring that sets its accuracy to within a few minutes out of the 1440 minutes per day. This wiring uses the neurotransmitter, GABA, to connect the individual cells of the biological clock in a fast network that changes strength with time of day.
Daily rhythms of sleep and metabolism are driven by a biological clock in the suprachiasmatic nucleus (SCN), a structure in the brain made up of 20,000 neurons, all of which can keep daily (circadian) time individually.
If the SCN is to be a robust, but sensitive, timing system, the neurons must synchronize precisely with one another and adjust their rhythms to those of the environment.
Herzog’s lab has discovered a push-pull system in the SCN that does both. In 2005 they reported that the neurons in the clock network communicate by means of a neuropeptide (VIP) that pushes them to synchronize with one another. And, as they now report in Neuron, these neurons also communicate with GABA that pulls on them weakly, so they are not too tightly coupled.
Together these two networks (VIP and GABA) ensure the clock runs as coordinated, precise timepiece but one that can still adjust its timing to synchronize with the environment.
“We think the neurotransmitter network is there to introduce enough jitter into the system to allow the neurons to resynchronize when environmental cues change, as they do with the seasons,” Herzog says. But, he says, since this biological ‘reset button’ evolved long before mechanical clocks, artificial lights, and high-speed travel, it doesn’t introduce enough jitter to allow us to adjust quickly to the extreme time shifts of modern life, such as flying “backward” (east) through several time zones.
Understanding the push-pull system in the SCN has enormous implications for public health, bearing, as it does, on daylight saving times, shift work, school starting times, medical intern schedules, truck driver hours, and many other issues where the clock in the brain is pitted against the clock in the hand.
Synchronizing the cellular clocks
The “clock” inside each SCN neuron depends on the cyclic expression of a family of genes such as the Period (PER) genes. The expression of these genes and the neuron’s firing rate typically peak at mid-day and fall at night. The gene activity is like the cogs in a clock, and the electrical activity like the hands on the clock.
Each neuron in the SCN keeps time, but because they’re different cells, they have slightly different rhythms. Some run a little bit fast and others a bit slow. If the SCN as a whole is to function as a clock, its neurons need to synchronize with one another.
The goal of the recent work in the Herzog lab has been to figure out how the clock cells are connected to each other. “It wasn’t clear, for example, if each neuron communicated with just a few of its neighbors or with all of them,” Herzog says.
Mark Freeman, a graduate student in the lab, developed a method for recording the firing rate of about 100 neurons simultanously on a multi-electrode array. “You float the SCN neurons down gently,” Herzog says, “and the neurons will attach to the electrodes, creating a clock in a dish that will tick away for weeks or months.”
Using these electrode arrays, his lab demonstrated that the neurons in the SCN are synchronized by the exchange of the neuropeptide VIP (vasoactive intestinal polypeptide), which alters the expression of PER to speed up or slow down neurons until they are all in synch.
These synchronized networks are very precise, says Herzog. If you let them free-run in constant darkness they will lose or gain only a few minutes out of the 1,440 minutes in a day. So they’re accurate to within 1 or 2 percent.
But they’re ever so slightly off the 24-hour cycle tied to one turn of the planet on its axis. Over time they would drift far enough off that cycle to be of little use to us, unless they also had some means of synchronizing to local time.
Resetting the cellular clocks
In the article published in Neuron, Herzog and his colleagues report on a second network in the biological clock.
In this network the connections are made by the neurotransmitter GABA (γ-amino-butyric acid). “We proved we had found a GABAergic network by applying drugs that block GABA receptors on the cells,” Herzog says. “All of the connections we had mapped between neurons dropped out.”
Remarkably, when the network drops out, the clock becomes more precise. So the GABAergic network destabilizes the clock; it jiggles it a little.
Herzog points out that the GABAergic network, is sparse, weak and fast (much faster than the VIP network, which relies on the slower action of a neuropeptide), as you might expect a jitter-generator to be.
“We think the GABAergic network is there to let our clocks adjust to environmental cues, such as gradual, seasonal changes in sunrise and sunset,” says Herzog.
It’s a bit like whacking an old television set that has lost vertical synch to get it to resynch with the broadcast signal.
But there isn’t enough jitter in the clock to allow it to make abrupt adjustments, such as the one-hour forward jump when Daylight Savings Time starts. That “spring forward” has been statistically shown to increase the likelihood of heart attacks and car accidents, Herzog says.
Some sleep aids, such as benzodiazepines, that activate the GABA receptors may make the circadian clock a little more jittery, helping people adjust to big time jumps, such as flying across time zones. “But we don’t yet know whether they can improve jetlag; if they do, we want to know if it is because they help you sleep on the long flight or because they help the biological clock adjust to the new time zone,” Herzog cautions.
In any case, it is clear that if people repeatedly force the clock to reset, they throw off more than sleep. The biological clock regulates metabolism and cell division as well as sleep/wake cycles. So shift work, for example, is associated both with metabolic disorders, such as diabetes, and with the unregulated cell division that characterizes cancer.
Fighting our biological clocks does a lot more than make us crabby coffee drinkers.
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.”