It’s About Time: Disrupted Internal Clocks Play Role in Disease

Study uncovers circadian disruption as risk factor in alcoholic liver disease

Thirty percent of severe alcoholics develop liver disease, but scientists have not been able to explain why only a subset is at risk. A research team from Northwestern University and Rush University Medical Center now has a possible explanation: disrupted sleep and circadian rhythms can push those vulnerable over the edge to disease.

The team studied mice that essentially were experiencing what shift workers or people with jet lag suffer: their internal clocks were out of sync with the natural light-dark cycle. Another group of mice had circadian disruption due to a faulty gene. Both groups were fed a diet without alcohol and next with alcohol, and the team then examined the physiological effects.

The researchers found the combination of circadian rhythm disruption and alcohol is a destructive double hit that can lead to alcoholic liver disease.

The study was published last month by the journal PLOS ONE.

“Circadian disruption appears to be a previously unrecognized risk factor underlying the susceptibility to or development of alcoholic liver disease,” said Fred W. Turek, the Charles E. and Emma H. Morrison Professor of Biology at Northwestern’s Weinberg College of Arts and Sciences and one of the senior authors of the paper.

“What we and many other investigators are doing is bringing time to medicine for the diagnosis and treatment of disease,” Turek said. “We call it circadian medicine, and it will be transformative. Medicine will change a great deal, similar to the way physics changed when Einstein brought time to physics.”

A number of years ago, Ali Keshavarzian, M.D., a gastroenterologist at Rush University Medical Center who has worked with and studied patients with gastrointestinal and liver diseases, had a hunch disrupted circadian rhythms could be a contributing factor to the disease.

Keshavarzian had noticed that some patients with inflammatory bowel disease (inflammation in the intestine and/or colon) had flare-ups of symptoms when working nights, but they could control the disease when working the day shift. He sought out Turek, director of Northwestern’s Center for Sleep and Circadian Biology, to help investigate the relationship between circadian rhythms and the disease.

The two investigators and their groups first studied the effect of circadian rhythm disruption in an animal model of colitis and noted that disruption of sleep and circadian rhythms (caused by modeling shift work and chronic jet lag in the animals) caused more severe colitis in mice.

Keshavarzian has been studying the effect of “gut leakiness” (the intestinal lining becomes weak and causes dangerous endotoxins to get into the blood stream) to bacterial products in gastrointestinal diseases for two decades. Because the mouse model of colitis is associated with leaky gut, he proposed that disruption of circadian rhythms from shift work could make the intestine more susceptible to leakiness. He wanted to test its effect in an animal model of alcoholic liver disease — where a subset of alcoholics develop gut leakiness and liver disease — in order to find out whether shift work is the susceptibility factor that promotes liver injury. 

“Non-pathogen-mediated chronic inflammation is a major cause of many chronic diseases common in Western societies and developing countries that have adopted a Western lifestyle,” said Keshavarzian, one of the senior authors of the paper. He is director of the Division of Digestive Diseases and the Josephine M. Dyrenforth Chair of Gastroenterology.

Crohn’s and ulcerative colitis, Parkinson’s disease, diabetes, multiple sclerosis, autoimmune disease and cardiovascular disease are examples of these diseases, to name just a few.

“Recent studies have shown that intestinal bacteria are the primary trigger for this inflammation, and gut leakiness is one of the major causes,” Keshavarzian said. “The factor leading to gut leakiness is not known, however. Our study suggests that disruption of circadian rhythms and sleep, which is part of life in industrial societies, can promote it and explain the susceptibility.”

In the study, the Northwestern and Rush researchers used two independent approaches, studying both genetic and environmental animal models. The circadian rhythms of one group of mice were disrupted genetically: Each animal had a mutant CLOCK gene, which regulates circadian rhythms. The second group’s circadian rhythms were disrupted environmentally: The animals’ light-dark cycle was changed periodically, leading to a state similar to chronic jet lag.

Mice in both groups, prior to ingesting alcohol, showed an increase in gut leakiness.

Next, both groups of mice were fed alcohol. After only one week, animals in both groups showed a significant additional increase in gut leakiness, compared to control mice on an alcohol-free diet. At the end of the three-month study, mice in both groups were in the early stages of alcoholic liver disease.

“We have clearly shown that circadian rhythm disruption can trigger gut leakiness, which drives the more severe pathology in the liver,” said Keith Summa, a co-first author of the study and an M.D./Ph.D. candidate working in Turek’s lab.

“For humans, circadian rhythm disruption typically is environmental, not genetic, so individuals have some control over the behaviors that cause trouble, be it a poor sleep schedule, shift work or exposure to light at night,” he said.

Sleep and circadian rhythms are an integral part of biology and should be part of the discussion between medical doctors and their patients, the researchers believe.

“We want to personalize medicine from a time perspective,” Turek said. “Our bodies are organized temporally on a 24-hour basis, and this needs to be brought into the equation for understanding health and disease.”

Helping SAD Sufferers Sleep Soundly

Lying awake in bed plagues everyone occasionally, but for those with seasonal affective disorder, sleeplessness is routine.University of Pittsburgh researchers report in the Journal of Affective Disorders that individuals with seasonal affective disorder (SAD)—a winter depression that leads to loss of motivation and interest in daily activities—have misconceptions about their sleep habits similar to those of insomniacs. These findings open the door for treating seasonal affective disorder similar to the way doctors treat insomnia.

Kathryn Roecklein, primary investigator and assistant professor in Pitt’s Department of Psychology within the Kenneth P. Dietrich School of Arts and Sciences, along with a team of researchers from Pitt’s School of Medicine and Reyerson University, investigated why, according to a previously published sleep study by the University of California, Berkeley, individuals with seasonal affective disorder incorrectly reported that they slept four more hours a night in the winter. 

“We wondered if this misreporting was a result of depression symptoms like fatigue and low motivation, prompting people to spend more time in bed,” said Roecklein. “And people with seasonal affective disorder have depression approximately five months a year, most years. This puts a significant strain on a person’s work life and home life.”

Roecklein and her team interviewed 147 adults between the ages of 18 and 65 living in the Pittsburgh metropolitan area during the winters of 2011 and 2012. Data was collected through self-reported questionnaires and structured clinical interviews in which participants were asked such questions as: “In the past month, have you been sleeping more than usual?” and “How many hours, on average, have you been sleeping in the past month? How does that compare to your normal sleep duration during the summer?” 

In order to understand participants’ ideas about sleep, Roecklein’s team asked them to respond to questions such as “I need at least 8 hours of sleep to function the next day” and “Insomnia is dangerous for health” on a scale from 0 to 7, where 7 means “strongly agree” and 0 means “disagree completely.”

Roecklein and her team found that SAD participants’ misconceptions about sleep were similar to the “unhelpful beliefs” or personal misconceptions about sleep that insomniacs often hold. Due to depression, individuals with SAD, like those with insomnia, may spend more time resting in bed, but not actually sleeping—leading to misconceptions about how much they sleep. These misconceptions, said Roecklein, play a significant role in sleep cognition for those with seasonal affective disorder.

“We predict that about 750,000 people in the Pittsburgh metro area suffer from seasonal affective disorder, making this an important issue for our community and the economic strength and vitality of our city,” said Roecklein. “If we can properly treat this disorder, we can significantly lower the number of sufferers in our city.”

Roecklein’s research data suggests that addressing, understanding, and managing these “unhelpful beliefs” about sleep by way of psychotherapy could lead to improved treatments for seasonal affective disorder. One of the most effective treatment options for insomnia, said Roecklein, is cognitive behavioral therapy for insomnia (known as CBT-I), which aims to help people take control of their thinking to improve their sleep habits as well as mood, behavior, and emotions.

Roecklein’s next research project aims to improve treatment for seasonal affective disorder by studying light perception and biological clock synchronization. Light from the environment synchronizes internal biological rhythms with the timing of dawn and dusk, which naturally changes with the seasons. This synchronization allows people to be awake and alert during the day and to sleep at night. Roecklein will examine whether people with seasonal affective disorder perceive this light from the environment differently because of changes in the function of neurological pathways from the eye to the brain. This could help uncover reasons why people suffer from seasonal affective disorder and could suggest new treatment options.

(Image: Shutterstock)

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)

Key Protein is Linked to Circadian Clocks, Helps Regulate Metabolism

Inside each of us is our own internal timing device. It drives everything from sleep cycles to metabolism, but the inner-workings of this so-called “circadian clock” are complex, and the molecular processes behind it have long eluded scientists. But now, researchers at the Gladstone Institutes have discovered how one important protein falls under direct instructions from the body’s circadian clock. Furthermore, they uncover how this protein regulates fundamental circadian processes—and how disrupting its normal function can throw this critical system out of sync.

In the latest issue of the Journal of Neuroscience, Gladstone Investigator Katerina Akassoglou, PhD, and her team reveal in animal models how the production of the p75 neurotrophin receptor (p75NTR) protein oscillates in time with the body’s natural circadian clock—and how these rhythmic oscillations help regulate vital metabolic functions. This discovery underscores the widespread importance of p75NTR by offering insight into how the circadian clock helps maintain the body’s overall metabolic health.

Virtually every organism on the planet—from bacteria to humans—has a circadian clock, a biological timing mechanism that oscillates with a period of about 24 hours and is coordinated with the cycle of day and night. And while it runs independent of external cues, it is influenced by the rhythms of light, temperature and food availability. Intriguingly, recent studies have also found a link between circadian clocks and metabolism.

“Important metabolic functions are also heavily influenced by circadian clocks, which is why activities such as chronic night-shift work—which can cause a misalignment of this clock—increase one’s risk for metabolic and autoimmune diseases such as obesity, Type 2 diabetes, cancer and multiple sclerosis,” said Dr. Akassoglou. Dr. Akassoglou is also a professor of neurology at the University of California, San Francisco, (UCSF) with which Gladstone is affiliated. “In this study, we pinpointed p75NTR as an important molecular ‘link’ between circadian clocks and metabolic health.”

Originally, p75NTR was only thought to be active in the nervous system. Later studies found it to be active in many cell types throughout the body, suggesting that it impacts a variety of biological functions. Last year, Gladstone researchers discovered that p75NTR was present in the liver and in fat cells, and that it regulates glucose levels in the blood—an important metabolic process. Since these findings uncovered a link between p75NTR and metabolism, the research team tested—first in a petri dish and then in animal models—whether there was also a link between p75NTR and the circadian clock.

The team focused on two genes called Clock and Bmal1. These so-called “circadian regulator genes,” and others like them, are found throughout the body. Their activity controls the body’s circadian clock. The researchers wanted to see if there was a connection between these circadian genes and p75NTR.

“Our initial experiments revealed such a connection,” recalls Gladstone Postdoctoral Fellow Bernat Baeza-Raja, PhD, the paper’s lead author. “In individual cells, we saw that p75NTR production was controlled by Clock and Bmal1, which bind directly to the gene that codes for the p75NTR and start production of the protein.”

But perhaps even more important than how p75NTR was produced was when. The team found that p75NTR production, like the circadian clock genes themselves, oscillated in a 24-hour cycle—in sync with the cells’ natural circadian rhythm. Experiments in mouse models further supported these findings.

And when the team genetically modified a group of mice so that it lacked the circadian Clock gene, everything else fell out of sync. The circadian oscillation of p75NTR production was disrupted, and p75NTR levels dropped.

However, what was most fascinating, say the researchers, was how a drop in p75NTR levels then affected a variety of circadian clock systems. Specifically, the regular oscillations of other circadian genes in the brain and the liver became disrupted, as well as genes known to regulate glucose and lipid metabolism.

“The finding that a loss of p75NTR affected circadian and metabolic systems is strong evidence that this protein is intricately tied to both,” said Life Sciences Institute Director Alan Saltiel, PhD, who is also a professor at the University of Michigan and was not involved in the study. “It will be fascinating to see what additional insight Dr. Akassoglou and her team will uncover as they continue to examine the role of p75NTR in circadian clocks and metabolic function.”

“While these findings reveal p75NTR to be an important link between circadian clocks and metabolism, the system is complex, and there are likely other factors at play,” said Dr. Akassoglou. “We are currently working to identify the relationship between the circadian clock, metabolism and the immune system, so that one day we could develop therapies to treat diseases influenced by circadian clock disruption—including not only obesity and diabetes, but also potentially multiple sclerosis and even Alzheimer’s disease.”

(Image: Brain Treatment Center)

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 rhythms control body’s response to intestinal infections

Circadian rhythms can boost the body’s ability to fight intestinal bacterial infections, UC Irvine researchers have found.

This suggests that targeted treatments may be particularly effective for pathogens such as salmonella that prompt a strong immune system response governed by circadian genes. It also helps explain why disruptions in the regular day-night pattern – as experienced by, say, night-shift workers or frequent fliers – may raise susceptibility to infectious diseases.

UC Irvine’s Paolo Sassone-Corsi, one of the world’s leading researchers on circadian rhythm genetics, and microbiologist Manuela Raffatellu led the study, which appears this week in the early online edition of Proceedings of the National Academy of Sciences. Marina Bellet, a postdoctoral researcher from Italy’s University of Perugia also played a key role in the experiments.

“Although many immune responses are known to follow daily oscillations, the role of the circadian clock in the immune response to acute infections has not been understood,” said Sassone-Corsi, the Donald Bren Professor of Biological Chemistry. “What we’re learning is that the intrinsic power of the body clock can help fight infections.”

Circadian rhythms of 24 hours govern fundamental physiological functions in almost all organisms. The circadian clock is an intrinsic time-tracking system in the human body that anticipates environmental changes and adapts to the appropriate time of day. Disruption of these normal rhythms can profoundly influence people’s health.

Up to 15 percent of human genes are regulated by the day-night pattern of circadian rhythms, including those that respond to intestinal infections.

In tests on mice infected with salmonella, the researchers noted that circadian-controlled genes govern the immune response to the invading pathogen, leading to day-night differences in infection potential and in the immune system’s ability to deal with pathogens.

Mice are nocturnal, with circadian rhythms opposite those of humans. While important differences exist in the immune response of mice and humans, Sassone-Corsi said, these test results could provide clues to how circadian-controlled intestinal genes regulate daily changes in the effectiveness of the human immune system.

“Salmonella is a good pathogen to study what happens during infection,” said Raffatellu, assistant professor of microbiology & molecular genetics. “We think these findings may be broadly applicable to other infectious diseases in the gut, and possibly in other organs controlled by circadian patterns.”

Sassone-Corsi added that it’s important to understand the circadian genetics regulating immunity. “This gives us the ability to target treatments that supplement the power of the body clock to boost immune response,” he said.

(Image: Stephen Sedam / Los Angeles Times)

Our internal clocks can become ticking time bombs for diabetes and obesity

New research in The FASEB Journal using mice suggests that disrupting our internal clocks can lead to a complete absence of 24-hour bodily rhythms and an immediate gain in body weight

If you’re pulling and all-nighter to finish a term paper, a new parent up all night with a fussy baby, or simply can’t sleep like you once could, then you may be snoozing on good health. That’s because new research published in The FASEB Journal used mice to show that proper sleep patterns are critical for healthy metabolic function, and even mild impairment in our circadian rhythms can lead to serious health consequences, including diabetes and obesity.

"We should acknowledge the unforeseen importance of our 24-hour rhythms for health," said Claudia Coomans, Ph.D., a researcher involved in the work from the Department of Molecular Cell Biology in the Laboratory of Neurophysiology at Leiden University Medical Center in Leiden, Netherlands. "To quote Seneca ‘We should live according to nature (secundum naturam vivere).’"

To make this discovery, Coomans and colleagues exposed mice to constant light, which disturbed their normal internal clock function, and observed a gradual degradation of their bodies’ internal clocks until it reached a level that normally occurs when aging. Eventually the mice lost their 24-hour rhythm in energy metabolism and insulin sensitivity, indicating that relatively mild impairment of clock function had severe metabolic consequences.

"The good news is that some of us can ‘sleep it off’ to avoid obesity and diabetes," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "The bad news is that we can all get the metabolic doldrums when our normal day/night cycle is disrupted."

Cell death in retina helps tune our internal clocks

With every sunrise and sunset, our eyes make note of the light as it waxes and wanes, a process that is critical to aligning our circadian rhythms to match the solar day so we are alert during the day and restful at night. Watching the sun come and go sounds like a peaceful process, but Johns Hopkins scientists have discovered that behind the scenes, millions of specialized cells in our eyes are fighting for their lives to help the retina set the stage to keep our internal clocks ticking.

In a study that appeared in a recent issue of Neuron, a team led by biologist Samer Hattar has found that there is a kind of turf war going on behind our eyeballs, where intrinsically photosensitive retinal ganglion cells (ipRGCs) are jockeying for the best position to receive information from rod and cone cells about light levels. By studying these specialized cells in mice, Hattar and his team found that the cells actually kill each other to seize more space and find the best position to do their job.

Understanding this fight could one day lead to victories against several conditions, including autism and some psychiatric disorders, where neural circuits influence our behavior. The results could help scientists have a better idea about how the circuits behind our eyes assemble to influence our physiological functions, said Hattar, an associate professor of biology in the Krieger School of Arts and Sciences.

“In a nutshell, death in our retina plays a vital role in assembling the retinal circuits that influence crucial physiological functions such as circadian rhythms and sleep-wake cycles,” Hattar said. “Once we have a greater understanding of the circuit formation underlying all of our neuronal abilities, this could be applied to any neurological function.”

Hattar and his team determined that the killing among rival ipRGCs is justifiable homicide: Without this cell death, circadian blindness overcame the mice, who could no longer distinguish day from night. Hattar’s team studied mice that were genetically modified to prevent cell death by removing the Bax protein, an essential factor for cell death to occur. They discovered that if cell death is prevented, ipRGCs distribution is highly affected, leading the surplus cells to bunch up and form ineffectual, ugly clumps incapable of receiving light information from rods and cones for the alignment of circadian rhythms. To detect this, the researchers used wheel running activity measurements in mice that lacked the Bax protein as well as the melanopsin protein which allows ipRGCs to respond only through rods and cones and compared it to animals where only the Bax gene was deleted.

What the authors uncovered was exciting: When death is prevented, the ability of rods and cones to signal light to our internal clocks is highly impaired. This shows that cell death plays an essential role in setting the circuitry that allows the retinal rods and cones to influence our circadian rhythms and sleep.

(Image: Advanced Retinal Institute, Inc.)