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Why do morning people have shorter biological clocks?

Why do morning people have shorter biological clocks?


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First of all, we all have a circadian clock than is run endogenously by differential gene expression and controls our change in awakeness, temperature, hormone levels, etc… Circadian clocks are not exactly 24 h and they vary among people: some people have shorter clocks and other have longer ones. Apparently, people who have shorter circadian rhythms are morning people, and those that have longer one, are night owls.

How is this possible? In the following article "https://www.futurity.org/biological-clocks-sleep-disorders-protein-mutations-2289312-2/" it says that a 20-hour biological clock will make a person fall asleep earlier because they will get tired earlier and they will get awake also earlier. But for me, that would only be possible the first period or two if both cycles start at the same point time. Afterward, the cycles will get out of phase and that will not be true any longer.


Circadian rhythms are entrained by light via the suprachiasmatic nucleus, a part of the brain that receives signals from special retinal ganglion cells that are directly sensitive to (mainly blue) light.

However, light is not strictly necessary: the internal circadian clock is the result of shifting gene expression that proceeds without outside stimulus. Light is only used to entrain (or "reset") the clock each day.

When people talk about the duration of an individual's circadian rhythm, they are referring to what happens in the absence of a light cycle (that is, without entrainment).

https://en.wikipedia.org/wiki/Circadian_rhythm https://en.wikipedia.org/wiki/Suprachiasmatic_nucleus https://en.wikipedia.org/wiki/Circadian_rhythm_sleep_disorder


The Circadian Rhythms of humans is reset by light exposure cycles, but for a cycle to be reset it has to exist first.

Without light there are cycles created by protein production and gene inhibition.

In the relevant 24 cycle there is a is a gene complex that produces a set of proteins that react and decay into a product shuts down the gene's expression (protein production) as long as it is present. that stops the initial proteins production thus creating a cycle based on the proteins reaction and decay rate. So the gene is active and the protein is produced, over a roughly se amount of time the protein reacts and decays into a protein that shuts down the gene expression (inhibitor), Will say this takes time A, of course the gene was till produce the protein until the inhibitor stopped it so the reaction and decay continues for time A again until all the inhibitor is used up and the gene starts producing the proteins again. So you get a cycle of expression and inhibitor that resets once every times Ax2.

But as you can guess genes and proteins a small change in the protein can change can change how long it takes to react and decay. This is how you get some people with slightly longer cycles and others with slightly shorter cycles.

https://pubs.niaaa.nih.gov/publications/arh25-2/85-93.htm


Biological Clock

When the sun rises on a warm and sunny day you can see the trumpet-shaped flowers of the morning glory open up. When they close late in the afternoon primrose flowers open and before daylight arrives the next morning they close again.

Biological rhythms, like the opening and closing of flowers happen all over nature. But not all of them are daily rhythms. Some, like the beating of our heart, occur every second. Other rhythms are based on months, seasons or years.

Scientists use the term biological clock to describe the timing that controls biological rhythms. But what is this clock and where can you find it? In animals it is probably controlled by the brain, but in plants and other living things that have no brain it must be something else.

The biological rhythms of seashore organisms are connected to the rise and fall of the water. When the tide comes in they open their shells and get food, when the water goes back the shells close to protect the animals from the dry air.

Bay of Funday - High and Low Tide - Samuel Wantman

The migration of animals is also an event that happens when a signal is sent out. When days become shorter birds leave the northern parts of the world and fly south where it is warm and they have enough food. In the summer they fly back to have babies .

Humans also have biological clocks that control their daily rhythms. Body temperature, blood pressure , sleeping and waking up have a 24-hour rhythm. Many illnesses have a yearly rhythm. Colds and flus often happen in winter. Measles occur mostly during the spring and summer.

When people travel by plane from one continent to another they often cross many time zones. Their internal clocks don&rsquot seem to work correctly. We call this jet lag. It makes you feel tired and it takes many days for your body&rsquos biological clock to get used to the new place.

People who work night shifts also have problems with their biological clocks. In general, they may not be as alert or active as people who work during the daytime . They also have more accidents during work. Sometimes they have more health and sleeping problems than other people.

By using the right medicine you can fight off problems that are connected with different times of day. Heart attacks and strokes often happen in the morning hours&mdashbetween the time you get up and noon. Asthma often occurs between midnight and the morning hours. So when people with weak hearts take their medicine right after waking up it might prevent a heart attack.

Biological clocks control many rhythms of life. We are learning more and more about these rhythms. Doctors are looking for new ways to make travelling more comfortable and medical treatment more effective.


Molecular switch mechanism explains how mutations shorten biological clocks

A new study of molecular interactions central to the functioning of biological clocks explains how certain mutations can shorten clock timing, making some people extreme "morning larks" because their internal clocks operate on a 20-hour cycle instead of being synchronized with the 24-hour cycle of day and night.

The study, published February 11 in eLife, shows that the same molecular switch mechanism affected by these mutations is at work in animals ranging from fruit flies to people.

"Many people with sleep phase disorders have changes in their clock proteins," said Carrie Partch, associate professor of chemistry and biochemistry at UC Santa Cruz and a corresponding author of the paper. "Generally, mutations that make the clock run shorter have a morning lark effect, and those that make the clock run longer have a pronounced night owl effect."

In the new study, researchers focused on mutations in an enzyme called casein kinase 1 (CK1), which regulates a core clock protein called PERIOD (or PER). Clock-altering mutations in CK1 had been known for years, but it was unclear how they changed the timing of the clock.

CK1 and other kinase enzymes carry out a reaction called phosphorylation, adding a phosphate to another protein. It turns out that CK1 can phosphorylate either of two sites on the PER protein. Modifying one site stabilizes PER, while the other modification triggers its degradation. Partch and her colleagues showed how mutations in either CK1 or PER itself can alter the balance, favoring degradation over stabilization.

PER proteins are part of a complex feedback loop in which changes in their abundance set the timing of circadian rhythms, so mutations that increase the rate of PER degradation throw off the clock.

"What we discovered is this neat molecular switch that controls the abundance of the PER proteins. When it's working right, it generates a beautiful 24-hour oscillation," Partch said.

Partch's lab performed structural and biochemical analyses of the CK1 and PER proteins that suggested how the switch works. To confirm that the interactions observed in the test tube matched the behavior of the proteins in living cells, they worked with researchers at the Duke-NUS Medical School in Singapore. Other collaborators at UC San Diego performed simulations of the molecular dynamics of the switch showing how the CK1 protein switches between two conformations, and how mutations cause it favor one conformation over another.

The switch involves a section of the CK1 protein called the activation loop. One conformation of this loop favors binding of CK1 to the "degron" region of PER, where phosphorylation leads to the protein's degradation. The clock-changing mutations in CK1 cause it to favor this degron-binding conformation.

The other conformation favors binding to a site on the PER protein known as the FASP region, because mutations in this region lead to an inherited sleep disorder called Familial Advanced Sleep Phase Syndrome. The stabilization of PER can be disrupted by either the FASP mutations, which interfere with the binding of CK1 to this region, or by the mutations in CK1 that favor the alternate conformation of the activation loop.

The new findings also suggest why binding of CK1 to the FASP region stabilizes PER. With phosphorylation of the FASP region, that region then acts to bind and inhibit CK1, preventing it from adopting the other conformation and phosphorylating the degron region.

"It binds and locks the kinase down, so it's like a pause button that prevents the PERIOD protein from being degraded too soon," Partch said. "This stabilizing region builds a delay into the clock to make it align with Earth's 24-hour day."

Partch noted that it is important to understand how these clock proteins regulate our circadian rhythms, because those rhythms affect not only the sleep cycle but almost every aspect of our physiology. Understanding these molecular mechanisms may enable scientists to develop therapies for intervening in the clock to alleviate disruptions, whether they are caused by inherited conditions or by shift work or jet lag.

"There might be ways to mitigate some of those effects," she said.

CK1 is also interesting because it seems to be the most ancient component of biological clocks. The whole feedback loop involving CK1, PERIOD, and other core clock proteins is found in all animals from insects to humans. CK1, however, is also found in every other organism with eukaryotic (nonbacterial) cells, including single-celled green algae in which it has been implicated in circadian rhythms.

"Our results provide a mechanistic foundation to understand the essentially universal role of CK1 as a regulator of eukaryotic circadian clocks," Partch said.


Contents

Chronobiology studies variations of the timing and duration of biological activity in living organisms which occur for many essential biological processes. These occur (a) in animals (eating, sleeping, mating, hibernating, migration, cellular regeneration, etc.), (b) in plants (leaf movements, photosynthetic reactions, etc.), and in microbial organisms such as fungi and protozoa. They have even been found in bacteria, especially among the cyanobacteria (aka blue-green algae, see bacterial circadian rhythms). The best studied rhythm in chronobiology is the circadian rhythm, a roughly 24-hour cycle shown by physiological processes in all these organisms. The term circadian comes from the Latin circa, meaning "around" and dies, "day", meaning "approximately a day." It is regulated by circadian clocks.

The circadian rhythm can further be broken down into routine cycles during the 24-hour day: [2]

    , which describes organisms active during daytime , which describes organisms active in the night , which describes animals primarily active during the dawn and dusk hours (ex: white-tailed deer, some bats)

While circadian rhythms are defined as regulated by endogenous processes, other biological cycles may be regulated by exogenous signals. In some cases, multi-trophic systems may exhibit rhythms driven by the circadian clock of one of the members (which may also be influenced or reset by external factors). The endogenous plant cycles may regulate the activity of the bacterium by controlling availability of plant-produced photosynthate.

Many other important cycles are also studied, including:

    , which are cycles longer than a day. Examples include circannual or annual cycles that govern migration or reproduction cycles in many plants and animals, or the human menstrual cycle. , which are cycles shorter than 24 hours, such as the 90-minute REM cycle, the 4-hour nasal cycle, or the 3-hour cycle of growth hormone production. , commonly observed in marine life, which follow the roughly 12.4-hour transition from high to low tide and back. , which follow the lunar month (29.5 days). They are relevant e.g. for marine life, as the level of the tides is modulated across the lunar cycle. – some genes are expressed more during certain hours of the day than during other hours.

Within each cycle, the time period during which the process is more active is called the acrophase. [3] When the process is less active, the cycle is in its bathyphase or trough phase. The particular moment of highest activity is the peak or maximum the lowest point is the nadir.

A circadian cycle was first observed in the 18th century in the movement of plant leaves by the French scientist Jean-Jacques d'Ortous de Mairan. [4] In 1751 Swedish botanist and naturalist Carl Linnaeus (Carl von Linné) designed a flower clock using certain species of flowering plants. By arranging the selected species in a circular pattern, he designed a clock that indicated the time of day by the flowers that were open at each given hour. For example, among members of the daisy family, he used the hawk's beard plant which opened its flowers at 6:30 am and the hawkbit which did not open its flowers until 7 am. [5]

The 1960 symposium at Cold Spring Harbor Laboratory laid the groundwork for the field of chronobiology. [6]

It was also in 1960 that Patricia DeCoursey invented the phase response curve, one of the major tools used in the field since.

Franz Halberg of the University of Minnesota, who coined the word circadian, is widely considered the "father of American chronobiology." However, it was Colin Pittendrigh and not Halberg who was elected to lead the Society for Research in Biological Rhythms in the 1970s. Halberg wanted more emphasis on the human and medical issues while Pittendrigh had his background more in evolution and ecology. With Pittendrigh as leader, the Society members did basic research on all types of organisms, plants as well as animals. More recently it has been difficult to get funding for such research on any other organisms than mice, rats, humans [7] [8] and fruit flies.

More recently, light therapy and melatonin administration have been explored by Alfred J. Lewy (OHSU), Josephine Arendt (University of Surrey, UK) and other researchers as a means to reset animal and human circadian rhythms. Additionally, the presence of low-level light at night accelerates circadian re-entrainment of hamsters of all ages by 50% this is thought to be related to simulation of moonlight. [9]

In the second half of 20th century, substantial contributions and formalizations have been made by Europeans such as Jürgen Aschoff and Colin Pittendrigh, who pursued different but complementary views on the phenomenon of entrainment of the circadian system by light (parametric, continuous, tonic, gradual vs. nonparametric, discrete, phasic, instantaneous, respectively [10] ).

Humans can have a propensity to be morning people or evening people these behavioral preferences are called chronotypes for which there are various assessment questionnaires and biological marker correlations. [11]

There is also a food-entrainable biological clock, which is not confined to the suprachiasmatic nucleus. The location of this clock has been disputed. Working with mice, however, Fuller et al. concluded that the food-entrainable clock seems to be located in the dorsomedial hypothalamus. During restricted feeding, it takes over control of such functions as activity timing, increasing the chances of the animal successfully locating food resources. [12]

Diurnal patterns on the Internet

In 2018 a study published in PLoS ONE showed how 73 psychometric indicators measured on Twitter Content follow a diurnal pattern. [13] A followup study appeared on Chronobiology International in 2021 showed that these patterns were not disrupted by the 2020 UK lockdown. [14]

Modulators of circadian rhythms

In 2021, scientists reported the development of a light-responsive days-lasting modulator of circadian rhythms of tissues via Ck1 inhibition. Such modulators may be useful for chronobiology research and repair of organs that are "out of sync". [15] [16]

Chronobiology is an interdisciplinary field of investigation. It interacts with medical and other research fields such as sleep medicine, endocrinology, geriatrics, sports medicine, space medicine and photoperiodism. [17] [18] [19]


Night Owls and Early Risers Have Different Brain Structures

Are you one of those people who rises before dawn and never needs an alarm clock? Or would you happily sleep until midmorning if you could? Do you feel like you are just hitting your day's stride by late afternoon, or do you like to get the big tasks of the day accomplished early?

Most of us have some degree of preference for late nights or early mornings. Where an individual falls on this spectrum largely determines his or her chronotype -- an individual disposition toward the timing of daily periods of activity and rest. Some of us are clearly "larks" -- early risers -- while others of us are distinctly night owls. The rest of us fall somewhere in between the two.

We're learning that these night owl and early riser tendencies are driven by some significant degree by biological and genetic forces. Different chronotypes are associated with genetic variations, as well as differences in lifestyle and mood disposition, cognitive function and risks for health problems, including sleep disorders and depression.

New research has now found evidence of physical differences in the brains of different chronotypes. Scientists at Germany's Aachen University conducted brain scans of early risers, night owls, and "intermediate" chronotypes who fell in between the two ends of the spectrum. They discovered structural differences in the brains of people with different sleep-wake tendencies. Researchers observed a group of 59 men and women of different chronotypes: 16 were early risers, 20 were intermediate sleepers, and 23 were night owls. They found that compared to early risers and intermediates, night owls showed reduced integrity of white matter in several areas of the brain. White matter is fatty tissue in the brain that facilitates communication among nerve cells. Diminished integrity of the brain's white matter has been linked to depression and to disruptions of normal cognitive function.

The cause of this difference in quality of white matter among night owls compared to other sleepers is not clear. Researchers speculate that the diminished integrity of white matter may be a result of the chronic "social jet lag" that characterizes the effects of the sleep-wake routines of many night owls. People who are disposed toward staying up late and sleeping late often find themselves at constant odds with the schedule of life that surrounds them, particularly work and school schedules that require early-morning starts. This can leave night owls chronically sleep deprived, and experiencing many of the same symptoms -- fatigue and daytime sleeplessness, difficulty focusing, physical pain and discomfort -- of travel-induced jet lag.

Research indicates that people who stay up late are at higher risk for depression. Studies have also shown night owls more prone to more significant tobacco and alcohol use, as well as inclined to eating more, and also less healthful diets than early risers or people with intermediate sleep patterns. But research on the influence of chronotype isn't all bad news for night owls. Some studies have shown that people who stay up late are more productive than early risers, and have more stamina throughout the length of their days. Other research has shown that night owls display greater reasoning and analytical abilities than their earlier-to-bed counterparts. Stay-up-late types, according to research, achieve greater financial and professional success on average than those people with earlier bedtimes and wake times.

This latest study is the first to offer physical evidence of neurological differences among people with different sleep tendencies. But other research has also shown that the inclinations toward staying up late or rising early are deeply rooted in biological and genetic differences:

Scientists have discovered an "alarm clock" gene that activates the body's biological clock in the morning from its period of overnight rest. Identifying this gene and its function may eventually tell us important new information about the influence of chronotype and circadian function on sleep and health.

Several studies involving twins have demonstrated genetic links to several aspects of sleep, including circadian timing and sleep/wake preferences.

Research has also revealed differences in brain metabolic function among night owls compared to early risers and middle-of-the-road sleepers. These metabolic differences were discovered in regions of the brain involved in mood, and may be one reason why night owls are at higher risk for depression related to insomnia.

Recently, scientists identified a gene variant that exerts a strong influence over the circadian clock, and with the inclination to stay up late or rise early. This genetic variation -- which affects nearly the entire population -- can shift the timing of an individual's 24-hour sleep-wake cycle by as much as 60 minutes.

If our preferences for sleep and wake times are strongly influenced by genetics and biology, what are we to do when faced with inclinations that don't match up with the demands and responsibilities of our lives? Genetic forces appear to play an important role in our preferences, but we're still working to understand just how, and how much. And we're far from powerless: The choices we make about our sleep environments and sleep habits can also make a significant difference. A recent study showed that limiting nighttime exposure to artificial light and increasing exposure to daytime sunlight can shift sleep-wake cycles earlier -- even for night owls. Strong sleep habits -- being careful about alcohol consumption close to bedtime, sticking to regular sleep and wake times, making sure your bedroom is dark and electronic-gadget free -- can help reinforce your sleep schedule, even if it doesn't align perfectly with your natural tendencies.

More broadly, I hope we'll see society begin to recognize the power of these biological sleep patterns, and the need for flexibility to enable people to construct work and school schedules that align better with their dispositions toward sleep. This is a smart, sleep-friendly strategy that would be good for public health and productivity.


Your Body's Internal Clock and How It Affects Your Overall Health

We all feel the ebb and flow of daily life, the daily rhythms that shape our days. The most basic daily rhythm we live by is the sleep-wake cycle, which (for most) is related to the cycle of the sun. It makes us feel sleepy as the evening hours wear on, and wakeful as the day begins. Sleep-wake and other daily patterns are part of our circadian rhythms, (circum means "around" and dies, "day") which are governed by the body's internal or biological clock, housed deep within the brain.

But research has been finding that the body's clock is responsible for more than just sleep and wakefulness. Other systems, like hunger, mental alertness, and mood, stress, heart function, and immunity also operate on a daily rhythm.

The existence of the biological clock can be particularly apparent when it's off kilter: Jet lag and shift work can throw our normal patterns out of whack and take a toll on physical and mental health. Even shifting the clock an hour forward or backward when daylight savings time begins or ends can disrupt our biological clocks.

Disrupting our body's natural cycles can cause problems. Studies have found there are more frequent traffic accidents and workplace injuries when we spring forward and lose an hour of sleep. Heart patients are at greater risk for myocardial infarction in the week following the Daylight Savings time shift. But even more significant is that science continues to discover important connections between a disrupted clock and chronic health issues, from diabetes to heart disease to cognitive decline.

It turns out that the same genes and biological factors that govern our internal clock are also involved in how other body systems operate -- and break down. It can be hard to determine whether a disrupted clock leads to health problems, or whether it's the other way around.

We're beginning to understand more about how the clock interacts with and helps govern the function of other systems and affects our overall health. In fact, keeping your body's daily cycle on an even keel may be one of the best things you can do for your overall health.

YOUR BODY WANTS TO RUN LIKE A SWISS WATCH

The idea of a biological clock may sound like a quaint metaphor, but there is actually a very distinct brain region that is charged with keeping time: It is an area called the suprachiasmatic nucleus (or SCN), situated right above the point in the brain where the optic nerve fibers cross. This location enables the SCN to receive the cues it needs from light in the environment to help it keep time.

But genes also influence the body's clock and circadian rhythms. The system requires both types of input -- light and genes -- to keep it on track. To stay on the 24-hour cycle, the brain needs the input of sunlight through the eyes to reset itself each day. When humans are allowed to run off their body's clock apart from input from the sun, by being kept in continuous darkness, the body's daily cycle tends to lengthen to about 25 hours. And when people or animals lack the genes that help control the clock's cycle, their sleep-wake cycles can stray even further, or be absent completely. The need for both kinds of cues -- light and genes -- make the biological clock a classic example of how genes and the environment work in tandem to keep the system functioning well.

Our Behaviors and Body Functions Run on Cycle

Melatonin is one hormone responsible for our body's daily cycle. When night falls and there is less light input to the SCN, the production of melatonin, the hormone responsible for making us feel sleepy, goes up. When it's dark, more melatonin is secreted, which signals the brain to go into sleep mode. When the sun rises, melatonin secretion is inhibited, and the brain's awake circuits resume.

Other systems also follow a daily rhythm, many of which are controlled by hormones and other compounds that receive cues from the biological clock. For example, the hormones responsible for hunger and metabolism rise and fall over the course of the day. The chemicals involved in immune system function also vary. Compounds that encourage the inflammatory response rise at night, (which is why fevers tend to spike then), and those that inhibit it rise during the day.

This is likely because the body is better at fighting infection while it is at rest, and energy can be poured into the effort, rather than into other functions. And activity of the stress response system -- particularly in secretion of the stress hormone, cortisol -- is reduced during the nighttime hours, and heightened in the early morning.

Although there are certain areas of the body, like the heart, that are able to govern their own function to some degree, there is strong evidence that the body clock plays a major role in controlling many of these fluctuations (such as in blood sugar) over the 24-hour period.

ENVIRONMENTAL DISRUPTIONS TO THE BODY'S CLOCK

Some of the best knowledge we have about the roles the biological clock plays in our health come from instances in which the cycle gets out of sync. This can happen for different reasons, and we're just starting to understand them in greater detail. Sometimes we do things ourselves that disrupt our normal rhythms, like flying to a distant time zone. Sometimes it's other factors, (like genes or biology) that play a role.

Flying across the country on the red-eye is a prime example of how we can disrupt our own clocks, and a far more extreme example than the spring forward/fall back ritual in many parts of the U.S.

When jet lag sets in, we feel disoriented, foggy, and sleepy at the wrong times of day because, after changing time zones, our body clock tells us it's one time and the outside environment tells us it's another. In fact, jet lag can be considered one type of circadian rhythm disorder. It can be treated simply be allowing the body to adjust to the new time, although it may take several days for external cues (light) to help the internal clock catch up or fall back with its new cycle.

Shift work is another example of how we can get ourselves off-cycle, and this too can develop into a circadian rhythm disorder over the long term. People who work the night shift not only have a hard time with their sleep patterns (feeling sleepy at work or experiencing insomnia during the day), but other systems in their bodies can also feel the effects -- and they can be chronic. It's not been clear exactly why this connection exists, but weight gain or metabolic changes may be involved. These phenomena underline how particular behaviors or lifestyles can affect the body's clock, but there are other factors at play, like genetics and body chemistry.

BIOLOGICAL AND GENETIC DISRUPTIONS AND THEIR IMPLICATIONS FOR HEALTH

The interactions of the clock are complex, and their effects on different body systems are intricate, but we're starting to understand more about how the nuts and bolts of the clock work, and affect each system of the body, from our hearts to our moods.

Since the biological clock is, in fact, a biological entity, things can go wrong with it that may have less to do with lifestyle or the environment, and more to do with the mechanisms of the clock itself. For example, there's more to the clock-diabetes link than just turning our sleep cycle around, though sleep can make a difference.

The same genes that control the receptors for the sleep hormone melatonin are involved in insulin release, which could also play a role in diabetes risk. When melatonin receptor genes have mutations that damage the connection between the biological clock and insulin release people have a significantly higher risk of developing diabetes.

The Rhythms of the Heart

The heart is one organ that, although it can keep time by itself to some degree, relies on the brain's biological clock for cues. For years doctors and researchers have noticed that heart problems like fatal arrhythmias are more likely to occur at certain times of the day, both in the early morning and to a lesser degree, in the evening hours. Taking blood pressure medication in the evening seems to improve its effectiveness because it works with the body's circadian rhythms.

The reason for this has recently become clear: A genetic factor involved in the rhythm of the brain's clock also controls the electrical activity in the heart. Mice who are bred to lack this factor -- Kruppel-like factor 15 (KLF15) -- or have too much of it, have many more heart problems than normal mice. Understanding this clock-heart connection could help experts design drugs to reduce the risk of heart problems in people by stabilizing the levels of these compounds.

Immunity and Vaccinations

Most of us have experienced being more susceptible to getting sick when sleep-deprived. The reason for this appears to be that certain chemicals responsible for immune function, like cytokines, wax and wane throughout the day and sleep deprivation deprives us of their best effects. Animals who are given vaccines at specific times of the day, when certain proteins that sense bacterial invaders are highest, have a much stronger immune response, even weeks later. The same is very likely true for humans.

Body rhythms don't just enhance vaccines' ability to provide immunity they can affect the body's ability to battle infection on its own. When mice were exposed to a bacterial infection, the severity of their infection reflected the time of day they were infected.

It's not just in the lab that these effects are seen. Babies who are given vaccines in the afternoon -- and who sleep more right after -- have better immune responses to the innoculations. It's likely that the same effect is true in adults, since our immune systems fluctuate in similar ways.

Our internal clocks also have a hand in whether we feel up or down emotionally. People with mood disorders like depression, bipolar disorder, and seasonal affective disorder (SAD) have altered circadian rhythms. In fact, sleep disturbances, both sleeping too much and too little, are one of the key symptoms of depression and other mood disorders.

The relationship between body rhythms and mood is an intricate one, and likely has to do with how the brain chemical serotonin fluctuates in relation to the light-dark cycle and throughout the year as the days become longer and shorter. Mice bred to have problems with serotonin function also have seriously altered daily rhythms. People's serotonin levels increase during the part of the day when there is more light available.

The circadian rhythm-mental health connection has also been linked to disease states like Alzheimer's, Parkinson's, and Huntington's, and even autism spectrum disorder. Researchers are finding that disrupted daily rhythms can be good predictors for the development of mild cognitive impairment that comes with age, and even for dementia.

Experiments in fruit flies (which may seem a far cry from humans, but actually serve as excellent models in biological clock studies) show that degeneration in the brain occurs much more rapidly when there are problems in the functioning of a key clock gene, and the lifespans of the flies are significantly shortened. Knowing more about how the clock is related to cognitive function and decline could help experts predict -- and perhaps one day prevent -- it from occurring in humans as well.

Paying attention to the body's natural rhythms is probably more important to our health than we realize. It's not just sleep deprivation that affects our well-being, but it's also the alteration of our biological rhythms that can interfere with so many body functions, making us more prone to health problems like infection, mood problems, and even heart disease.

Why the biological clock becomes disrupted in certain people, or naturally with age, is not completely clear, but some have recently suggested that it could in part have to do with the aging of the eyes. Natural changes in the lens and even the development of cataracts let less light into the eye and, therefore, the brain and this can affect biological rhythms.

There are many other reasons our bodies' clocks can go out of sync, which probably involve a combination of genetic predisposition and lifestyle choices, such as alcohol consumption. Sometimes the clock can get unset -- as with the changes associated with daylight savings time, air travel, or shift work -- and there's only so much we can do until our body and its clock are in equilibrium again.

But keeping your schedule on track as much as possible is probably the best advice. You probably have a pretty good sense of your body's natural rhythms intuitively. Avoid disruptions to your eat-sleep cycles. Practice good sleep hygiene, and stick to a sleep schedule that works well for your body to keep the system in its natural rhythm. Turning in a little earlier, cutting back on caffeine late in the day, and saving that last bit of work for the morning rather than staying late up to finish it, can make a big difference in how your internal clock functions and in how you feel.


How the clock works

At the heart of the clock is a “negative feedback loop” which consists of the following sequence of events. The clock genes produce messages that are translated into proteins. The proteins then interact to form complexes and move from the cytoplasm of the cell into the nucleus and then inhibit their own genes. These inhibitory clock protein complexes are then broken down and the clock genes are then once more free to make more messages and fresh protein – and the cycle continues day after day.

This negative feedback loop generates a near 24-hour rhythm of protein production and degradation that drives the internal biological day.

Based on the findings of Hall, Rosbash and Young in the fruit fly, very similar clock genes were then discovered in mice, humans and many other animals. So the biological clocks that “tick” in us are broadly similar to the clocks found in insects, worms, fish and birds.

We now know that the morning and evening preferences of individuals who describe themselves as either “larks” or “owls” also appear to be related to small changes in some of these clock genes that either speed up or slow down our circadian rhythms.


Science Explains Why We Should All Work Shorter Hours in Winter

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Photograph: Laurie Noble/Getty Images

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For many of us, winter, with its chilly days and long nights, brings with it a general sense of malaise. It’s harder to peel ourselves out of bed in the half-light of morning, and hunched over our desks at work, we can feel our productivity draining away with the remnants of the afternoon sun.

This story originally appeared on WIRED UK.

For the small subsection of the population who experience full-blown seasonal affective disorder (SAD), it’s even worse—winter blues mutate into something far more debilitating. Sufferers experience hypersomnia, low mood, and a pervasive sense of futility during the bleaker months. SAD notwithstanding, depression is more widely reported during winter, suicide rates increase, and productivity in the workplace drops during January and February.

While it’s easy to put all of this down to some nebulous idea of winter gloominess, there might be a scientific reason for all of this despondency. If our body clocks are out of sync with our waking—and working—hours, shouldn’t we be tweaking our office hours to help improve our mood?

“If our body clock is saying it wants us to wake up at 9:00, because it's a dark winter's day, but we're getting ourselves up at 7:00—then we are missing out on a complete sleep phase,” says Greg Murray, professor of psychology at Swinburne University, Australia. Research into the area of chronobiology—the study of how our body regulates sleep and wakefulness—supports the idea that during winter, our sleep needs and preferences change, and the constraints of modern life might be particularly ill-fitting during these months.

What do we mean when we talk about biological time? The circadian clock is a concept that scientists use to measure our internal sense of time. It’s a 24-hour timer that determines when we want to place various events of the day—most importantly, when we want to get up and when we want to fall asleep. “The body likes to do those things in synchrony with the body clock, which is the master controller of where our body and behavior is relative to the sun,” explains Murray.

There are a huge number of hormones and other chemicals involved in regulating our body clocks, as well as an array of external factors. A particularly important one is the sun, and where it happens to be in the sky. Photoreceptors nested at the back of our eyes known as ipRGCs are especially sensitive to blue light, and therefore perfectly primed to help calibrate the circadian clock. There’s evidence these cells have a crucial role in helping to regulate sleep.

The evolutionary value of this biological mechanism was to promote changes in our physiology, biochemistry, and behavior according to different times of the day. “This is what the predictive function of a circadian clock is,” says Anna Wirz-Justice, professor at the Centre for Chronobiology at the University of Basel in Switzerland. “And it's there in all living creatures.” Given daylight shifts over the course of the year, it prepares organisms for seasonal changes in behavior too, like reproduction or hibernation.

While there hasn’t been an abundance of research specifically examining the question of whether we would respond well to more sleep and different wake times during winter, there’s evidence that this could be the case. "From a theoretical viewpoint, decreased availability of natural light in the morning in winter should encourage what we call a phase delay," says Murray. "And biologically, there's good reason to think that that probably does happen to some extent." A phase delay means that our circadian clocks are nudged later during winter, explaining why the urge to stab the snooze button becomes increasingly tough to fight.

The idea of a phase delay might at first appear to suggest that we would want to go to bed later in winter too, but Murray hypothesizes that this tendency would likely be counteracted by a growing desire to slumber in general. Studies suggest that humans require (or at least desire) more sleep during winter. A study looking at three preindustrial societies—that is, those without alarm clocks, smartphones, and 9-to-5 working hours—in South America and Africa found that these communities collectively snoozed for about an hour longer during winter. Given that these communities are located in equatorial regions, this effect could be even more pronounced in the northern hemisphere where winters are colder and darker.

This soporific winter mode is at least partly mediated by one of the major players in our chronobiology—melatonin. This endogenous hormone is controlled by the circadian clock, while also influencing it in turn. It’s the sleep drug, meaning its production ramps up before we’re due to fall into bed. “In humans, the melatonin profile is much broader in winter than in summer,” says chronobiologist Till Roenneberg. “That's the biochemical background of why circadian clocks can react to two different seasons of the year.”

But what does it mean if our internal clocks are ticking out of time with the demands of our school or work schedules? “The discrepancy between what your biological clock wants and what your social clock wants—we have called this social jet lag,” says Roenneberg. “And social jet lag is stronger in winter than it is in summer.” Social jet lag is similar to the kind of jet lag we’re more acquainted with, but instead of flying across the world, it’s merely the timing of our social demands—like getting up for work or school—that push us out of joint.

Social jet lag is a well documented phenomenon, and it can have serious consequences on health, well-being, and how well we’re able to function in daily life. If it’s true that winter produces a form of social jet lag, to discern what its effects might be, we can look to populations that experience this phenomenon on a grander scale.

One potentially insightful group to examine includes people who live at the western edges of time zones. Since time zones can cover vast areas, people living at the eastern edges of time zones experience sunrise about an hour to an hour and a half before those living at the western edge. Despite this, the entire population must abide by the same working hours, meaning that many people will be forced to get up before sunrise. This essentially means that people in one part of the time zone are constantly out of sync with their circadian clocks. And while this might not seem like such a big deal, it’s associated with a number of damaging consequences. People living at the western edges experience higher rates of breast cancer, obesity, diabetes, and heart disease—put down by researchers primarily to the chronic disruption of circadian rhythms that arises from having to wake up in the dark.

Another extreme example of social jet lag is experienced in Spain, which abides by central European time, despite being geographically in line with the UK. This means the country is shifted one hour forward, and that the population must follow a social schedule which is not in keeping with their biological timings. As a result, the whole country suffers from sleep deprivation—getting an hour less on average than the rest of Europe. This degree of sleep loss has been linked to increased absenteeism, stress, work-related accidents, and failure at school in the country.

Yet another population that may demonstrate symptoms similar that of a winter-addled populace, is a group that has a natural tendency towards night owlery throughout the year. The circadian clock of the average teen is naturally shifted up to four hours later than an adult, meaning that a teen’s biology pressures them to go to bed later and wake up later. Despite this, for years, they’ve been forced to struggle up at 7 am to get to school on time.

While these are more extreme examples, could the effects of slogging through winter with ill-adjusted work schedules be contributing to some similar, if milder, effects? This idea is supported in part by a theory about what causes SAD. While there are still a number of hypotheses about the exact biochemical basis of the condition, a sizable portion of researchers believe it could be due to a particularly severe response to the body clock being out of sync with natural daylight and the sleep-wake cycle—known as the phase-delay hypothesis.


Why are our circadian rhythms longer than 24 hours?

I've read that most people's circadian rhythms are slightly longer than 24 hours and has to regularly be "reset" by exposure to outdoor light. Why wouldn't our biologically rhythms be synced more closely to the 24 hour day? Is there any reason for this?

The short answer is we don't know exactly why that trait evolved, but it does have an effect on the alignment of circadian and sleep/wake cycles relative to the natural light/dark cycle.

The average human circadian period is about 24.15 hours, but differs slightly between individuals

First, as others have noted, the persistent idea that our intrinsic circadian period (i.e., the period we express in the absence of any time cues) is 25 hours is incorrect. This was shown to be incorrect about 20 years ago, yet maddeningly still appears in places like undergraduate psychology textbooks.

This number was obtained from experiments in which individuals lived in isolation from environmental time cues but were able to decide when to switch on/off the lights in their own living environment. This resulted in a feedback whereby light caused delays of the rhythm, effectively extending the period.

When all time cues and stimuli that affect the circadian clock are carefully removed, most humans express circadian rhythms within a small range around 24.15 hours. There are small individual differences in the circadian period. On average, females have slightly shorter periods, and on average the longer your circadian period the more your tendency towards going to bed later. While healthy individuals all tend to fall within a range of

24.7 hours, some studies have suggested that individuals with Delayed Sleep Phase Disorder can have longer periods (around 25 hours).

So long as your period is sufficiently close to your day-length, you can synchronize

Humans aren't unique in having a non-24-hour intrinsic circadian period. Some species have 24.5 hour periods on average, others have 23.5 hour periods on average. The important thing, from a functional perspective, is that the period is close enough to the day-length (24.0 hours in the case of Earth) to allow the circadian rhythm to be entrained (synchronized).

The circadian clock responds to certain environmental time cues, such as temperature and light. In humans, light is by far the most important factor in changing the timing of the clock. Our brain's master circadian clock is a group of cells in the hypothalamus called the suprachiasmatic nucleus, which lies just above the optic chiasm and receives inputs directly from the retina.

Depending on when in the circadian cycle you are exposed to light, the circadian clock responds differently. Light exposure early in the circadian day (i.e., in the hours around the time you would naturally awaken) advances the clock, or sets it forward. Light exposure in the late evening approaching bedtime and in the hours after bedtime delays the clock, or sets it backwards. This is partly why artificial light exposure at nighttime tends to cause people to have later circadian rhythms and more difficulty getting to bed early or waking up early (in addition, light exposure suppresses the nighttime release of the sleep-promoting hormone melatonin).

There is a maximum amount by which a block of daytime light can shift your circadian rhythm each day, which is around about 2 hours of advance or 3 hours of delay. This means an individual with an intrinsic circadian period of 24 hours could theoretically entrain to day lengths from about 22-27 hours, but in practice it would be extremely difficult and would require very carefully designed light exposure patterns towards either end of that range, due to the amount of resetting required.

As an example, this experiment attempted to entrain humans to a day length 1 hour longer than their intrinsic circadian period. Ordinary room light (100 lux) was sufficient to entrain the participants, but most failed to entrain using dimmer light (20 lux). Candlelight (1.5 lux) is sufficient to entrain most individuals to a 24.0 hour day, but not to a 23.5 hour day or a 24.6 hour (Mars) day.

The circadian period determines how the circadian rhythm is aligned with the natural light/dark cycle

The take-home message from the above is that if your circadian period is anywhere close to 24 hours (let's say about 23-25 hours), you're not going to have any difficulty entraining to the natural 24-hour light/dark cycle given a bright light source like the Sun. You might therefore say that close enough is good enough and there's no functional difference between a 23.8-hour period and a 24.2-hour period.

However, the difference is in where light exposure must occur in the cycle to achieve entrainment. An individual with a circadian period shorter than 24 hours needs more light exposure in their circadian evening than their circadian morning to achieve net phase delay each day. As a result, their circadian cycle will be aligned earlier relative to the natural light/dark cycle, so that more of the light exposure occurs relatively later in their circadian cycle.

Similarly, an individual with a period longer than 24 hours needs more light exposure in their circadian morning than their circadian evening to achieve net phase advance each day. As a result, their circadian cycle will be aligned later relative to the natural light/dark cycle, so that more of the light exposure occurs relatively earlier in their circadian cycle.

Your natural circadian period therefore has an important functional role in determining when you would naturally wake up and go to sleep relative to the natural light/dark cycle. Although, let's be clear that it's certainly not the only factor. For example, there is a tendency for humans (and many other mammalian species) to go to sleep later in adolescence. This may not be due to a significant lengthening of the circadian period, which seems to be quite stable across the lifespan, but rather to a change in the rate at which sleepiness builds up across the day.

If we look at different species, which each have different intrinsic circadian periods, they all occupy slightly different temporal niches. By this, I mean they are active during specific parts of the day, depending on a variety of ecological and biological factors, including how food availability varies throughout the day, how their predation risk varies throughout the day, and their own sensitivity to ambient temperature. One of the ways in which this timing difference is achieved is via differences in the circadian period.

We can therefore speculate that our period of

24.15 hours was selected due to it being in some way well-suited to our ancestral environment. People have also sometimes speculated that the natural variation in circadian period between individuals within a population ensures that different individuals are going to bed and waking up at slightly different times, allowing them to keep watch for the others, but again we're limited to speculation when it comes to determining why traits like this evolved.


Part 2: Clock Genes, Clock Cells and Clock Circuits Continued

00:00:07.28 So, in this second section,
00:00:10.10 what I'd like to do is to really
00:00:12.21 look in more detail
00:00:14.15 at the differences between
00:00:16.26 central and peripheral oscillators
00:00:20.16 using both genetic and non-genetic methods
00:00:25.17 of perturbing the circadian system.
00:00:28.02 So, one way that we have looked at this
00:00:31.22 is to go back and examine
00:00:34.25 some of what we would call
00:00:36.19 the classic mutants
00:00:39.05 of either Period or Cryptochrome,
00:00:42.09 which are shown here
00:00:44.11 for Cryptochrome 1 and 2.
00:00:45.29 These are loss of function or knockout mice,
00:00:49.04 and in this case what we found
00:00:51.20 is that if you delete Cry1,
00:00:54.11 the mouse still has a rhythm,
00:00:56.14 but it's one hour short.
00:00:58.22 If you delete Cry2,
00:01:00.23 the mouse still has a rhythm,
00:01:03.20 but in this case it's long.
00:01:08.12 And then if you delete both genes,
00:01:10.15 Cry1 and Cry2,
00:01:12.15 the mouse then loses its rhythm,
00:01:14.06 and this is really the reason that we called
00:01:19.02 Cry1 and Cry2
00:01:21.09 part of the central clock gene network.
00:01:23.06 And so Cry1 and 2 mice
00:01:26.10 have no rhythm they're arrhythmic.
00:01:28.25 And so what we've done is to then ask,
00:01:31.15 what are the effects of these mutations,
00:01:33.22 such as Cry1 and 2,
00:01:35.16 on the SCN clock and a peripheral clock,
00:01:40.16 in this case this example shows the lung.
00:01:44.02 And so this is using this PER::LUC imaging
00:01:48.10 in a wild type mouse
00:01:51.00 for the SCN and for lung,
00:01:53.23 and what you can see is
00:01:58.00 both tissues have very nice rhythms of PER::LUCIFERASE,
00:02:01.08 but if we knock out either Per1 or Cry1,
00:02:06.06 this leads to a strong reduction
00:02:10.06 in the rhythm in the lung,
00:02:12.28 but has very little effect
00:02:15.08 in the suprachiasmatic nucleus.
00:02:17.23 In the suprachiasmatic nucleus,
00:02:20.03 we have to do the double knockout,
00:02:21.14 as we did for behavior for Cry1 and Cry2.
00:02:24.14 This of course works in the lung as well,
00:02:27.21 but in peripheral tissues
00:02:30.26 we see a clear difference.
00:02:33.19 It's not just any Cry gene
00:02:35.20 that has this effect,
00:02:37.04 so for example Cry1
00:02:39.12 leads to this loss of rhythm phenotype,
00:02:41.05 shown here,
00:02:42.17 but Cry2 doesn't.
00:02:44.08 The same is true for Per1 and Per3.
00:02:47.02 So, there is clearly some difference
00:02:49.19 in the Per and Cry genes,
00:02:51.15 and some specificity in their role in the clock system.
00:02:56.24 So, to look into this further,
00:03:00.05 we then asked,
00:03:02.16 what effect do these mutations have
00:03:04.25 on single-cell rhythm?
00:03:07.19 So these are now single-cell recordings
00:03:09.29 from either fibroblasts or
00:03:14.18 dissociated, isolated SCN neurons.
00:03:17.10 Okay?
00:03:19.02 And what we find is a very interesting result,
00:03:21.15 and that is that the gene mutations Cry1 and Per1
00:03:26.10 have the same effect in a fibroblast
00:03:30.08 as they do in the SCN neuron,
00:03:33.13 and this is surprising because we thought before
00:03:36.05 that perhaps the SCN might be different,
00:03:38.09 it might be more robust.
00:03:40.17 And as you remember,
00:03:42.09 in the previous slide
00:03:44.11 I showed you that the SCN
00:03:46.04 was resistant to these mutations,
00:03:47.28 but that's because
00:03:50.14 in that experiment the SCN itself
00:03:54.07 was somewhat intact,
00:03:56.16 it was in an organotypic slice,
00:04:00.04 where the organization of the SCN it still intact,
00:04:04.04 as compared to
00:04:06.27 physically dissociated SCN neurons.
00:04:08.13 So, here's an experiment
00:04:12.16 in which the SCN in a slice
00:04:17.03 is compared to SCN dissociated neurons,
00:04:21.00 looking at the effect of the Cry2 knockout.
00:04:24.10 So, on the bottom are shown
00:04:26.23 heat map representations
00:04:28.12 of single-cell recordings from SCN neurons,
00:04:32.29 about 20 cells in each case,
00:04:34.28 and what you can see is in Cry2 knockout SCN neurons,
00:04:40.09 the cells are coherent and synchronized,
00:04:45.18 as indicated by the red and green stripes,
00:04:50.15 but in dissociated SCN neurons,
00:04:52.23 each of the cells can generate
00:04:54.22 intact circadian rhythms,
00:04:56.17 but they are no longer coupled,
00:04:58.16 and so the pattern becomes fragmented.
00:05:02.06 In contrast, in Cry1 knockout SCN neurons,
00:05:07.12 we see that in the intact SCN,
00:05:09.24 rhythms are generated and are coherent,
00:05:14.07 but when we dissociate the cells
00:05:16.17 the SCN cells can no longer
00:05:19.05 generate strong circadian rhythms,
00:05:21.14 and at the cell-autonomous level
00:05:23.13 the rhythms are disrupted.
00:05:25.13 So, these genetic experiments
00:05:27.20 have really uncovered
00:05:30.07 a new role for the suprachiasmatic nucleus,
00:05:35.28 and that is to be able to integrate the information
00:05:39.21 from many cells.
00:05:40.26 And so what we saw in these genetic experiments
00:05:45.25 is that the Cry1 mutation
00:05:48.14 could actually lead to a loss of rhythm
00:05:50.23 in the cell-autonomous level,
00:05:53.19 which was then reflected in peripheral tissues,
00:05:58.04 but in contrast the Cry2 neurons,
00:06:02.17 which have intact rhythms,
00:06:05.04 then did not have any effect
00:06:08.14 on peripheral tissues.
00:06:10.20 In contrast, in suprachiasmatic nucleus tissue,
00:06:14.18 we found a very interesting result,
00:06:17.10 where the cell-autonomous defect
00:06:20.07 can actually be rescued
00:06:22.25 by the SCN network.
00:06:24.10 Interestingly, because the SCN
00:06:26.29 then regulates circadian behavior,
00:06:29.26 we can see that at the behavioral level
00:06:33.21 the Cry1 mutant is also rescued.
00:06:38.27 And so I think these experiments
00:06:40.21 are important for a number of reasons.
00:06:42.07 One is that it shows that
00:06:47.00 circadian behavior is really
00:06:50.14 not a direct reflection of the cell-autonomous oscillator
00:06:55.26 information at the cell-autonomous level
00:06:57.18 can be transformed by the SCN network
00:07:01.20 to rescue that function,
00:07:04.22 which then in turn rescues circadian behavior.
00:07:08.17 On the other hand,
00:07:10.09 at another level,
00:07:11.21 if we were interested in the specific role
00:07:14.01 of, say, Cry1 or Cry2,
00:07:15.29 then trying to interpret
00:07:19.11 the role of Cry1 and Cry2
00:07:21.07 purely on the basis of behavior
00:07:23.19 might be misleading,
00:07:25.20 because we see this very
00:07:28.12 different cell-autonomous defect
00:07:30.16 at the level of Cry1 and Cry2.
00:07:33.07 And so if we're trying to understand
00:07:35.26 the biochemical function of Cry1,
00:07:38.08 then it might make more sense, for example,
00:07:43.00 to study the cell-autonomous clock,
00:07:45.08 rather than the SCN or behavioral clock.
00:07:50.26 So, going back to the organization
00:07:53.13 of circadian rhythms,
00:07:55.17 how is it that rhythms
00:07:58.16 are really synchronized and orchestrated
00:08:01.21 throughout the entire organism?
00:08:04.26 So, we know that the SCN
00:08:07.01 is really still in charge.
00:08:08.19 So for example,
00:08:10.01 in these experiments shown on the left.
00:08:12.10 these are records of control mice,
00:08:15.00 and then at the bottom
00:08:16.29 are records of SCN lesion mice.
00:08:19.26 What SCN lesion does
00:08:21.29 is to disrupt the behavioral rhythm,
00:08:25.17 and with PER::LUC recording of peripheral tissues,
00:08:28.29 we can then ask,
00:08:30.24 what is the effect of SCN lesioning
00:08:33.08 of the central clock
00:08:35.00 on peripheral rhythms?
00:08:36.26 And so shown here
00:08:40.27 are PER::LUCIFERASE tracings from the pituitary,
00:08:43.19 a peripheral oscillator,
00:08:46.28 and in intact mice
00:08:51.06 the pituitary gland rhythms
00:08:53.03 are actually very normal
00:08:56.11 in either light-dark cycles or in constant darkness.
00:09:01.06 But when we lesion the suprachiasmatic nucleus,
00:09:03.28 what we find is that
00:09:07.22 peripheral tissues become desynchronized,
00:09:11.14 so when we compare the peripheral rhythms
00:09:13.25 from different mice,
00:09:15.10 we see that they have adopted different phases.
00:09:18.07 Each mouse has a slightly different phase
00:09:21.22 for its pituitary and other peripheral tissues.
00:09:27.00 So, interestingly,
00:09:29.12 the SCN is not necessary for maintaining rhythms
00:09:32.23 in peripheral tissues,
00:09:34.12 but it plays a role
00:09:36.28 in synchronizing or coordinating those rhythms.
00:09:41.01 So, how is it that the SCN
00:09:44.14 really communicates this information?
00:09:47.20 So, we know that light
00:09:49.07 is one of the major
00:09:51.15 inputs to the brain and the SCN,
00:09:54.05 which then controls many behaviors,
00:09:56.18 such as feeding and sleep-wake cycles,
00:09:59.07 but recent work has also shown
00:10:01.24 a very important role for
00:10:05.08 nutritional cycles and signals,
00:10:07.08 as well as feeding behavior,
00:10:10.03 particularly for regulating peripheral tissues
00:10:14.16 such as the liver.
00:10:18.27 Now, to really address this,
00:10:22.05 we've gone back and examined
00:10:24.14 a second environmental signal,
00:10:26.09 and that is temperature.
00:10:28.08 So, in almost every organism
00:10:32.06 living in the free world,
00:10:34.26 light and temperature both synchronize clocks,
00:10:39.20 and temperature
00:10:42.22 is involved both in entrainment,
00:10:44.19 or synchronization of rhythms,
00:10:46.00 but there's also an interesting feature of rhythms
00:10:50.03 called temperature compensation,
00:10:51.23 and that is that the period of the rhythm
00:10:54.15 is resistant to dramatic changes in temperature,
00:10:59.06 so the period is actually compensated
00:11:02.07 against temperature fluctuations.
00:11:06.24 Now, mammals are actually a little bit unusual.
00:11:09.12 So, this is a record of a mouse,
00:11:11.16 it's a very long activity record,
00:11:14.20 and at the top the mouse
00:11:17.18 is in a constant temperature,
00:11:19.02 but it's exposed to a light cycle
00:11:20.13 which synchronizes its rhythm, shown here.
00:11:23.06 It goes into darkness at this point
00:11:25.02 and then, at the bottom of this record,
00:11:27.15 shown in the gray bar,
00:11:29.24 is a temperature cycle
00:11:32.20 of about 24-32°C,
00:11:37.06 and what you can see is that
00:11:39.15 this temperature cycle
00:11:42.12 can synchronize the rhythm transiently,
00:11:45.13 but it's not very strong,
00:11:47.01 so over time the activity rhythm
00:11:50.29 breaks away and free runs.
00:11:52.14 So, in mammals, temperature is
00:11:56.12 kind of a weak entraining signal
00:11:58.19 for circadian rhythms
00:12:00.26 at the whole-organismal level.
00:12:03.01 But interestingly, mice, as in humans,
00:12:07.14 have a very dramatic circadian body temperature rhythm,
00:12:10.23 and so this is a temperature recording
00:12:13.14 from a mouse over a ten day period,
00:12:16.16 and what you can see is the body temperature
00:12:19.02 fluctuates from about 36°C
00:12:21.18 at the lowest
00:12:23.08 to about 38.5°C at the peak,
00:12:25.25 each day.
00:12:27.25 And so Ethan Buhr asked,
00:12:31.13 can this subtle change in temperature, 2.5°C,
00:12:36.22 actually perturb or entrain
00:12:39.16 the phase of clocks in the periphery?
00:12:42.07 So, this is a PER::LUC recording
00:12:45.11 from liver tissue samples,
00:12:48.07 and at this point they were given
00:12:52.03 a temperature pulse of just 2.5°C
00:12:55.07 for six hours to the liver,
00:12:58.09 shown in the red trace,
00:13:00.09 and in the blue trace is another liver sample
00:13:04.00 that was handled the same,
00:13:05.26 but did not receive the temperature change,
00:13:08.24 and what you can see is, after this treatment,
00:13:12.07 the liver exposed to this temperature pulse
00:13:15.26 is delayed.
00:13:17.24 The phase is changed.
00:13:20.10 And if we do this experiment systematically,
00:13:23.04 we give a temperature pulse
00:13:26.05 at all times of the cycle,
00:13:28.02 shown on the x-axis of this graph.
00:13:30.26 this is a graph called a phase transition curve,
00:13:33.27 it plots the phase of the rhythm on the x-axis
00:13:38.26 and then the new phase of the rhythm on the y-axis.
00:13:43.01 Okay?
00:13:45.15 So, if you were to give
00:13:50.22 a stimulus that had no effect,
00:13:53.08 then the old phase and the new phase
00:13:56.07 would be the same,
00:13:58.19 and all the data points would lie on this 45° line,
00:14:03.20 where the blue points are.
00:14:05.06 Those are the handling controls.
00:14:07.26 You can see that they have no effect.
00:14:10.10 But temperature has a very strong resetting effect,
00:14:13.17 those data are shown in red dots.
00:14:15.26 They reset at almost any time of day
00:14:20.03 to a new set of phases,
00:14:22.27 okay?
00:14:24.00 And these data have a horizontal slope,
00:14:29.04 a slope of 0.
00:14:31.02 This is called strong resetting.
00:14:34.02 It's also called type 0 resetting,
00:14:36.08 because the slope is 0,
00:14:38.04 as opposed to type 1 resetting,
00:14:40.06 a slope of 1,
00:14:41.16 which is weak resetting.
00:14:43.10 So, temperature turns out to be
00:14:46.00 a very strong signal to peripheral clocks
00:14:49.28 such as those found in the liver.
00:14:53.04 And so, this is another set of experiments,
00:14:56.26 in this case, the pituitary gland.
00:15:00.11 The blue and red dots now
00:15:02.17 indicate different duration temperature pulses.
00:15:05.12 The blue dots are 1 hour temperature pulses
00:15:08.08 and the red dots are six hour temperature pulses,
00:15:11.01 as we saw before.
00:15:12.25 And as we can see here,
00:15:15.05 the pituitary shows strong resetting
00:15:18.15 the slope of these data are 0.
00:15:21.03 Okay?
00:15:22.08 But surprisingly,
00:15:24.06 when we look at the suprachiasmatic nucleus
00:15:26.29 in the same kind of conditions,
00:15:30.04 those data are all type 1,
00:15:34.04 or very weak resetting,
00:15:36.07 so the SCN is resistant
00:15:38.26 to temperature resetting pulses.
00:15:43.25 So, we then asked,
00:15:48.09 can the body temperature profile in a mouse
00:15:51.08 act to synchronize rhythms in peripheral tissues?
00:15:55.00 So, this shows you the average profile
00:15:58.25 measured from a mouse over one day,
00:16:03.28 and what Ethan Buhr then did
00:16:06.15 was to program this temperature profile
00:16:09.15 into an incubator
00:16:13.21 and expose different peripheral tissues
00:16:16.03 to these cycles.
00:16:17.15 So, the blue cycles
00:16:19.21 indicate one phase
00:16:21.18 and the red cycles indicate
00:16:23.20 a temperature cycle that's shifted
00:16:25.22 to the opposite phase.
00:16:27.27 And in these two examples shown here,
00:16:29.23 these are pituitary glands
00:16:31.25 that were exposed to three cycles
00:16:33.19 at these temperature cycles.
00:16:35.24 The red trace indicates
00:16:38.07 the phase of the pituitary rhythm
00:16:40.08 exposed to the red temperature cycles,
00:16:43.00 and the blue trace
00:16:44.29 indicates the phase of the rhythm
00:16:47.26 in a pituitary gland exposed
00:16:50.08 to the blue temperature cycles.
00:16:51.10 And what you can see is
00:16:53.29 the two sets of pituitaries
00:16:56.17 are out of phase,
00:16:58.20 and they match the phase of the temperature cycle.
00:17:01.03 That means that the temperature cycle
00:17:03.20 reset the phase,
00:17:05.25 within three days,
00:17:07.26 of both the pituitary gland and the lung,
00:17:10.24 in this case at that bottom.
00:17:13.01 So, the very subtle body temperature variation
00:17:16.19 in the mouse
00:17:18.13 is a very strong signal
00:17:20.07 and can completely reset the oscillators
00:17:23.06 in different organs.
00:17:25.07 Okay.
00:17:26.22 So, what I'd like to do now is
00:17:29.02 to go back to the SCN and ask,
00:17:31.09 why is it that the SCN
00:17:33.16 is different from a peripheral tissue?
00:17:36.24 Why is it resistant to temperature?
00:17:40.01 And as we saw in the case of
00:17:42.00 those genetic experiment before,
00:17:43.14 coupling in the SCN
00:17:46.13 might be an important factor.
00:17:48.25 And so we can use a drug
00:17:51.27 called tetrodotoxin, or TTX,
00:17:54.21 which blocks sodium-dependent action potentials
00:17:58.12 in the suprachiasmatic nucleus,
00:18:00.26 and can uncouple or desynchronize
00:18:03.21 the neurons in the SCN.
00:18:05.17 So, this panel on the left
00:18:08.10 shows single cell recordings of SCN neurons,
00:18:12.14 indicated in [red/green] heatmaps,
00:18:16.15 which were treated with tetrodotoxin,
00:18:18.28 and what happens is, at the single cell level,
00:18:21.09 those neurons start desynchronizing.
00:18:24.12 And when we give a temperature pulse,
00:18:26.13 incredibly,
00:18:28.22 now the SCN becomes sensitive to temperature.
00:18:31.11 So, at the top this is showing
00:18:34.18 SCN slices not treated with tetrodotoxin
00:18:37.21 -- they're resistant, they have type 1 resetting --
00:18:40.22 and at the bottom
00:18:43.01 are SCN slices treated with tetrodotoxin.
00:18:46.05 Just that single manipulation alone
00:18:48.13 then converts the temperature sensitivity
00:18:51.02 to type 0 resetting, or very strong resetting,
00:18:55.01 just like a peripheral tissue.
00:18:57.08 So, this suggests that it is really the coupling
00:19:00.09 within the SCN
00:19:02.15 that is making it more robust
00:19:04.11 and more resistant to temperature resetting,
00:19:06.22 and also making it different from a peripheral tissue.
00:19:12.23 Now, interestingly,
00:19:14.09 the SCN has two major subdivisions.
00:19:17.19 One is called the ventrolateral or VL
00:19:20.01 and the other is called dorsomedial (DM),
00:19:23.10 and you can do a very simple experiment
00:19:26.01 and transect the SCN
00:19:29.12 to separate the dorsal and ventral regions of the nucleus,
00:19:33.29 as shown here.
00:19:35.12 When you culture those two
00:19:38.05 halves of the SCN, they both have rhythms,
00:19:41.12 but incredibly they now have strong,
00:19:45.01 or type 0 resetting.
00:19:47.07 In contrast, if we were to cut the SCN
00:19:50.15 down the midline,
00:19:52.26 both the right and the left SCN, of course,
00:19:54.23 still have rhythms,
00:19:56.22 but in this case they remain robust,
00:20:00.29 or resistant to temperature.
00:20:03.22 So, this very simple experiment
00:20:05.21 suggests that there's a pathway
00:20:07.28 between the ventrolateral and dorsomedial SCN
00:20:11.05 that confers this kind of temperature resistance,
00:20:15.24 again suggesting that coupling
00:20:18.04 is actually important within the nucleus
00:20:21.02 to make it robust.
00:20:24.15 So, what is it that senses temperature?
00:20:27.20 And so, in experiments from Ueli Schibler's lab,
00:20:32.13 where they screened
00:20:35.07 different transcription factors in the liver
00:20:37.19 for circadian expression patterns,
00:20:40.09 one of the most robust transcription factors that they found
00:20:44.17 was HSF1.
00:20:46.15 So, this is a western blot
00:20:48.19 showing the amount of HSF protein
00:20:53.16 in the nucleus of liver cells
00:20:56.06 over the time of day,
00:20:57.20 and what you can see is that in the daytime
00:21:00.08 there's virtually no HSF in the nucleus,
00:21:02.29 and then at night HSF1 is very abundant,
00:21:06.25 so this leads to a very strong pattern of HSF1
00:21:10.21 in the nucleus of liver cells.
00:21:16.28 And so, to test
00:21:20.04 whether HSF1 might be involved
00:21:22.20 in temperature sensing for resetting the clock,
00:21:27.25 we used an inhibitor of HSF1 called KNK437.
00:21:34.01 This inhibitor can very strongly
00:21:37.01 block the heatshock response in cells.
00:21:40.23 This is the HSP72 response to temperature.
00:21:44.17 In the presence of drug,
00:21:46.20 this is very strongly blocked.
00:21:49.11 And when we apply this inhibitor for HSF1
00:21:53.15 to different peripheral tissues,
00:21:55.12 such as the lung,
00:21:57.11 as a pulse for one hour,
00:22:00.04 we find that it causes
00:22:02.04 very strong resetting of the clock,
00:22:05.26 but interestingly the phase of that resetting curve
00:22:09.21 is slightly different from what we saw with temperature.
00:22:12.26 So, in the gray
00:22:16.11 are shown the temperature pulses
00:22:18.17 that we saw before for temperature increases.
00:22:23.01 In light blue are shown
00:22:26.16 resetting curves for "cool" pulses,
00:22:30.21 a reduction in temperature.
00:22:33.23 This also shifts the clock very effectively
00:22:35.25 and, interestingly,
00:22:37.19 KNK and cool pulses
00:22:40.07 have the same kind of effect on the clock.
00:22:43.07 So this suggests that inhibition of HSF1
00:22:46.23 mimics a temperature reduction,
00:22:49.00 and this is consistent with the idea,
00:22:51.17 because temperature normally increases HSF1.
00:22:55.12 A lowering of temperature would reduce HSF1,
00:22:59.18 as would inhibition of HSF1.
00:23:02.09 And so we think that this is evidence
00:23:07.01 that HSF1, in part,
00:23:08.27 can mediate the effects of both
00:23:11.06 cool and warm pulses
00:23:14.06 in resetting peripheral tissues.
00:23:16.11 Now, does HSF1
00:23:20.05 mediate temperature pulses?
00:23:21.16 And we can ask that question
00:23:23.13 by doing a blocking experiment.
00:23:25.00 We can ask, if we block
00:23:27.07 the increase in HSF1 with KNK437,
00:23:31.08 will this block the temperature shift,
00:23:34.02 and so this is an experiment shown on the top here.
00:23:37.08 The gray bar shows the effect of temperature
00:23:40.21 using a vehicle control,
00:23:42.25 so temperature is giving a very large reset.
00:23:46.19 At this same phase,
00:23:48.23 we can give the drug alone,
00:23:50.05 it causes no shift at this phase,
00:23:52.19 and then the third condition
00:23:55.05 is the drug plus the temperature pulse,
00:23:56.17 and you can see that there's no shift,
00:23:59.01 showing that KNK can completely block
00:24:02.00 temperature resetting.
00:24:03.12 So this is very strong evidence that
00:24:05.23 HSF1 elevations
00:24:08.20 are required for temperature resetting
00:24:10.10 in peripheral tissues.
00:24:13.14 And we can also do this experiment
00:24:15.20 in a more complex manner
00:24:17.06 by testing all phases of the cycle,
00:24:19.16 and that's shown in these resetting curves.
00:24:23.14 And what's important to see in these curves
00:24:25.22 is the gray dots
00:24:27.26 show the effect of temperature by itself,
00:24:29.21 and then the orange and red dots
00:24:31.22 show the effect of either drug,
00:24:33.29 or drug plus temperature,
00:24:35.10 which are indistinguishable.
00:24:37.06 And this shows the drug is
00:24:40.03 blocking the effect of temperature
00:24:41.22 at all phases of the cycle.
00:24:44.00 This is of course in a peripheral tissue.
00:24:47.20 And then finally,
00:24:49.26 interestingly, the SCN,
00:24:51.13 which was resistant to temperature,
00:24:54.14 is also resistant to the inhibitor of HSF1, KNK
00:24:59.17 -- it has a type 1 resetting curve
00:25:02.04 to the drug --
00:25:04.01 further indicating that
00:25:07.13 this drug is working on the same pathway,
00:25:10.02 and that the SCN coupling network
00:25:13.02 can interfere with not only temperature pulses,
00:25:16.11 but also HSF1 interference.
00:25:21.27 Finally, the other feature of temperature
00:25:25.12 was this phenomenon that I mentioned before,
00:25:29.09 which is called temperature compensation.
00:25:33.07 And so this is an illustration
00:25:35.12 of temperature compensation in the SCN
00:25:37.06 and in the pituitary.
00:25:39.22 If you measure the period length
00:25:43.01 of the rhythm, shown here,
00:25:45.13 at different temperatures,
00:25:47.18 what we see is the period
00:25:50.20 is very similar.
00:25:51.25 And when we calculate the temperature coefficient,
00:25:54.14 or Q10,
00:25:56.03 we see that that coefficient is very close to 1
00:25:58.25 -- 0.97 in the case of pituitary
00:26:02.07 and 1.04 in the case of the SCN --
00:26:05.18 almost perfect temperature compensation.
00:26:09.10 But if we expose these tissues
00:26:12.14 to the HSF1 inhibitor, KNK437,
00:26:16.10 we see that the Q10s now
00:26:20.08 are taken out of the circadian range
00:26:21.23 and become much bigger,
00:26:23.16 and you can see the orange curves here
00:26:25.21 are kind of slanted.
00:26:28.03 Finally, in blue, in the SCN,
00:26:31.22 we can ask,
00:26:33.23 what is the effect of treatment
00:26:37.16 with tetrodotoxin
00:26:39.22 and uncoupling the network?
00:26:42.06 And what we find is that
00:26:44.18 the Q10 is still the same, 1.06.
00:26:47.28 So, this is a very interesting difference.
00:26:49.20 Temperature compensation of period
00:26:51.27 does not depend on the SCN network.
00:26:54.27 It is a cell-autonomous property,
00:26:57.02 not only of SCN cells,
00:26:59.28 but the pituitary, peripheral tissues, and fibroblasts.
00:27:03.09 But temperature resistance
00:27:06.22 is a network phenomenon
00:27:09.08 that's characteristic of the SCN
00:27:11.16 and not peripheral tissues.
00:27:15.03 Okay.
00:27:17.10 So this is kind of an overall summary
00:27:19.23 of our understanding
00:27:21.27 of the role of temperature
00:27:24.18 as a signal for resetting peripheral clocks.
00:27:28.00 The suprachiasmatic nucleus
00:27:30.08 generates a circadian rhythm of body temperature,
00:27:34.28 this signal is propagated throughout the organism,
00:27:39.23 and can be used by
00:27:41.25 many different peripheral clocks,
00:27:44.00 and we believe that in these peripheral clocks
00:27:46.29 HSF1 is one of the signaling pathways
00:27:50.25 for mediating this temperature information
00:27:53.05 to reset those clocks.
00:27:56.04 Now, the SCN itself
00:27:58.22 is resistant to this body temperature signal
00:28:02.15 and in retrospect that kind of makes sense.
00:28:05.01 If the SCN is setting out a resetting signal,
00:28:10.01 then it might not be a good idea
00:28:12.15 for it to be sensitive
00:28:14.01 to its own resetting signal.
00:28:15.12 That might cause some kind of feedback problems.
00:28:19.01 And so we think that that could be the reason,
00:28:22.06 or one of the reasons,
00:28:24.12 that the SCN is really resistant to temperature,
00:28:27.09 because it wouldn't make sense
00:28:30.10 to be paying attention to its own signal
00:28:33.14 that it's trying to propagate out.
00:28:36.10 So, I've tried to give you
00:28:40.27 a sort of an introduction to clock genes,
00:28:44.13 clock cells,
00:28:46.02 and clock circuits
00:28:48.19 in the circadian system,
00:28:50.24 and I think in the field of neuroscience
00:28:55.07 we're really at a very exciting time today,
00:28:58.25 because the tools of both genetics and genomics
00:29:02.11 are really enabling us
00:29:05.07 to understand how
00:29:08.01 behavior and physiology are really regulated.
00:29:10.14 And we can very easily
00:29:14.28 go all the way from genes,
00:29:17.03 cells, circuits, to behavior,
00:29:19.27 in the circadian system,
00:29:22.28 where we have,
00:29:24.15 correspondingly at these many levels of organization,
00:29:26.19 clock genes, clock cells, clock circuits
00:29:29.19 in the SCN,
00:29:31.21 which then can regulate both physiology and behavior.
00:29:35.01 And it's a very exciting time
00:29:37.24 because both normal behavior
00:29:40.06 as well as pathological conditions
00:29:43.10 might be regulated by this system.
00:29:47.11 So, I'd like to end here
00:29:49.07 and acknowledge all of my colleagues
00:29:51.24 over the many years
00:29:53.26 who contributed to all of this work.
00:29:55.21 Thank you very much.


Science of Awakening

Andries Kalsbeek , . Eric Fliers , in International Review of Neurobiology , 2010

Awakening from sleep is a clear example of an event for which (biological) clocks are of great importance. We will review some major pathways the mammalian biological clock uses to ensure an efficient and coordinated wake-up process. First we show how this clock enforces daily rhythmicity onto the hypothalamo-pituitary-adrenal (HPA) axis, via projections to neuroendocrine neurons within the hypothalamus. Next we demonstrate how this brain clock controls plasma glucose concentrations, via projections to sympathetic and parasympathetic pre-autonomic neurons within the hypothalamus. Orexin neurons in the lateral hypothalamus appear to be an important hub in this awakening control network.



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