Category Archives: Chronobiology

Circadian Rhythms, or Not, in Arctic Reindeer

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Circadian Rhythms, or Not, in Arctic ReindeerA January 20, 2006 post placing a cool physiological/behavioral study into an evolutionary context.

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Another Clock Gene

Considering that circadian clocks were first discovered in plants, and studied almost exclusively in plants for almost a century before people started looking at animals in the early 20th century, it is somewhat surprising that the molecular aspects of the circadian rhythm generation mechanisms have lagged behind those in insects, vertebrates, fungi and bacteria. It is always nice to see a paper reporting a discovery of a new plant clock gene:
New function for protein links plant s circadian rhythm to its light-detection mechanism:

Plants set their clocks by detecting the light cycle, and Chua’s lab found that an accessory protein, called SPA1, is important for keeping the internal clock set. When they bred Arabidopsis plants with a mutated SPA1 protein, the plants flowered early, producing shoots and flowers weeks ahead of wild-type plants.
“The regulation of flowering initiation in response to the length of the day is mediated by the interaction of light with the plant s circadian clock system,” says Chua. Plants detect light with proteins called phytochromes and cryptochromes. SPA1 regulates one of these phytochromes, called PhyA.
The PhyA protein links light detection with the circadian clock system and directly influences when a plant flowers. But Chua’s finding suggests that SPA1 normally represses PhyA function, holding the plant back from flowering until the right time. “We knew that SPA1 negatively regulated PhyA immediately after germination, but didn t know if it played a role in the adult,” says Chua. “Our results show that SPA1 is important in the adult for regulating PhyA and the circadian period. When SPA1 is mutated, the plants precociously flower, affecting their entire reproductive cycle.”

It’s not the quantity, but timing

Study says no video games on school nights:

According to Dr. Iman Sharif, the results were clear-cut. “On weekdays, the more they watched, the worse they did,” said Dr. Sharif. Weekends were another matter, with gaming and TV watching habits showing little or no effect on academic performance, as long as the kids spent no more than four hours per day in front of the console or TV. “They could watch a lot on weekends, and it didn’t seem to correlate with doing worse in school,” noted Dr. Sharif.

The study was using self-reporting by kids, which has its problems, but is OK in this case, I think. The key information they did not gather was the timing of game-playing and TV watching.
On schooldays, the only time they can do this is late in the evening, after homework and dinner and sports and everything else have been done. Exposure to light from the screens, as well as the emotional involvement (perhaps raised adrenaline?) phase-delays the kids’ already delayed circadian clocks. Instead of getting 9 hours of sleep, they get 5 or 6. Of course they perform miserably at school and the athletic field, feel lousy and misbehave – they are chronically sleep-deprived.
On weekends, kids are likely to play and watch in the morning or early afternoon, which does not affect the phase of their sleep-wake cycle.
I let my kids play games first thing when they come home from school. They do homework later – it gradually puts them to sleep so they are not sleep deprived.
Hat-tip: Ed Cone.

Diversity of insect circadian clocks – the story of the Monarch butterfly

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Diversity of insect circadian clocks - the story of the Monarch butterflyFrom January 20, 2006, on the need to check the model-derived findings in non-model organisms.

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How Period and Timeless Interact in Fruitflies

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How Period and Timeless Interact in FruitfliesA very cool study that I could not help but comment on (January 18, 2006)…

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Alternative sleep therapies

Over 1.6 Million Americans Use Alternative Medicine For Insomnia Or Trouble Sleeping:

A recent analysis of national survey data reveals that over 1.6 million American adults use some form of complementary and alternative medicine (CAM) to treat insomnia or trouble sleeping according to scientists at the National Center for Complementary and Alternative Medicine (NCCAM), part of the National Institutes of Health.
———–snip——————
Those using CAM to treat insomnia or trouble sleeping were more likely to use biologically based therapies (nearly 65 percent), such as herbal therapies, or mind-body therapies (more than 39 percent), such as relaxation techniques. A majority of people who used herbal or relaxation therapies for their insomnia reported that they were helpful. The two most common reasons people gave for using CAM to treat insomnia were they thought it would be interesting to try (nearly 67 percent) and they thought CAM combined with a conventional treatment would be helpful (nearly 64 percent).

I don’t really know what to think. On one hand, someone is making a lot of money on this. On the other hand, placebo effect may be quite effective for relaxing a person enough to fall asleep. Meditation certainly will help a person relax – it is so boring you have to fall asleep after a while. And who knows, one of those therapies may actually have some effectiveness after all – we don’t know because it was never tested. On the other hand, many herbal remedies, because they are never tested and approved, may contain some nasty chemicals that can kill you. Such deadly molecules were discovered in some brands of melatonin a few years back. So, they are not safe even if they are effective. I’d like to see Orac and Abel comment on this.

In addition to looking at the data on CAM use and insomnia, the researchers also looked at the connection between trouble sleeping and five significant health conditions: diabetes, hypertension, congestive heart failure, anxiety and depression, and obesity. They found that insomnia or trouble sleeping is highly associated with four of the five conditions: hypertension, congestive heart failure, anxiety and depression, and obesity.

All of those connecitons have been seen before and some of those have been studied in quite a lot of detail. Unfortunately, there appears to be a vicious cycle – these conditions negatively affect sleep and lack of sleep negatively affects these conditions.

News on familial advanced sleep phase syndrome

So, is extreme “larkiness” due to overphosphorilation or underphosphorilation of PERIOD2?
Hypotheses get tested, studies conflict with each other and, in the end, there is a resolution. In this case, we are still waiting for resolution. Science marches on.

Influence of Light Cycle on Dominance Status and Aggression in Crayfish

Influence of Light Cycle on Dominance Status and Aggression in CrayfishIn this post from April 06, 2006, I present some unpublished data that you may find interesting.

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Sleep Deprivation in the classroom, in the cockpit and on the space shuttle

Students not getting enough sleep:

College students may believe they are being more productive when they sleep less, but in reality it is causing harm to their bodies. The National Sleep Foundation points out that receiving less than six hours of sleep a night is associated with 1.7 times greater risk of disease, according to http://www.sleepfoundation.org. The chance of decreased academic performance, driving accidents, colds and flu and mental illnesses are all increased.

Workplace fatigue risky business at 30,000 ft.:

Fatigue is worsened when lack of sleep is coupled with a disruption to the body’s circadian rhythm, which regulates high and low energy periods throughout the day – common among flight and ground crews as well as controllers.
And it’s also magnified by jetlag. One U.S. sleep researcher estimates 96 per cent of airline pilots and flight attendants operate in a permanent state of jetlag.

Solar wings unfurl on Atlantis orbit:

“On our mission, with where the sun is, we have 55 minutes of daylight followed by 75 minutes of darkness … and that does affect your circadian rhythm,” MacLean replied.

Are cryptochromes involved in magnetoreception in migratory birds?

Scientists discover molecule behind birds’ magnetic sense:

“Some birds, notably migratory species, are able to detect the Earth’s magnetic field and use it to navigate. New results from a team of Franco-German researchers suggest that light-sensitive molecules called cryptochromes could be the key to the birds’ magnetic sense.

They did not suggest it – they tested a 10-year old hypothesis.

Cryptochromes are photoreceptors which are sensitive to blue light, and they are involved in a number of processes linked to the circadian cycle, such as growth and development.

Caution: cryptochromes have different functions in different organisms. They are very closely related to photolyases, molecules involved in DNA repair. They are photopigments in plants, but have no circadian function in them. They are involved in circadian phototransduction in insects, but are not pigments and are not clock genes in them. They are core circadian genes in vertebrates, but are not pigments in them. So, we have to be careful when dealing with such a jack-of-all-trades.

Birds’ ability to detect magnetic fields is affected by light; this ‘sixth sense’ only works properly in the presence of blue or green light, while light of other wavelengths disrupts the magnetic sense.

Do you know how much I hate the phrase “sixth sense’?

The scientists realised that the cryptochromes could well be involved in the perception of the magnetic field, as they have all the physical and chemical properties needed, notably the absorption of blue and green light and the formation of ‘radical pairs’ – molecules which respond to magnetic fields. Crucially, the retina of birds’ eyes is rich in cryptochromes.
Unable to test their hypothesis on migratory birds, the researchers turned to a laboratory plant, Arabidopsis thaliana, with similar properties. It is known that the activation of their cryptochromes by blue light influences the behaviour of these plants; for example it inhibits the growth of the hypocotyle (stem).

This is creative, but poses a problem that I mentioned above – in different environments (i.e. inside the bodies of different organisms with different genomes), cryptochromes assume different functions.

To determine whether the magnetic field influences the function of the cryptochromes, researchers from France’s National Centre for Scientific Research (CNRS) and universities in Frankfurt and Marbourg grew the plants in the presence of blue and red light and magnetic fields of varying strengths. They found that increasing the magnetic field only increases the inhibition of the growth of the hypocotyle in the presence of blue light. When red light is used, the plant uses other photoreceptors called phytochromes, and the growth of the hypocotyle is not affected by changes in the magnetic field. Furthermore, mutant plants which have no cryptochromes are also insensitive to changes in the magnetic field.

This is a nice piece in the puzzle, but nothing conclusive yet, of course.

The study shows for the first time that in plants, the work of the cryptochromes is affected by magnetic fields and suggests that the mechanisms of magnetic field perception in plants, and by extension in migratory birds, use the same photosensitive molecules. The researchers also suggest that, as cryptochromes have been strongly conserved throughout evolution, all biological organisms could have the ability to detect magnetic fields, even if they do not use them.”

The phrase “and by extension” worries me for the reasons I noted above.
As for all organisms detecting magnetic fields – yes, decades of research show that most can, from bacteria to, perhaps, even humans. However, this does not mean that cryptochromes are the magnetosensory molecules in all of them, or even that the radical-pair model of magnetoreception applies to all organisms.
It is well established that many organisms do not require the presence of blue-green light in order to orient by he magnetic fields. It is also known that many organisms, from bacteria through salmon to pigeons, possess miniscule crystals of feromagnetite. In bacteria, those form a chain running through the posterior medial line of the cell. In salmon and pigeons, they are embedded inside cell membranes of the dendrites of the trigeminal nerve.
So, cryptochromes may be involved in some way in magnetic sense of some organisms. Extrapolating any broader (i.e., it is the only mechanism; cryptochromes are the main element of the mechanism; this mechanism works in all organisms) is unlikely to be correct. So, the press release is hypoing the work beyond what it really shows. It is good. Actually, it is really cool. But the press release soured me on it.
For an excellent (and quite current) review of the topic, see this review (pdf) and for a moer lay-audience oriented, also quite current article, see this article on The Science Creative Quarterly.

When Should Schools Start in the morning?

When Should Schools Start in the morning?The fourth part of a four-part series on the topic, this one from April 02, 2006….

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More on sleep in adolescents

More on sleep in adolescentsThis is the third part of the series on the topic, from April 01, 2006…

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ClockNews – Adolescent Sleep

ClockNews - Adolescent Sleep
Here is the second post on the topic, from March 28, 2006. A couple of links are broken due to medieval understanding of permalinks by newspapers, but you will not miss too much, I hope….

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Sleep Schedules in Adolescents

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Sleep Schedules in AdolescentsEarlier this year, during the National Sleep Awareness Week, I wrote a series of posts about the changes in sleep schedules in adolescents. Over the next 3-4 hours, I will repost them all, starting with this one from March 26, 2006. Also check my more recent posts on the subject here and here…

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Adolescent Sleep Schedule

This kind of ignorant bleating makes me froth at the mouth every time – I guess it is because this is my own blogging “turf”.
One of the recurring themes of my blog is the disdain I have for people who equate sleep with laziness out of their Puritan core of understanding of the world, their “work ethic” which is a smokescreen for power-play, their vicious disrespect for everyone who is not like them, and the nasty feeling of superiority they have towards the teenagers just because they are older, bigger, stronger and more powerful than the kids. Not to forget the idiotic notions that kids need to be “hardened”, or that, just because they managed to survive some hardships when they were teens, all the future generations have to be sentenced to the same types of hardships, just to make it even. This is bullying behavior, and disregarding and/or twisting science in the search for personal triumphalism irks me to no end.

I hated getting up early, too. I still hate it, and I’m so far beyond growth hormones that I don’t even remember how they felt. But I do remember that in middle and high school, I dragged myself out of the house at 5 a.m. every day of the week to deliver papers before I caught the 6:45 a.m. bus to school. I never fell asleep in class. Neither did anybody else. And something caused me to grow 6 inches and add 35 pounds between sophomore and junior year. At the end of that kind of day, complete with cross-country, basketball or track, I had no trouble falling asleep at 10 p.m.

He said that he grew up in height and weight when he was in high school. Who knows how much more he would have grown if he was not so sleep deprived (if his self-congatulatory stories are to be believed and he did not slack off every chance he had). Perhaps he would not grow up to be so grouchy and mean-spirited if he had a more normal adolescence.
I don’t know where he got the idea that growth hormone is a cause of the phase-delay of circadian rhythms in adolescence. It could be, but it is unlikely – we just don’t know yet. But, if a hormone is a cause, than it is much more likely to be sex steroids. Perhaps his sleep-deprived and testosterone-deprived youth turned him into a sissy with male anxiety he channels into lashing at those weaker than him?

In previous centuries, adolescents in an agrarian society got up at 4:30 or 5 a.m. with their parents to milk the cows or do any other of a long list of chores. Did growth hormones pass them by? Where were the “studies” that showed they really needed to go to bed after midnight and sleep until 10? And why weren’t their parents all being reported to the DSS? Oh, that’s right, there was no DSS. How did that generation survive?

He assumes that in times before electricity, teenagers used to wake up and fall asleep at the same time adults did. Well, they did not. Studies of sleep patterns in primitive tribes show that adolescents are the last ones to wake up (and nobody bashes them for it – it is the New Primitives with access to media that do that) and the last ones to fall asleep – they serve as first-shift sentries during the night watch.

Even in this, the 21st century, kids who enter the military at 17 find that they can fall asleep easily at 9:30 or 10, because they know they’re going to be getting up at 4:30 or 5. Apparently the Army hasn’t read the study on circadian rhythms.

Actually, the military being the most worried by this problem is funding a lot of research on circadian rhythms and sleep and has been for decades. Because they know, first hand, how big a problem it is and that yelling sargeants do not make alert soldiers.

Kids, if you need more sleep, my study shows there’s a simple way to get it. Turn off – I mean “power down” – the cell phone, the iPod and the computer sometime before 11 p.m. Turn off the TV. Turn off the light. Lie down in bed and close your eyes.

…and sit in the dark for the next four hours, heh?
This being the beginning of the school year, I can expect to see more of such nonsense printed in the MSM and on blogs soon, so I may repost (tomorrow) some of the stuff I have already written against the societal equation of sleep with laziness in general, as well as specifically concerning adolescents (see this, this, this, this and this, for instance).
What especially drives me crazy is that so many teachers, people who work with adolescents every day, succumb to this indulgence in personal power over the children. It is easier to get into a self-righteous ‘high’ than to study the science and do something about the problem. It is easier to blame the kids than to admit personal impotence and try to do something about it by studying the issue.
I am also currently reading a very good National Academies Press book on the topic of sleep in teenagers which I intend to review soon, as well as use as a source for future rants on the topic.
Addendum: Alon Levy extends this discussion to the general issue of ageism as a conservative way to supress change by supressing the habringers of change – the next generation. Excellent read.
I’d like to go in a slightly different direction – the issue of Moral Order (scroll down to the “Adults Over Children” subheading). Of course, adults have moral authority over children. But what it means, i.e., how is this phrase understood and put to practice, differs between authoritarian/conservative and authoritative/liberal worldviews.
A conservative thinks about his child: “I am good and you are bad. I will beat the sh**t out of you for every little transgression and I hope that will teach you well. Learn to love the rod, because the discipline I am giving out today will turn into your self-discipline later. Once you are 18, get the hell out of my house – by that time you should be as moral as I am now.”
That is the recipe for the development of the External Locus of Moral Authority.
A liberal thinks about his child: “I am older, thus more educated, experienced and mature than you are. You are a good child and have a potential to become a deeply moral person. I am here to help you and guide you in solving day-to-day moral dilemmas so, by the time you are an adult, you will naturally strive to do good and behave ethically.”
That is the recipe for the development of the Internal Locus of Moral Authority.

It’s not just the amount of rest, but also the timing of rest

Do pilots get enough rest?:

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The federal rules on pilot duty hours and rest periods aren’t the most comprehensible of reads.
One rule allows airlines to schedule pilots to fly for eight hours or less during a 24-hour period without a “rest period during those eight hours.” Another gives pilots who fly for more than eight hours in a 24-hour stretch a break of at least twice the number of hours flown, either “at or before the end of” the eight hours. Pilots who fly more than eight hours during a 24-hour period must receive 18 hours of rest before being assigned any other duties.
“Those rules underwent a modest updating in 1988,” Mazor said. “Then there was a proposal 10 years ago that was far from satisfactory to begin with, and we haven’t even gotten that.”
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Mark Rosekind, a psychologist and president of Alertness Solutions in Cupertino, Calif., took part in that 1995 effort to rewrite the FAA flight crew duty and rest rules. At the time, he was a principal investigator with NASA’s Fatigue Countermeasures Program. Today, in addition to running his consulting company, he teaches a course on sleep, fatigue and circadian factors – the internal “clock” that affects numerous body functions – for the NTSB Academy in Ashburn, Va.
“Current FAA regulations were written in 1937 and have not been rewritten in any dramatic way since,” Rosekind said. “In 1937, jets didn’t exist. Today we have airplanes that have more range, travel into more time zones and do more short-haul routes. The regulations don’t reflect the industry today or changes in the science of sleep and circadian rhythms in 50 years.”
The FAA’s 1995 proposal called for a decrease in consecutive duty hours – which includes duties on the ground – from 16 to 14 hours, but an increase in maximum flying time to 10 hours during that 14-hour span. An FAA spokeswoman said the proposed rules drew more than 2,000 comments, mostly in opposition.
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Clocks in Bacteria V: How about E.coli?

Clocks in Bacteria V: How about E.coli?Fifth in the five-part series on clocks in bacteria, covering more politics than biology (from May 17, 2006):

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Clocks in Bacteria IV: Clocks in other bacteria

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Clocks in Bacteria IV: Clocks in other bacteriaFourth in the five-part series on clocks in bacteria (from April 30, 2006):

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Clocks in Bacteria III: Evolution of Clocks in Cyanobacteria

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Clocks in Bacteria III: Evolution of Clocks in CyanobacteriaThe third installment in the five-part series on clocks in bacteria (from April 19, 2006):

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Clocks in Bacteria II: Adaptive Function of Clocks in Cyanobacteria

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Clocks in Bacteria II: Adaptive Function of Clocks in CyanobacteriaSecond post in a series of five (from April 05, 2006):

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Some hypotheses about a possible connection between malaria and jet-lag

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Some hypotheses about a possible connection between malaria and jet-lagHypotheses leading to more hypotheses (from March 19, 2006 – the Malaria Day):

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Clocks in Bacteria I: Synechococcus elongatus

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Clocks in Bacteria I: Synechococcus elongatus
First in a series of five posts on clocks in bacteria (from March 08, 2006)…

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Circadian Clocks in Microorganisms

Circadian Clocks in MicroorganismsThe first in a series of posts on circadian clocks in microorganisms (from February 23, 2006)…

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Biological Effects of the Moon

I rarely write about biological rhythms outside of circadian range (e.g., circannual, circalunar, circatidal rhythms etc.), but if you liked this post on lunar rhythms in antlions, you will probably also like this little review of lunar rhythms in today’s Nature:
Pull of the Moon:

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Studies of fiddler crabs, for example, have shown that even when kept in the lab under constant light and temperature, the animals are still most active at the times that the tide would be out. A similar internal ‘circalunar’ clock is thought to tick inside many animals, running in synchrony with the Moon and tides, and working in conjunction with the animal’s 24-hour circadian clock. This is thought to help animals anticipate tide movements; a skill that might give some creatures an edge. Ecologist Martin Wikelski of Princeton University, New Jersey, has found for example, that Galapagos marine iguanas with the most accurate circalunar clock are more likely to survive tough times, presumably because they are best at reaching feeding spots first.
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Moonlight can also change animal behaviour. Many marine organisms move up and down in the sea depending on the level of moonlight in order to keep their light levels constant. On land, some nocturnal animals come out on a well-lit night to hunt, others stay hidden to avoid predators.
And African dung beetles, oddly, can walk in a straighter line when the Moon is out: Eric Warrant at the University at the University of Lund, Sweden, and his colleagues reported in 2003 that Scarabaeus zambesianus can detect the pattern of polarized moonlight in the night sky and use it to navigate2. This means they can roll their dung balls in a straight line on a moonlit night.
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And yeah, for the anthropocentric readers, the article has a bunch on humans as well….

Clock News

Melatonin improves mood in winter depression:

Alfred Lewy and his colleagues in the OHSU Sleep and Mood Disorders Lab set out to test the hypothesis that circadian physiological rhythms become misaligned with the sleep/wake cycle during the short days of winter, causing some people to become depressed.
Usually these rhythms track to the later dawn in winter, resulting in a circadian phase delay with respect to sleep similar to what happens flying westward. Some people appear to be tracking to the earlier dusk of winter, causing a similar amount of misalignment but in the phase-advance direction. Symptom severity in patients with seasonal affective disorder correlated with the misalignment in either direction.

Model of Internal Clocks Reveals How Jet Lag Disrupts the System:

Recent research suggests that every cell in the body actually has its own clock–liver cells prepare for digestion at particular times of day; patterns of hormone production and brain activity exhibit cyclic peaks and valleys, says Siegelmann.
“The circadian system is really fundamental, it affects our behavior, our physiology and emotions,” she says. “The clock organizes the whole body into a very nice dance, and it organizes people together into a larger social orchestra.”
The so-called “local clocks” have natural circadian cycles that range from 21 to 26 hours, says Siegelmann. They are synchronized by the SCN, but the pathways and mechanisms by which this coordination happens aren’t fully understood. Evidence has recently emerged that the SCN itself is compartmentalized. One clump of cells responds to and processes information about light, they then alert an intermediate group of cells that transmit the information to more peripheral components.
This hierarchy within the circadian system introduces a time-delay in getting the entire body adjusted to a new environment, suggests Siegelmann. The delay is based, in part, on the strength of the connections between the different parts of the SCN, between the SCN and the peripheral clocks, and on the differing rhythms of the local clocks, she says.
To explore the dynamics of the system and how it responds to disruption Siegelmann and Leise designed a model with parameters reflecting this hierarchical nature. The model accounts for the SCN’s light-responsive component, its intermediate component, and the various peripheral components. It incorporates behavioral data, physiological data and what’s known about differences in natural circadian rhythms in the peripheral tissues. In rats, for example, internal organs such as the liver and lungs take a relatively long time to become synchronized with the SCN.
Simulations of the model revealed certain properties about both the stability and adaptability of the system, Siegelmann says. The light sensitive compartment of the master clock responds quickly, providing flexibility, whereas the intermediate compartment of the SCN seems to act as a buffer against small perturbations in the cycle.
The simulations suggest that the system gets most out of whack when the master clock is shifted forward between five and eight hours. After such a large leap, it appears that the master clock actually overshoots the desired time. Then, following a slight delay, the intermediate component and some of the peripheral components overshoot as well, depending on their inherent circadian time and their connectivity with the master clock. For example, the peripheral components that already tend to lag actually try to catch up by backtracking, achieving a leap forward of six hours by delaying themselves 18 hours.

The Clock Metaphor

Chad wrote a neat history of (or should we say ‘evolution of’) clocks, as in “timekeeping instruments”. He points out the biological clocks are “…sort of messy application, from the standpoint of physics…” and he is right – for us biologists, messier the better. We wallow in mess, cherish ambiguity and relish in complexity. Anyway, he is talking about real clocks – things made by people to keep time. And he starts with a simple definition of what a clock is:

In order to really discuss the physics of timekeeping, you need to strip the idea of a clock down to the absolute bare essentials. At its core, a clock really has only one defining characteristic: A clock is a thing that ticks.
OK, I’m using a fairly broad definition of “tick,” here, but if you’ll grant that leeway, “ticking” is the essential property of clocks. In this context, “ticking” just refers to some regular, repetitive behavior that takes place in a periodic fashion.

This reminds me that a “biological clock” is a metaphor. A useful metaphor, but a metaphor nonetheless (and just like metaphors of cellular machinery are taken literally by Creationists, they have been known on occasion to talk about circadian clocks as if they had real wheels and cogs and gears!).
I want to stress that the clock metaphor has been very useful for the study of biological rhythms. Without Pittendrigh’s insight that cycles in nature can be modeled with the math of physical oscillators, we would be probably decades behind (unless someone else of authority in the field at the time had the same insight back then) in our understanding of the underlying biology. Just check how useful it was in the entire conceptualization of entrainment and photoperiodism. The Phase-Response Curve, based on the math of physical oscillators, is the Number One tool in the chronobiological repertoire.
But, just as most people in the field take the clock metaphor for granted and without much thinking, there have been a few people who questioned its utility for some areas of research. For instance, for the study of biological rhythms in nature within an ecological and evolutionary context, Jim Enright proposed a metaphor of an audio-tape set on continuous play (Enright, J.T. (1975). The circadian tape recorder and its entrainment. In Physiological Adaptation to the Environment (ed. F.J.Vernberg), pp. 465-476. Intext Educational Publishers, Ney York.). Only a dozen or so publications since then took him seriously and tried to apply this concept. Today, in the age of CDs and iPods, who even remembers audio tapes?
While fully utilizing the utility of the clock metaphor and applying it myself in my own work, I was always cautious about it. Aware that it is a metaphor, I always wondered if it constrains the way we think about the biological process and if we may miss important insights by not thinking in terms of other possible metaphors.
While far from mature, my thinking is that different metaphors apply best to different areas of research and different questions. While the clock metaphor is great for understanding the entrainment of the circadian system (including whole organism, tissues and individual cells) and photoperiodism, and Enright’s endless tape (or some modern substitute) may be useful for ecological studies (including temporal learning and memory), other angles of study may require other concepts.
For instance, I think that the study of what goes inside the cell can benefit from a different metaphor. Studying the molecular basis of circadian rhythms may best be done by utilizing a Rube-Goldberg Machine metaphor: event A triggers event B which starts process C which results in event D….and so on until the event Z causes the event A to happen again. If that last step is missing, it is not a circadian rhythm – it is more akin to an hourglass clock in which something outside of the system needs to start the process all over again.
For studying the outputs, i.e., how the circadian system orchestrates timing of all the other processes in the body, the metaphor may have to fit the organism. An ON-OFF switch is the best metaphorical description of the clock system in (Cyano)bacteria, where there are only two states of the system: the day state and the night state. For something a little bit more eukaryotic, a relay may be a better metaphor (more than two, but not too many states). The metaphor of a rod in car engines (how are those called in English and do modern cars even have those any more?) that times the opening and closing of cylinders would be fine for fungi and plants and perhaps some invertebrates.
But I had a hard time coming up with a decent metaphor that could apply to complex animals, like us. So far, the best I could come up with is the barrel of a Player Piano. Many little knobs on its surface determine when each note will be played. If you make the barrel rotate slowly and the song lasts 24 hours, then outputs from circadian pacemakers are knobs and the target organs (and peripheral oscillators in them) are those long prongs that make music. Can you think of a better metaphor?

Lithium, Circadian Clocks and Bipolar Disorder

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Lithium, Circadian Clocks and Bipolar DisorderYou probably realize by now that my expertise is in clocks and calendars of birds, but blogging audience forces me to occasionally look into human clocks from a medical perspective. Reprinted below the fold are three old Circadiana posts about the connection between circadian clocks and the bipolar disorder, the third one being the longest and most involved. Here are the links to the original posts if you want to check the comments (especially the first comment on the third post):
January 18, 2005: Clocks and Bipolar Disorder
August 16, 2005: Bipolar? Avoid night shift
February 19, 2006: Lithium, Circadian Clocks and Bipolar Disorder

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Another time-scale in insect brains

Bumble Bees Can Estimate Time Intervals:

In a finding that broadens our understanding of time perception in the animal kingdom, researchers have discovered that an insect pollinator, the bumble bee, can estimate the duration of time intervals. Although many insects show daily and annual rhythms of behavior, the more sophisticated ability to estimate the duration of shorter time intervals had previously been known only in humans and other vertebrates.
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Bees and other insects make a variety of decisions that appear to require the ability to estimate elapsed durations. Insect pollinators feed on floral nectar that depletes and renews with the passage of time, and insect communication and navigation may also require the ability to estimate the duration of time intervals.
In the new work, the researchers investigated bumble bees’ ability to time the interval between successive nectar rewards. Using a specially designed chamber in which bumble bees extended their proboscis to obtain sucrose rewards, the researchers observed that bees adjusted the timing of proboscis extensions so that most were made near the end of the programmed interval between rewards. When nectar was delivered after either of two different intervals, bees could often time both intervals simultaneously. This research shows that the biological foundations of time perception may be found in animals with relatively simple neural systems.

Clock News

Three interesting press releases/news-reports today. Click on links to read the whole articles:
Daytime light exposure dynamically enhances brain responses:

Exposure to light is known to enhance both alertness and performance in humans, but little is understood regarding the neurological basis for these effects, especially those associated with daytime light exposure. Now, by exposing subjects to light and imaging their brains while they subsequently perform a cognitive test, researchers have begun to identify brain regions involved in the effects on brain function of daytime light exposure. The findings are reported by Gilles Vandewalle and Pierre Maquet of the University of Li ge, Derk-Jan Dijk of the University of Surrey, and additional colleagues and appear in the August 22nd issue of the journal Current Biology, published by Cell Press.
Our brain does not use light only to form images of the world. Ambient light levels are detected by our nervous system and, without forming any image, profoundly influence our brain function and various aspects of our physiology, including circadian rhythms, hormone release, and heart rate. These responses are induced by a special non-image-forming (NIF) brain system, which researchers have begun to characterize in animal models. In human studies, much work has focused on the effects of nighttime light exposure, but little is known about daytime responses to light. Especially mysterious are the neural correlates of these responses, and their temporal dynamics. Such issues are of significant interest given that daytime sleepiness is a major source of complaint in modern society and has considerable socio-economic implications.
In the present study, the researchers showed that a brief (21-minute) morning exposure to a bright white light increases alertness and significantly boosts the brain’s responses to an experimental test that requires attention only to sound. In a parallel neuroimaging analysis, this boost in alertness was found to correlate with responses in various areas of the brain, including regions of the cortex known to support performance on the auditory test. The regional brain changes were found to be highly dynamic, dissipating within a few minutes. These new findings therefore show that light exposure, even during the day, can quickly modulate regional brain function in areas involved in alertness and non-visual cognitive processes.

UM scientist sheds light on workings of internal clock:

Meredith specifically studied gates known as BK channels that control large flows of potassium out of the cell. Prior research suggested that BK channels were controlled by the core clock, so it made sense to Meredith that the channels might play some role in the generation of circadian behaviors.
To make the connection, Meredith, a self-described scientific jack-of-all-trades, brought a mixed bag of new scientific tools and techniques to an old problem.
The first step required her to combine genetic engineering with behavioral science. She engineered mice that had no functioning BK channels in their clock neurons, then watched how they acted. When exposed to light, the engineered mice behaved just like those with BK channels: They ran on their wheels at night and slept during the day. But when the engineered mice were kept in the dark they went haywire.
“We saw a very dramatic difference,” Meredith said.
Their strict schedule loosened and they roamed their cages and ran on their wheels at erratic times. Their daily amount of activity stayed about the same, but it was spread out more evenly over the 24-hour period.
Their strict schedule loosened and they roamed their cages and ran on their wheels at erratic times. Their daily amount of activity stayed about the same, but it was spread out more evenly over the 24-hour period.
Meredith had, for the first time, established a link between specific circadian behaviors in the mice and an ion channel on clock neurons.
But the jump from cellular structure to behaviors was a large one. She still needed to find out how her engineering had affected the intermediate step in the process: the electrical signaling in the brain. This phase of the study required her to switch gears and study the electrical properties of nerve cells.
She found that the clock neurons in her engineered mice generated signals different from those in normal mice. Moreover, the odd patterns of signaling corresponded to the odd patterns of behavior in the mice.
Meredith and her colleagues at Stanford had connected the dots between the BK channel and mice behavior patterns. In the engineered mice, the core genetic clocks seemed to be working fine, but the clock appeared to be unable to communicate well with the parts of the brains where actions such as wheel running were generated.
“The signal for time is no longer being transmitted to the legs,” Meredith said. “It’s like you have an actual clock and you put a piece of tape over it so you can’t see the dial anymore.”
The results of her study were published in June in the journal Nature Neuroscience. Her work appears to be the first to link a specific cellular structure in the clock neurons to specific circadian behaviors patterns they generate, said Roberto Refinetti, a psychologist at the University of South Carolina and editor of the Journal of Circadian Rhythms.
“The clock itself has been much-studied,” Refinetti said. “The novelty of this is being on the output side.”

Constant Lighting May Disrupt Development of Preemie’s Biological Clocks:

Every year about 14 million low-weight babies are born worldwide and are exposed to artificial lighting in hospitals.
“Today, we realize that lighting is very important in nursing facilities, but our understanding of light’s effects on patients and staff is still very rudimentary,” said William F. Walsh, chief of nurseries at Vanderbilt’s Monroe Carrel Jr. Children’s Hospital. “We need to know more. That is why studies like this are very important.”
Although older facilities still use round-the-clock lighting, modern NICUs, like that at Vanderbilt, cycle their lighting in a day/night cycle and keep lighting levels as low as possible, Walsh said. Also, covers are kept over the isolets that hold the babies in an effort to duplicate the dark conditions of the womb.
The finding that exposure to constant light disrupts the developing biological clock in baby mice provides an underlying mechanism that helps explain the results of several previous clinical studies. One found that infants from neonatal units with cyclic lighting tend to begin sleeping through the night more quickly than those from units with constant lighting. Other studies have found that infants placed in units that maintain a day/night cycle gain weight faster than those in units with constant light.
The research is a follow-up from a study that the McMahon group published last year which found that long periods of constant light disrupt the synchronization of the biological clock in adult mice. In all mammals, including mice and humans, the master biological clock is located in an area of the brain called the suprachiasmatic nuclei (SCN). It influences the activity of a surprising number of organs, including the brain, heart, liver and lungs and regulates the daily activity cycles known as circadian rhythms.

Reading Recommendations: Books about Clocks and Sleep

Reading Recommendations: Books about Clocks and SleepThis list, written on December 17, 2005, is still quite up-to-date. There are also some more specialized books which are expensive, and many of those I’d like to have one day, but I cannot afford them (though I have placed a couple of them on my wish list, just in case I see a cheap copy come up for sale):

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Why hibernating animals occasionally wake up?

One of the several hypotheses floating around over the past several years to explain the phenomenon of repeated wake-up events in hibernating animals although such events are very energy-draining, is the notion that the immune system needs to be rewarmed in order to fend off any potential bacterial invasions that may have occured while the animal was hibernating:

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Chossat’s Effect in humans and other animals

Chossat’s Effect in humans and other animalsChossat's Effect in humans and other animalsThis April 09, 2006 post places another paper of ours (Reference #17) within a broader context of physiology, behavior, ecology and evolution.
The paper was a result of a “communal” experiment in the lab, i.e., it was not included in anyone’s Thesis. My advisor designed it and started the experiment with the first couple of birds. When I joined the lab, I did the experiment in an additional number of animals. When Chris joined the lab, he took over the project and did the rest of the lab work, including bringin in the idea for an additional experiment that was included, and some of the analysis. We all talked about it in our lab meetings for a long time. In the end, the boss did most of the analysis and all of the writing, so the order of authors faithfully reflects the relative contributions to the work.
What is not mentioned in the post below is an additional observation – that return of the food after the fasting period induced a phase-shift of the circadian system, so we also generated a Phase-Response Curve, suggesting that food-entrainable pacemaker in quail is, unlike in mammals, not separate from the light-entrainable system.
Finally, at the end of the post, I show some unpublished data – a rare event in science blogging.

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Watch out for the Big Trucks….

Many Commercial Drivers Have Impaired Performance Due To Lack Of Sleep

Truck drivers who routinely get too little sleep or suffer from sleep apnea show signs of fatigue and impaired performance that can make them a hazard on the road, according to a major new study by researchers at the University of Pennsylvania School of Medicine. The study results are published in the August 15th issue of the American Journal of Respiratory and Critical Care Medicine.

Phase-Response Curve and T-Cycles: Clocks and Photoperiodism in Quail

Blogging on Peer-Reviewed Research

This is a summary of my 1999 paper, following in the footsteps of the work I described here two days ago. The work described in that earlier post was done surprisingly quickly – in about a year – so I decided to do some more for my Masters Thesis.
The obvious next thing to do was to expose the quail to T-cycles, i.e., non-24h cycles. This is some arcane circadiana, so please refer to the series of posts on entrainment from yesterday and the two posts on seasonality and photoperiodism posted this morning so you can follow the discussion below:
There were three big reasons for me to attempt the T-cycle experiment at that time:

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Clock Tutorial #16: Photoperiodism – Models and Experimental Approaches

Clock Tutorial #16:  Photoperiodism - Models and Experimental ApproachesThis post (written on August 13, 2005) describes the basic theory behind photoperiodism and some experimental protocols developed to test the theory.

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Clock Tutorial #15: Seasonality

Clock Tutorial #15:  SeasonalityThis post (click on the icon) was originally written on May 07, 2005, introducing the topic of neuroendocrine control of seasonal changes in physiology and behavior.

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Clock News

Different strokes occur at different times

Different types of strokes occur most often at different times of day say scientists at Iwate Medical University in Iwate, Japan.
The team based their findings on data from 12,957 cases of first-ever stroke diagnosed by CT or MRI scans and drawn from the Iwate Stroke Registry between 1991 and 1996.The researchers chose patients who had experienced cerebral infarctions, or ischemic strokes, where cells die because blood flow to the brain is restricted, and two kinds of hemorrhagic strokes: intercerebral hemorrhages that occur within the brain, and subarachnoid hemorrhages that occur in arteries at the brain’s surface.
The wake-sleep cycle (circadian rhythm) was divided into 12 two-hour intervals. All three types of stroke had peaks between 6 and 8 in the morning and 6 and 8 in the evening with fewer incidents during sleep when blood pressure is the lowest. But cerebral infarctions had a higher peak in the morning and a lower peak in the afternoon and the two hemorrhagic strokes had a higher peak in the afternoon and a lower peak in the morning.

Update: There is more information on this page.

Downloadable Database of Phase Response Curves

Downloadable Database of Phase Response CurvesThis April 16, 2005 post gives you links to further online resources and literature on entrainment and Phase-Response Curves, as well as a link to a database of PRCs so you can play with them yourself.

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Clock Tutorial #14: Interpreting The Phase Response Curve

Clock Tutorial #14:  Interpreting The Phase Response CurveThis is the sixth post in a series about mechanism of entrainment, running all day today on this blog. In order to understand the content of this post, you need to read the previous five installments. The original of this post was firt written on April 12, 2005.

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Clock Tutorial #13: Using The Phase Response Curve

Clock Tutorial #13:  Using The Phase Response CurveThis is the fifth post in a series about mechanism of entrainment. Orignally written on April 11, 2005.

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Clock Tutorial #12: Constructing the Phase Response Curve

Clock Tutorial #12:  Constructing the Phase Response CurveThe fourth post in the series on entrainment, originally written on April 10, 2005, explains the step-by-step method of constructing a PRC.

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Clock Tutorial #11: Phase-Shifting Effects Of Light

Clock Tutorial #11: Phase-Shifting Effects Of LightThe third post in the series on entrainment, first written on April 10, 2005, starts slowly to get into the meat of things…As always, clicking on the spider-clock icon will take you to the site of the original post.

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Clock Tutorial #10: Entrainment

Clock Tutorial #10: EntrainmentThis is the second in a series of posts on the analysis of entrainment, originally written on April 10, 2005.

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Clock Tutorial #6: To Entrain Or Not To Entrain, That Is The Question

 Clock Tutorial #6: To Entrain Or Not To Entrain, That Is The QuestionThis post from February 03, 2005 covers the basic concepts and terms on entrainment.

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Does circadian clock regulate clutch-size in birds? A question of appropriatness of the model animal.

Blogging on Peer-Reviewed Research

 Does circadian clock regulate clutch-size in birds? A question of appropriatness of the model animal.This post from March 27, 2006 starts with some of my old research and poses a new hypothesis.

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Quail: How many clocks?

Blogging on Peer-Reviewed Research

One of the assumptions in the study of circadian organization is that, at the level of molecules and cells, all vertebrate (and perhaps all animal) clocks work in roughly the same way. The diversity of circadian properties is understood to be a higher-level property of interacting multicelular and multi-organ circadian systems: how the clocks receive environmental information, how the multiple pacemakers communicate and synchronize with each other, how they convey the temporal information to the peripheral clocks in all the other cells in the body, and how perpheral clocks generate observable rhythms in biochemistry, physiology and behavior.

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Persistence In Perfusion

Blogging on Peer-Reviewed Research

Persistence In PerfusionThis post, from January 25, 2006, describes part of the Doctoral work of my lab-buddy Chris.

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How eyes talk to each other?

Blogging on Peer-Reviewed Research

One of the important questions in the study of circadian organization is the way multiple clocks in the body communicate with each other in order to produce unified rhythmic output.

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Clock Tutorial #9: Circadian Organization In Japanese Quail

Circadian Organization In Japanese QuailGoing into more and more detail, here is a February 11, 2005 post about the current knowledge about the circadian organization in my favourite animal – the Japanese quail.

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Clock Tutorial #8: Circadian Organization In Non-Mammalian Vertebrates

Blogging on Peer-Reviewed Research

Circadian Organization In Non-Mammalian Vertebrates This post was originally written on February 11, 2005. Moving from relatively simple mammalian model to more complex systems.

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