Category Archives: Clock News

Oxytocin and Childbirth. Or not.

Blogging on Peer-Reviewed Research

When teaching human or animal physiology, it is very easy to come up with examples of ubiqutous negative feedback loops. On the other hand, there are very few physiological processes that can serve as examples of positive feedback. These include opening of the ion channels during the action potential, the blood clotting cascade, emptying of the urinary bladder, copulation, breastfeeding and childbirth. The last two (and perhaps the last three!) involve the hormone oxytocin. The childbirth, at least in humans, is a canonical example and the standard story goes roughly like this:

When the baby is ready to go out (and there’s no stopping it at this point!), it releases a hormone that triggers the first contraction of the uterus. The contraction of the uterus pushes the baby out a little. That movement of the baby stretches the wall of the uterus. The wall of the uterus contains stretch receptors which send signals to the brain. In response to the signal, the brain (actually the posterior portion of the pituitary gland, which is an outgrowth of the brain) releases hormone oxytocin. Oxytocin gets into the bloodstream and reaches the uterus triggering the next contraction which, in turn, moves the baby which further stretches the wall of the uterus, which results in more release of oxytocin…and so on, until the baby is expelled, when everything returns to normal.

As usual, introductory textbook material lags by a few years (or decades) behind the current state of scientific understanding. And a brand new paper just added a new monkeywrench into the story. Oxytocin in the Circadian Timing of Birth by Jeffrey Roizen, Christina E. Luedke, Erik D. Herzog and Louis J. Muglia was published last Tuesday night and I have been poring over it since then. It is a very short paper, yet there is so much there to think about! Oh, and of course I was going to comment on a paper by Erik Herzog – you knew that was coming! Not just that he is my friend, but he also tends to ask all the questions I consider interesting in my field, including questions I wanted to answer myself while I was still in the lab (so I live vicariously though his papers and blog about every one of them).
Unfortunately, I have not found time yet to write a Clock Tutorial on the fascinating topic of embryonic development of the circadian system in mammals and the transfer of circadian time from mother to fetus – a link to it would have worked wonderfully here – so I’ll have to make shortcuts, but I hope that the gist of the paper will be clear anyway.

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Endocrine rhythms

Circadian clocks: regulators of endocrine and metabolic rhythms by Michael Hastings, John S O’Neill and Elizabeth S Maywood is a new and excellent review of the interaction between the clocks and hormones in mammals, focusing at the molecular level. The pre-print PDF of the article is freely available on the Journal of Endocrinology site.

JETLAG – new circadian gene in Drosophila

JETLAG - new circadian gene in DrosophilaFrom June 26, 2006….

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The Amplitude Problem

Blogging on Peer-Reviewed Research

If you are one of the few of my readers who actually slogged through my Clock Tutorials, especially the difficult series on Entrainment and Phase Response Curves, you got to appreciate the usefulness of the oscillator theory from physics in its application to the study of biological clocks. Use of physics models in the study of biological rhythms, pioneered by Colin Pittendrigh, is an immensely useful tool in the understanding of the process of entrainment to environmental cycles.
Yet, as I warned several times, a Clock is a metaphor and, as such, has to be treated with thought and caution. Is the physics model always applicable? Is it sometimes deceptive? How much does it oversimplify the behavior out in the natural environment?
The few tests of the theory conducted in the field demonstrate that the models of entrainment (the PRCs) work quite well, though not always perfectly. Use of Limit Cycles (something that is, IMHO, too complex for me to try to explain on a blog) is also useful. The theory appears to work quite well in regard to period and phase, but the effects of amplitude of the oscillation are not as well tested, although a number of studies, especially regarding photoperiodism in non-mammalian vertebrates and invertebrates, suggests that the amplitude is an important parameter of a biological rhythm.
oscillation.jpg
The main problem with the amplitude is that it is not clear if the measured amplitude of the overt rhythms (e.g., activity, body temperature, melatonin release, etc.) faithfully reflects the amplitude of the underlying oscillator. It is not even certain that the amplitude of the expression of core clock genes and proteins is the equivalent of the amplitude of the idealized physical system.
In a recent paper (provisional PDF) in the Journal of Circadian Rhythms (an Open Access journal, where you can also comment on the papers, just like on PLoS ONE), Daniel Kripke, Jeffrey Elliott, Shawn Youngstedt and Katharine Rex, using that most difficult laboratory model of all – the human – tried to kill two birds with one stone: test if the physical oscillatory models apply for the amplitude of circadian clocks and test if the amplitude of the overt rhythms is a good reflection of the amplitude of the underlying biological oscillator. The medical implicaitons of their work, no matter what the results, is quite obvious as well.
It is well known that the amplitude of overt rhythms (activity, sleep-wake cycle, temperature, melatonin, cortisol, etc.) gets a little smaller with advanced age in humans. Measuring simultaneously several overt rhythms (always a good thing!) while constructing a Phase-Response Curve to light pulses in two groups – young and old people – they excpected, from theory, to see a change in the shape and size of the PRC. According to theory, an oscillator with a higher amplitude (young) would be more difficult to shift, i.e., the size of phase-shifts would be smaller than in the old cohort (for some odd reason – typo perhaps? – they state they expected the opposite, i.e., smaller shifts in the older group).
If they got positive results, i.e., if the size of phase-shifts differed between the two age groups, they would have demonstrated that a) physical model of oscillatons applies to biological clocks in respect to amplitude, and b) that the amplitude of overt rhythms faithfully reflects the amplitude of the underlying biological oscillator.
But, their results were negative, i.e., there was no difference in the size of phase-shifts between young and old cohorts (or, for that matter, between women and men), though the phase of all rhythms (except temperature and the offset of melatonin metabolites in the urine – likely due to the slower metabolism itself) was advanced and the PRCs, as expected, moved somewhat to the left to reflect this.
This unfortunate result suggests one (or both) of the two possibilities:
– Oscillator models borrowed from physics do not apply to biology in regard to amplitude, or
– Amplitude of overt rhythms does not reflect the amplitude of the underlying oscillator
As they say, more work needs to be done.

Everything Important Cycles

Everything Important CyclesMicroarrays have been used in the study of circadian expression of mammalian genes since 2002 and the consensus was built from those studies that approximately 15% of all the genes expressed in a cell are expressed in a circadian manner. I always felt it was more, much more.
I am no molecular biologist, but I have run a few gels in my life. The biggest problem was to find a control gene – one that does not cycle – to make the comparisons to. Actin, which is often used in such studies as control, cycled in our samples. In the end, we settled on one of the subunits of the ribosome as we could not detect a rhythm in its expression. The operative word is “could not detect”. My sampling rate was every 3 hours over a 24-hour period, so it is possible that we could have missed circadian expression of a gene that has multiple peaks, or a single very narrow peak, or a very low amplitude of cycling (it still worked as a control in our case, for different reasons). Thus, my feeling is that everything or almost everything that is expressed in a cell will be expressed in a rhythmic pattern.
If you have heard me talk about clocks (e.g., in the classroom), or have read some of my Clock Tutorials, you know that I tend to say something like “All the genes that code for proteins that are important for the core function of a cell type are expressed in a circadian fashion”. So, genes important for liver function will cycle in the liver cells, genes important for muscle function will cycle in muscle cells, etc.
But I omit to note that all such genes that are important for the function of the cell type are all the genes that are expressed in that cell. The genes not used by that cell are not expressed. But I could not go straight out and say “all the genes that are expressed in a cell are expressed in a circadian pattern”, because I had no data to support such a notion. Until yesterday.
What happened yesterday?

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How Period and Timeless Interact in Fruitflies

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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VIP synchronizes mammalian circadian pacemaker neurons

VIP synchronizes mammalian circadian pacemaker neuronsNo other aspect of behavioral biology is as well understood at the molecular level as the mechanism that generates and sustains circadian rhythms. If you are following science in general, or this blog in particular, you are probably familiar with the names of circadian clock genes like per, tim, clk, frq, wc, cry, Bmal, kai, toc, doubletime, rev-erb etc.
The deep and detailed knowledge of the genes involved in circadian clock function has one unintended side-effect, especially for people outside the field. If one does not stop and think for a second, it is easy to fall under the impression that various aspects of the circadian oscillations, e.g., period, phase and amplitude, are determined by the clock genes. After all, most of these genes were discovered by the study of serendipitously occuring mutations, usually period-mutations.
If the circadian properties are really deteremined by clock genes, then the predictions from this hypothesis are that: 1) every cell in the body shows the same period (phase, amplitude, etc.), 2) every cell in the body has the same period throughout its life, 3) every cell removed from the body and placed in the dish continues to oscillate with the same period as it had inside the body, and 4) the properties of the circadian rhythms are not alterable by environmental influences.
Stated this bluntly, one has to recoil in horror: of course it is not determined by genes! But without such an exercise in thinking, much work and writing (especially by the press) tacitly assumes the strict genetic determination. However, the experimental data show this not to be true. Period (and other properties) of the whole organism’s rhythms are readily modified by environmental influences, e.g., light intensity (Aschoff Rule), heavy water, lithium, sex steroids and melatonin. They change with age and reproductive state. There is individual variation even in clonal species (or highly-inbred laboratory strains). The period of the rhythms measured in cells or cell-types in a dish is not always the same as exhibited by the same cells inside the organism. Finally, the occurrence of splitting (of one unified circadian output into two semi-independent components differing in period)suggests that two or more groups of circadian pacemakers simultaneously exhibit quite different periods within the same animal.
Several years ago, Dr. Eric Herzog (disclosure – a good friend) has shown that even the individual pacemaker cells within the same SCN (suprachiasmatic nucleus – the site of the main mammalian circadian clock in the brain) exhibit different periods. When dispersed in culture, pacemaker neurons (originally taken from a single animal) tend to show a broad variation in periods (amplitudes, etc…).
As they grow cellular processes, two neurons in a dish may touch and form connections. As soon as they do, their periods change and from then on the two cells show the SAME period, i.e., they are synchronized. As more and more cells connect, they build an entire network of neurons, all cycling in sync with each other – same period, same phase, same amplitude. This is assumed to happen inside the whole animal as well – the unconnected SCN neurons of the fetus start making connections just before (or immediately after, depending on the species) birth and as a result, an overt, whole-organism rhythm emerges out of arrhytmic background.
But, what molecules are involved in cell-cell communication that allows the pacemaker cells to synchronize their rhythms? For several years, the most likely candidate was thought to be GABA, an inhibitory neurotransmitter produced by all SCN cells. Sara Aton, a graduate student in Eric Herzog’s lab (now postdoc at UPenn), set out to test this hypothesis. Over a few years and several papers, a different story emerged, culminating in this months paper in PNAS:

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Is That Your Jet-Lag Treatment Showing or are you just Happy To See Me?

Is That Your Jet-Lag Treatment Showing or are you just Happy To See Me?If this gets more widely known (and, with this post, I am trying to help it become so), you can just imagine the jokes about the new challenges to the aviation industry and the renewed popularity of the Mile High Club, or the cartoons utilizing the phallic shape of airplanes!
Hamsters on Viagra Have Less Jet Lag, Research Shows (also Viagra helps jet-lagged hamsters, maybe humans, too: study and Viagra ‘improves jet lag’):

Hamsters given Pfizer Inc.’s Viagra adapted more quickly to changes in their internal clocks, scientists said.
Hamsters given sildenafil, the chemical name of the drug sold as Viagra, adapted more easily to altered patterns of light exposure to simulate changes caused by air travel across time zones. Long-haul travel desynchronizes the body’s alignment to the day-night cycle, leading to the disorientation of jet lag.
————snip—————-
The researchers synchronized the hamsters to a 24-hour day by simulating light-dark cycles. Once the hamsters adjusted to a cycle, they shifted the light-dark phases forward six hours. One group of hamsters was given saline; the other was given Viagra. The hamsters given Viagra got used to the change 4 days faster, on average, than their counterparts given a placebo. Viagra eased the transition that mimicked crossing the international dateline from west to east, known as phase advancing, and had no effect on a transition that mimicked westward travel.

There should be a rule in journalism making sure that no article about Viagra ever contains the words “harder” and “screw”, especially close to each other. Oooops!

“All animals, including humans, have a harder time with phase advancing,” said Colwell in a telephone interview today. “Humans are unique in our ability to screw up our timing system — you know, jet lag, shift work, staying up too late playing video games, or whatever.”

OK, now seriously…what does the study say?

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Clock News

menaker%26friend.gif
Menaker Awarded Farrell Prize in Sleep Medicine:

Michael Menaker, professor of biology and an international leader in the field of circadian rhythm research, received the Peter C. Farrell Prize in Sleep Medicine from the Harvard Medical School Division of Sleep Medicine during an event there on June 6.
The prize was awarded “in celebration of the life and work of Michael Menaker, trailblazer in circadian biology and prescient illuminator of how Light and Dark, the alternating ancient heritages of our planet, come to govern and synchronize living clocks.”
Menaker was cited as a “ground-breaking investigator of the first circadian genetic mutation in mammals as well as the architect of landmark experiments that elucidate how central and peripheral circadian oscillators are coordinated to each other and with the environment.
Previously Menaker was honored with Virginia’s Outstanding Scientists and Industrialists 2003 Lifetime Achievement Award.

Mike is my academic grandfather, which makes me a very common beast, really! Yes, he has published amazing stuff over the decades and did some really pioneering and revolutionary science. But, his probably greatest contribution to science is the enormous number of students he has advised over the years. He finishes every talk by showing slides (two slides? three these days?) with many, many names of all of his graduate students (typed in a freerunning actograph style) which reads like a who-is-who of Chronobiology. And that is just first generation of his academic offspring – the academic grandkids and great-grandkids are all over the world as well, doing top-notch and exciting science.

A naturally occuring mutation of the core clock gene timeless in European Drosophila affects photoperiodic response

Surprise, surprise – a paper in Science is up there with a free online access (not the PDF, but the Full Text and that is something!):
A Molecular Basis for Natural Selection at the timeless Locus in Drosophila melanogaster:

Diapause is a protective response to unfavorable environments that results in a suspension of insect development and is most often associated with the onset of winter. The ls-tim mutation in the Drosophila melanogaster clock gene timeless has spread in Europe over the past 10,000 years, possibly because it enhances diapause. We show that the mutant allele attenuates the photosensitivity of the circadian clock and causes decreased dimerization of the mutant TIMELESS protein isoform to CRYPTOCHROME, the circadian photoreceptor. This interaction results in a more stable TIMELESS product. These findings reveal a molecular link between diapause and circadian photoreception.
————snip—————
A reduced L-TIM/CRY interaction may explain the differences in the fly’s circadian photoresponsiveness and the enhanced L-TIM stability. The observation that ls-tim females are more prone to diapause at any day length (1) is also consistent with the results presented here. As in the corresponding diapause profiles (1), the transformants conclusively reveal that the circadian photoresponsive phenotypes of natural tim variants are not due to linkage disequilibrium between tim and a nearby locus, but they are attributable to tim itself. Furthermore, the similarity in behavior of natural s-tim variants and P[S-TIM] transformants suggests that the residual putative truncated N-terminal 19-residue TIM product from the s-tim allele does not play any major role in the phenotypes we have studied (2).
It has been argued that the light sensitivity of the circadian clock needs to be abated in temperate zones because of the dramatic increase in summer day lengths in northern latitudes (18, 19). One mechanism for this process involves a reduced sensitivity to light-induced disturbance by having a higher pacemaker amplitude (18, 19). However, the amplitude of TIM cycling in DD was not significantly different between the two variants (fig. S1), nor were there any significant differences in amplitude or phase of the tim mRNA cycle between the s-tim and ls-tim genotypes (fig. S2). Another way to attenuate circadian photoresponsiveness in temperate zones may be by filtering light input into the clock. The molecular changes to the L-TIM protein may buffer the circadian response to light in ls-tim individuals, even in the presence of S-TIM, and may contribute to the positive Darwinian selection observed for ls-tim in the European seasonal environment (1).

So, here is another nice evidence for the connection between the core circadian clock and the photoperiodic response found in a nice evolutionary and ecological context.

Everything Important Cycles

Blogging on Peer-Reviewed Research

Microarrays have been used in the study of circadian expression of mammalian genes since 2002 and the consensus was built from those studies that approximately 15% of all the genes expressed in a cell are expressed in a circadian manner. I always felt it was more, much more.
I am no molecular biologist, but I have run a few gels in my life. The biggest problem was to find a control gene – one that does not cycle – to make the comparisons to. Actin, which is often used in such studies as control, cycled in our samples. In the end, we settled on one of the subunits of the ribosome as we could not detect a rhythm in its expression. The operative word is “could not detect”. My sampling rate was every 3 hours over a 24-hour period, so it is possible that we could have missed circadian expression of a gene that has multiple peaks, or a single very narrow peak, or a very low amplitude of cycling (it still worked as a control in our case, for different reasons). Thus, my feeling is that everything or almost everything that is expressed in a cell will be expressed in a rhythmic pattern.
If you have heard me talk about clocks (e.g., in the classroom), or have read some of my Clock Tutorials, you know that I tend to say something like “All the genes that code for proteins that are important for the core function of a cell type are expressed in a circadian fashion”. So, genes important for liver function will cycle in the liver cells, genes important for muscle function will cycle in muscle cells, etc.
But I omit to note that all such genes that are important for the function of the cell type are all the genes that are expressed in that cell. The genes not used by that cell are not expressed. But I could not go straight out and say “all the genes that are expressed in a cell are expressed in a circadian pattern”, because I had no data to support such a notion. Until yesterday.
What happened yesterday?

Continue reading

Timing of duration of protein activity – a molecular clock or timer?

This article, of course, got my attention:
Clocking In And Out Of Gene Expression

Using steroid receptor coactivator-3 (SRC-3), they demonstrated that activation requires addition of a phosphate molecule to the protein at one spot and addition of an ubiquitin molecule at another point. Each time the message of the gene is transcribed into a protein, another ubiquitin molecule is chained on. Five ubiquitins in the chain and the protein is automatically destroyed.
“It’s built-in self destruction,” said O’Malley. “It prevents you from activating a potent factor in the cells that just keeps the clock running and the gene continuing to be expressed.” In that scenario, the result could be cancer, too much growth or an abnormal function.
“It means there’s a fixed length of time that the molecule can work. When it’s activated, it’s already preprogrammed to be destroyed. The clock’s running and each time an ubiquitin is added, it is another tick of the clock.”

So, it is a five-step ‘hourglass’ timer of sorts, which I would not, for he fear of confusion, imprecisely call a ‘clock’. A clock ends a cycle at the same state at which it begins, so the cycle can spontaneously repeat. An hourglass timer has a beginning and an end, and does not spontaneously restart the cycle.

Sleep News

More stuff from SLEEP 2007, the 21st Annual Meeting of the Associated Professional Sleep Societies:
Sleep Deprivation Affects Eye-steering Coordination When Driving:

Driving a vehicle requires coordination of horizontal eye movements and steering. Recent research finds that even a single night of sleep deprivation can impact a person’s ability to coordinate eye movements with steering.

Extra Sleep Improves Athletes’ Performance:

Athletes who get an extra amount of sleep are more likely to improve their performance in a game, according to recent research.

Going To Bed Late May Affect The Health, Academic Performance Of College Students:

College students who go to bed late are more likely to have poor quality sleep, which may affect their mental health and academic performance, according to new research.

Safety And Well-being Of Medical Interns And Patients At Risk From Extended Duration Work Shifts:

Working an extended duration shift can pose a risk to not only the safety and well-being of medical interns, but also to that of their patients, according to a recent research.

Sleep-related Breathing Disorder Common Among Aggressive, Bullying Schoolchildren:

Aggressive behavior and bullying, common among schoolchildren, are likely to have multiple causes, one of which may be an undiagnosed sleep-related breathing disorder (SRBD), according to recent research.

Late Weekend Sleep Among Teens May Lead To Poor Academic Performance:

Teenagers who stay up late on school nights and make up for it by sleeping late on weekends are more likely to perform poorly in the classroom. This is because, on weekends, they are waking up at a time that is later than their internal body clock expects. The fact that their clock must get used to a new routine may affect their ability to be awake early for school at the beginning of the week when they revert back to their old routine, according to new research.

Sleep Deprivation Can Lead To Smoking, Drinking:

Sleep loss or disturbed sleep can heighten the risk for adolescents to take up smoking and drinking, two habits that may prove to be detrimental to their health, according to recent research.

Children’s Brain Responses Predict Impact Of Sleep Loss On Attention:

The brain responses of those children who don’t get enough sleep can accurately predict the impact sleep loss has on their ability to pay attention during the course of a day, according to a recent research.

Snoring Children: Poor Sleep Hygiene In Children Associated With Behavioral Problems:

A snoring child’s poor sleep hygiene habits can have a negative influence on his or her daytime behavior, according to a new study.

Chronic Sleep Restriction Negatively Affects Cardiac Activity:

Chronic sleep restriction has a negative effect on a person’s cardiac activity, which may elevate the risk of cardiovascular disease and mortality, according to a research abstract presented at SLEEP 2007, the 21st Annual Meeting of the Associated Professional Sleep Societies (APSS).

Sleep Deprivation Is Common Among Members Of The US Marine Corps:

Members of the U.S. Marine Corps (USMC) experience combined stressors, including physical exertion and the threat of enemy fire. A research abstract that presentedJune 13 at SLEEP 2007, the 21st Annual Meeting of the Associated Professional Sleep Societies, finds that sleep deprivation, which can result in fatigue, is another factor that can impair troops’ vigilance and decision-making with potentially dangerous consequences.

Catastrophic Events Can Affect A Person’s Sleep:

A significant disruption of day-to-day life can take place in those areas affected by a natural disaster. One of the more recent disasters occurred when Hurricane Katrina struck the Gulf Coast in late August 2005, causing loss of lives, extensive damage, and the evacuation of hundreds of thousands of residents. Disasters such as Hurricane Katrina are more likely to affect the quality and the quantity of a person’s sleep, according to recent research.

Previously

Sleep News

Children With Sleep Disorder Symptoms Are More Likely To Have Trouble Academically:

Students with symptoms of sleep disorders are more likely to receive bad grades in classes such as math, reading and writing than peers without symptoms of sleep disorders, according to recent research.

Slow Wave Activity During Sleep Is Lower In African-Americans Than Caucasians:

Slow wave activity (SWA), a stable trait dependent marker of the intensity of non-rapid eye movement (NREM) sleep, is lower in young healthy African-Americans compared to Caucasians who were matched for age, gender and body weight, according to recent research.

Sleep Disorders Highly Prevalent Among Police Officers:

A sampling of police officers shows a high incidence of sleep disorders among the members of this profession. Sleep disorders are common, costly and treatable, but often remain undiagnosed and untreated. Unrecognized sleep disorders adversely affect personal health and may lead to chronic sleep loss, which, in turn, increases the risk of accidents and injuries. These problems are exacerbated in shift workers such as police officers, who may experience chronic sleep loss due to their schedules. A sampling of police officers shows a high incidence of sleep disorders among the members of this profession, according to recent research.

Sleep Restriction Affects Children’s Speech:

Research examining the impact of sleep in school-age children suggests that even mild sleep loss produces marked deficits in their cognitive development and functioning. Sleep restriction can alter children’s initial stages of speech perception, which could contribute to disruptions in cognitive and linguistic functioning — skills necessary for reading and language development and comprehension, according to recent research.

Link Between Common Sleep Disorder And High Blood Pressure Discovered:

An international team of researchers, led by Emory University clinician scientists, has found evidence that people suffering from moderate to severe cases of restless legs syndrome (RLS) are at significantly increased risk for developing hypertension.

Patient Care Improves When Medical Residents Work Fewer Hours:

When medical residents work shorter hours, fewer patients are transferred to intensive care and there are not as many interventions by pharmacists to avoid errors in medication, according to a Yale School of Medicine study in Annals of Internal Medicine.

Sleep Problems May Affect A Person’s Diet:

Sleep problems can influence a person’s diet. Those who don’t get enough sleep are less likely to cook their own meals and, instead, opt to eat fast food. It is the lack of nutritional value of this restaurant-prepared food that may cause health problems for these people in the long-run, according to new research.

CPAP Improves Sleep In Patients With Alzheimer’s Disease, Sleep-related Breathing Disorder:

Patients with both Alzheimer disease and a sleep-related breathing disorder (SRBD) experience disrupted sleep, resulting in increased nocturnal awakenings and a decreased percentage of REM sleep. However, in another example of the effectiveness of continuous positive airway pressure (CPAP), CPAP has been found to reduce the amount of time spent awake during the night, increase the time spent in deeper levels of sleep, and improve oxygenation, according to a recent study.

Sleep News

Sleep Deprivation Affects Airport Baggage Screeners’ Ability To Detect Rare Targets:

A lack of sleep may affect the performance of airport employees, which can, in turn, compromise the safety of airline passengers. Sleep deprivation can impair the ability of airport baggage screeners to visually search for and detect infrequently occurring or low prevalence targets that may ultimately pose a threat to an airline and its passengers, according to new research.

Night Shift Nurses More Likely To Have Poor Sleep Habits:

Nurses who work the night shift are more likely to have poor sleep habits, a practice that can increase the likelihood of committing serious errors that can put the safety of themselves as well as their patients at risk, according to recent research.
Arlene Johnson, of the University of Alabama at Birmingham, surveyed 289 licensed nurses while they were working on the night shift in the hospital setting, and classified the subjects as either sleep deprived or not sleep deprived. The results showed that 56 percent of the sample was sleep deprived.

Sleep News

Wide Range Of Sleep-related Disorders Associated With Abnormal Sexual Behaviors, Experiences:

A paper published in the June 1st issue of the journal SLEEP is the first literature review and formal classification of a wide range of documented sleep-related disorders associated with abnormal sexual behaviors and experiences. These abnormal sexual behaviors, which emerge during sleep, are referred to as “sleepsex” or “sexsomnia”.

See also this, this and this.
Why Patients With Obstructive Sleep Apnea Are At Higher Risk For Cardiovascular Disease:

Researchers have found that patients with obstructive sleep apnea (OSA) have higher levels of a type of dead cells (apoptotic cells) from the lining (endothelium) of their blood vessels circulating in their bloodstream than people who do not have OSA. The finding may help explain why those with OSA are at higher risk for cardiovascular disease (CVD).

Is That Your Jet-Lag Treatment Showing or are you just Happy To See Me?

Blogging on Peer-Reviewed Research

If this gets more widely known (and, with this post, I am trying to help it become so), you can just imagine the jokes about the new challenges to the aviation industry and the renewed popularity of the Mile High Club, or the cartoons utilizing the phallic shape of airplanes!
Hamsters on Viagra Have Less Jet Lag, Research Shows (also Viagra helps jet-lagged hamsters, maybe humans, too: study and Viagra ‘improves jet lag’):

Hamsters given Pfizer Inc.’s Viagra adapted more quickly to changes in their internal clocks, scientists said.
Hamsters given sildenafil, the chemical name of the drug sold as Viagra, adapted more easily to altered patterns of light exposure to simulate changes caused by air travel across time zones. Long-haul travel desynchronizes the body’s alignment to the day-night cycle, leading to the disorientation of jet lag.
————snip—————-
The researchers synchronized the hamsters to a 24-hour day by simulating light-dark cycles. Once the hamsters adjusted to a cycle, they shifted the light-dark phases forward six hours. One group of hamsters was given saline; the other was given Viagra. The hamsters given Viagra got used to the change 4 days faster, on average, than their counterparts given a placebo. Viagra eased the transition that mimicked crossing the international dateline from west to east, known as phase advancing, and had no effect on a transition that mimicked westward travel.

There should be a rule in journalism making sure that no article about Viagra ever contains the words “harder” and “screw”, especially close to each other. Oooops!

“All animals, including humans, have a harder time with phase advancing,” said Colwell in a telephone interview today. “Humans are unique in our ability to screw up our timing system — you know, jet lag, shift work, staying up too late playing video games, or whatever.”

OK, now seriously…what does the study say?

Continue reading

Flirting under Moonlight on a Hot Summer Night, or, The Secret Night-Life of Fruitflies

Blogging on Peer-Reviewed Research

As we mentioned just the other day, studying animal behavior is tough as “animals do whatever they darned please“. Thus, making sure that everything is controlled for in an experimental setup is of paramount importance. Furthermore, for the studies to be replicable in other labs, it is always a good idea for experimental setups to be standardized. Even that is often not enough. I do not have access to Science but you may all recall a paper from several years ago in which two labs tried to simultaneously perform exactly the same experiment in mice, using all the standard equipment, exactly the same protocols, the same strain bought from the same supplier on the same date, the same mouse-feed, perhaps even the same colors of technicians’ uniforms and yet, they got some very different data!
The circadian behavior is, fortunately, not chaotic, but quite predictable, robust and easily replicable between labs in a number of standard model organisms. Part of the success of the Drosophila research program in chronobiology comes from the fact that for decades all the labs used exactly the same experimental apparatus, this one, produced by Trikinetics (Waltham, Massachusetts) and Carolina Biologicals (Burlington, North Carolina):
drosophila%20apparatus.jpg
This is a series of glass tubes, each containing a single insect. An infrared beam crosses the middle of each tube and each time the fly breaks the beam, by walking or flying up and down the tube, the computer registers one “pen deflection”. All of those are subsequently put together into a form of an actograph, which is the standard format for the visual presentation of chronobiological data, which can be further statistically analyzed.
The early fruitfly work was done mainly in Drosophila pseudoobscura. Most of the subsequent work on fruitfly genetics used D.melanogaster instead. Recently, some researchers started using the same setup to do comparative studies of other Drosophila species. Many fruitfly clock labs have hundreds, even thousands, of such setups, each contained inside a “black box” which is essentially an environmental chamber in which the temperature and pressure are kept constant, noise is kept low and constant (“white noise”), and the lights are carefully controlled – exact timing of lights-on and lights-off as well as the light intensity and spectrum.
In such a setup, with a square-wave profile of light (abrupt on and off switches), every decent D.melanogaster in the world shows this kind of activity profile:
fruitfly%20crepuscular.JPG
The activity is bimodal: there is a morning peak (thought to be associated with foraging in the wild) and an evening peak (thought to be associated with courtship and mating in the wild).
The importance of standardization is difficult to overemphasize – without it we would not be able to detect many of the subtler mutants, and all the data would be considered less trustworthy. Yet, there is something about standardization that is a negative – it is highly artificial. By controlling absolutely everything and making the setup as simple as possible, it becomes very un-representative of the natural environment of the animal. Thus, the measured behavior is also likely to be quite un-natural.
Unlike in the lab, the fruitflies out in nature do not live alone – they congregate with other members of the species. Unlike in a ‘black box’, the temperature fluctuates during the day and night in the real world. Also unlike the lab, the intensity and spectrum of light change gradually during the duration of the day while the nights are not pitch-black: there are stars and the Moon providing some low-level illumination as well. Thus, after decades of standardized work, it is ripe time to start investigating how the recorded behaviors match up with the reality of natural behavior in fruitflies.
Three recent papers address these questions by modifying the experimental conditions in one way or another, introducing additional environmental cues that are usually missing in the standard apparatus (and if you want to know what they found, follow me under the fold):

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Bacteria do it differently

I recently mentioned a study reporting circadian oscillations of bacterial clock-proteins KaiA, KaiB and KaiC in a dish with no transcription and translation whatsoever – the oscillations being due entirely to polymerization of proteins. Now, a mathematical model of this system has also been published describing how the working of the system is possible.

A Pacemaker is a Network

Blogging on Peer-Reviewed Research

This is going to be a challenging post to write for several reasons. How do I explain that a paper that does not show too much new stuff is actually a seminal paper? How do I condense a 12-page Cell paper describing a gazillion experiments without spending too much time on details of each experiment (as much as I’d love to do exactly that)? How do I review it calmly and critically without gushing all over it and waxing poetically about its authors? How do I put it in proper theoretical and historical perspective without unnecessarily insulting someone? I’ll give it a try and we’ll see how it turns out (if you follow me under the fold).
Clock Genes – a brief history of discovery
Late 1990s were a period of amazing activity and rate of discovery in chronobiology, specifically in molecular basis of circadian rhythms. Sure, a few mutations resulting in period changes or arrhythmicity were known before, notably period in fruitflies, frequency in the fungus Neurospora crassa, the tau mutation in hamsters and some unidentified mutations in a couple of Protista.
But in 1995, as the molecular techniques came of age, flood-gates opened and new clock genes were discovered almost every week (or so it appeared).

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Big Circadian Changes at UVA

One chronobiological pioneer is leaving and another one is coming in. Gene Block is going to UCLA and Joe Takahashi is leaving Northwestern (What are Fred Turek and others going to do there without him? What happens to the Howard Hughes institute?) and coming in to head the new Center for Circadian and Systems Biology. A very interesting game of musical chairs. Stay tuned.

Three labs simultaneously discover a new clock gene!

Thus reports The Scientist:

Researchers from three different labs have identified a new circadian gene in the mouse, according to two papers in Science and one paper in Cell published online this week. Mutagenesis screens revealed that mutations in a protein called FBXL3 lengthen the mouse circadian period by several hours, and biochemical analyses showed that FBXL3 is necessary for degradation of key circadian clock proteins.

I’ll probably have something more to say once I get hold of the actual papers.
In a perfect world, the three groups would have done Open Notebook science, found each other, collaborated, minimized waste of parallel work, and ended with a kick-ass monster paper in PLoS-Biology that would get cited hundreds of times within a year. Ah well….

Rotating shifts shorten lives

This is the first study I know that directly tested this – the effects of rotating shifts on longevity – in humans, though some studies of night-shift nurses have shown large increases in breast cancers, stomach ulcers and heart diseases, and similar studies have been done in various rodents and fruitflies:
Working in shifts shortens life span: Study:

A study of 3,912-day workers and 4,623 shift workers of the Southeastern Central Railway in Nagpur showed the former lived 3.94 years longer than their counterparts on shift duties, said the study by Atanu Kumar Pati of The School of Life Sciences in Pt Ravishankar Shukla University, Raipur.
—————
Shift work affects the circadian rhythm, the 24-hour cycle in the physiological processes of humans that leads to several sleep-related and social problems.
Circadian rhythms are important in determining the sleeping and feeding patterns of all animals, including humans. Brain wave activity, hormone production, cell regeneration and other biological activities are linked to this daily cycle.
Pati and his colleague K Venu Achari analysed a database of dates of death, retirement and death of each worker and published their findings in the latest issue of “current science”.
They also studied data on deaths due to all causes of 594 railway employees, including 282 day workers and 312 shift workers, over a span of 25 years. The cause of death was not documented in the database. An analysis of the data showed that day workers tend to live 3.94 years longer than counterparts working in shifts.
All day workers performed duty between 9 am and 6 pm with an hour-long lunch break from 1 pm and included those on office job and doing miscellaneous duties, the study said.
Those coming for shift duties worked in a rotating system consisting of a day shift (8 am to 4 pm), first night (4 pm to midnight) and second night (midnight to 8 am).
They worked in each shift continuously for six days and had a single day break before resumption of the next shift. The shift workers included running staff, gangmen and those doing miscellaneous jobs.
“The longevity of each worker was computed from the dates of birth, retirement and death,” Pati said. The researchers cited a number of animal studies that documented the life-shortening effects of weekly shifting of light-dark cycles.
It has been argued that these effects could be mediated through disruption of the circadian rhythm. Lighting schedule manipulation has also been reported to produce detrimental effects on the lifespan of insects.

Mouse model for Bipolar Disorder

I made only a brief mention of the study when the press release first came out, but the actual paper (which is excellent) is out now. It is on PLoS so it is free for all to see: Mania-like behavior induced by disruption of CLOCK:

Circadian rhythms and the genes that make up the molecular clock have long been implicated in bipolar disorder. Genetic evidence in bipolar patients suggests that the central transcriptional activator of molecular rhythms, CLOCK, may be particularly important. However, the exact role of this gene in the development of this disorder remains unclear. Here we show that mice carrying a mutation in the Clock gene display an overall behavioral profile that is strikingly similar to human mania, including hyperactivity, decreased sleep, lowered depression-like behavior, lower anxiety, and an increase in the reward value for cocaine, sucrose, and medial forebrain bundle stimulation. Chronic administration of the mood stabilizer lithium returns many of these behavioral responses to wild-type levels. In addition, the Clock mutant mice have an increase in dopaminergic activity in the ventral tegmental area, and their behavioral abnormalities are rescued by expressing a functional CLOCK protein via viral-mediated gene transfer specifically in the ventral tegmental area. These findings establish the Clock mutant mice as a previously unrecognized model of human mania and reveal an important role for CLOCK in the dopaminergic system in regulating behavior and mood.

If that is too technical for you, check out a nice summary by Grrrlscientist and for the background (and some additional information), you may want to check out this post of mine.

A Circadian Clock that works in a test-tube explained

Blogging on Peer-Reviewed Research

One of the big questions in circadian research is how does the transcription/translation feedback loop manage to get stretched to such a long time-frame: 24 hours. If one took into account the normal dynamics of transcription and translation, the cycle would last a couple of hours at best. The usual answer is that, probably, interactions with a variety of other cellular components slows down the cycle. And this may be correct in Eukaryotes, but a paper came out a couple of years ago showing that placing three cyanobacterial clock genes and some ATP into a test-tube results in a 24-hour cycle. That was quite a shocker!
Now, a new paper in PLoS-Biology (free for all to read) came out explaining how that is possible:
Elucidating the Ticking of an In Vitro Circadian Clockwork:

Circadian biological clocks are present in a diverse range of organisms, from bacteria to humans. A central function of circadian clocks is controlling the adaptive response to the daily cycle of light and darkness. As such, altering the clock (e.g., by jet lag or shiftwork) affects mental and physical health in humans. It has generally been thought that the underlying molecular mechanism of circadian oscillations is an autoregulatory transcriptional/translational feedback loop. However, in cyanobacteria, only three purified clock proteins can reconstitute a circadian rhythm of protein phosphorylation in a test tube (in vitro). Using this in vitro system we found that the three proteins interact to form complexes of different compositions throughout the cycle. We derived a dynamic model for the in vitro oscillator that accurately reproduces the rhythms of complexes and of protein phosphorylation. One of the proteins undergoes phase-dependent exchange of its monomers, and the model demonstrates that this monomer exchange allows the maintenance of robust oscillations. Finally, we perturbed the in vitro oscillator with temperature pulses to demonstrate the resetting characteristics of this unique circadian oscillator. Our study analyzes a circadian clockwork to an unprecedented level of molecular detail.

A similar mathematical model was recently published on the clock in the fungus Neurospora crassa.

Cortisol necessary for circadian rhythm of cell division

A new paper just came out today on PLoS-Biology: Glucocorticoids Play a Key Role in Circadian Cell Cycle Rhythms. The paper is long and complicated, with many control experiments, etc, so I will just give you a very brief summary of the main finding.
One of the three major hypotheses for the origin of circadian clocks is the need to shield sensitive cellular processes – including cell division – from the effects of UV radiation by the sun, thus relegating it to night-time only:

The cyclic nature of energetic availability and cycles of potentially degrading effects of the sun’s ultraviolet rays on particular pigmented enzymes, provided the selective environment. A cell with a timer can predict the changes and adjust its metabolic activities to minimize energetic and material loss. This cell will outcompete the other cells in the Archeozoic sea (Pittendrigh 1967).

Biological clocks in various organisms regulate timing of many different biochemical, physiological and behavioral events, but the circadian control of cell-cycle is really ubiqutous – it has been found in everything from bacteria to humans.
In many large organisms, the distinction between pacemakers and peripheral clocks is mainly in the ability of the pacemaker to synchronize itself to the outside environment and to send daily signals that act to synchronize all the peripheral clocks in all the cells in the body. The local clocks, then, regulate timing of local events.
In some organisms, peripheral clocks are also capable of direct sampling of the environment. Zebrafish is one such animal – its peripheral clocks (in every cell of the body) are photosensitive and entrainable directly by light-dark cycles. Only in constant light conditions does the brain pacemaker assume the role of the “conductor of the orchestra”, synchronizing all the clocks in the body.
In vertebrates, it has been thought for a long time now that the central pacemaker (the SCN in the hypothalamus of the brain) uses, among else, cortisol as a signal for synchronizing the peripheral clocks. It times the release of corticotropins from the pituitary which in turn releases cortisol from the adrenal gland into the circulation at particular time of day. Various tissues are sensitive to cortisol and will use its surge as a timing/entraining signal.
In this paper, circadian rhythms of cell-division were shown to get attenuated in mutants that do not produce corticotropins (and thus do not produce cortisol). However, the clock genes still cycle normally in the periphery. Placing the fish in continous bath of cortisol agonist reinstates the circadian rhythms of cell division.
This suggests that cortisol is not a timing signal from the center to the periphery as the peripheral clocks keep cycling in its absence (and entrain directly – no need for any input from the eyes).
This also suggests that cortisol is neccessary for the coupling of the peripheral clock mechanism and its own output – the cell cycle. The presence of cortisol need not be rhythmic – it just needs to be there if the clock is to time the daily rhythms of cell division.

A potential animal model for Bipolar Disorder

It has been known for quite a while now that bipolar disorder is essentially a circadian clock disorder. However, there was a problem in that there was no known animal model for the bipolar disorder.
Apparently that has changed, if this report is to be believed:

“There’s evidence suggesting that circadian genes may be involved in bipolar disorder,” said Dr. Colleen McClung, assistant professor of psychiatry and the study’s senior author. “What we’ve done is taken earlier findings a step further by engineering a mutant mouse model displaying an overall profile that is strikingly similar to human mania, which will give us the opportunity to study why people develop mania or bipolar disorder and how they can be treated.”

PERIOD clock gene variants affect sleep need in humans

The most exciting thing about this study is that this is, as far as I am aware, the first instance in which it was shown that a circadian clock gene has any effect on sleep apart from timing of it, i.e., on some other quality or quantity of sleep (not just when to fall asleep and wake up, but also the depth of sleep and the amount of sleep need):
Performing Under Sleep Deprivation: Its In Your Genes:

People are known to differ markedly in their response to sleep deprivation, but the biological underpinnings of these differences have remained difficult to identify.
Researchers have now found that a genetic difference in a so-called clock gene, PERIOD3, makes some people particularly sensitive to the effects of sleep deprivation. The findings, reported by Antoine Viola, Derk-Jan Dijk, and colleagues at the University of Surrey’s Sleep Research Center, appear in the journal Current Biology, published by Cell Press.
There are two variants of the PERIOD3 gene found in the human population, encoding either long or short versions of the corresponding protein. Each individual will possess two copies of the gene, either of which might be the long or short form. Previous work had indicated that the different forms of the gene appear to influence characteristic morning and evening activity levels–for example, “owl” versus “lark” tendencies.
In the new work, a multidisciplinary research team consisting of biological scientists and psychologists compared how individuals possessing only the longer gene variant and those possessing only the shorter one coped with being kept awake for two days, including the intervening night. The researchers found that although some participants struggled to stay awake, others experienced no problems with the task.
The results were most pronounced during the early hours of the morning (between 4 and 8 a.m.), during which individuals with the longer variant of the gene performed very poorly on tests for attention and working memory.
The authors point out that this early-morning period corresponds to stretches of time when shift workers struggle to stay awake, during which many accidents related to sleepiness occur. But the scientists also emphasize that the new research was conducted in the laboratory, and whether forms of the PERIOD3 gene also predict individual differences in the tolerance to night-shift work remains to be demonstrated.
An additional finding was that the effects of this gene on performance may be mediated by its effects on sleep. When the volunteers were allowed to sleep normally, those possessing only the longer form of the gene spent about 50% more of their time in slow-wave sleep, the deepest form of sleep. Slow-wave sleep is a marker of sleep need, and it is known that carrying a sleep debt makes it very difficult to stay awake and perform at night.
The findings highlight a possible role for clock genes in human sleep physiology and structure, and the influence these genes might have on performance by unrested individuals.

In Memoriam: Charles Frederick Ehret, 1924-2007

This news just came in:

Charles F- Ehret died of natural causes on February 24th at his home in Grayslake, Illinois, a suburb of Chicago.

His Wikipedia entry is quote short:

Charles Frederick Ehret is a WWII veteran (Battle of the Bulge/Ardennes along the Siegfried Line) as well as a world renowned molecular biologist who worked at Argonne National Laboratory (ANL) in Lemont, Illinois, USA, for 40 years. Dr. Ehret researched the effects of electromagnetic radiation on bacillus megaterium with Dr. Edward Lawrence (Larry) Powers, as well as the effects of time shifts on paramecia, rats and humans. A graduate of City College of CCNY (College of the City of New York) and the University of Notre Dame, Dr. Ehret formulated the term “circadian dyschronism”, popularized the term “zeitgeber” = “time giver” in the 1980’s while appearing on morning TV news shows, and helped millions of travellers overcome Jet Lag with the Jet Lag Diet, and Overcoming Jet Lag book, both available online. Dr. Ehret once created the worlds largest spectrograph, a rainbow 100 feet long, that was large enough to bathe many petri dishes of tetrahymena in each angstrom of the color spectrum.

While his later interest in human clocks and his book Overcoming Jet Lag made him popular outside of chronobiological circles, within the field he is famous for some ingeniously creative pioneering experiments on circadian clocks in protists, mainly Paramecium and Tetrahymena. Here are the links to a couple of his more popular papers on the topic:
Light synchronization of an endogenous circadian rhythm of cell division in Tetrahymena
Circadian rhythm of pattern formation in populations of a free-swimming organism, Tetrahymena.
Testing the chronon theory of circadian timekeeping (DNA-RNA molecular hybridization testing of chronon theory of circadian timekeeping in protozoa cells)
That last link refers to “the chronon theory” of circadian rhythms, the first serious molecular model for a circadian rhythm generation within a cell, which Ehret proposed back in 1967 when he was only one of a handful of researchers who were actively trying to study the biological clock below the level of the cell. Thus, his longest lasting contribution to science will not be his jet-lag book (which is already a bit aged), but his original Chronon paper:
Ehret, C. F., and Trucco, E., (1967), Molecular models for the circadian clock. I. The chronon concept., J. theor. Biol., 15, 240-262 .
I have mentioned the Chronon Model earlier, when I wrote a quick review of the history of clock genetics and this is what I wrote:

In this model, a series of genes induce each other’s expression, i.e., protein A induces trasncription of gene B, protein B induces expression of gene C and so on until the last protein in the series, about 24 hours later, induces expression of gene A again. This model is, actually, not that far from the currently understood mechanism of interlocking trasncription/translation feedback loops

Lesson of the Day: Circadian Clocks are HARD to shift!

This is a story about two mindsets – one scientific, one not – both concerned with the same idea but doing something very different with it. Interestingly, both arrived in my e-mail inbox on the same day, but this post had to wait until I got out of bed and started feeling a little bit better.
First, just a little bit of background:

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Small Arctic Mammals Entrain to Something during the Long Summer Day

There are several journals dedicated to biological rhythms or sleep. Of those I regularly check only two or three of the best, so I often miss interesting papers that occur in lower-tier journals. Here is one from December 2006 that caught my eye the other day:
Mammalian activity – rest rhythms in Arctic continuous daylight:

Activity – rest (circadian) rhythms were studied in two species of Arctic mammals living in Arctic continuous daylight with all human-induced regular environmental cues (zeitgebers) removed. The two Arctic species (porcupine and ground squirrel) lived outdoors in large enclosures while the Arctic summer sun circled overhead for 82 days. Would local animals maintained under natural continuous daylight demonstrate the Aschoff effect described in previously published laboratory experiments using continuous light, in which rats’ circadian activity patterns changed systematically to a longer period, expressing a 26-hour day of activity and rest? The outdoor experiments reported here, however, showed that under natural continuous daylight, both species (porcupine and ground squirrel) had specific times of activity and rest on a nearly 24-hour scale, and their activity peaks did not come later each day. The daily rhythms of the two species were recorded using implanted physiological radio capsules, and from direct observation.

You may recall that I wrote about a similar study in a much larger Arctic mammal – the reindeer, which loses the overt behavioral rhythmicity during the long summer. Apparently, these two small mammals, the porcupine and ground squirrel are different.
In the press release, they explain:

It seemed that although the scientists were very careful not to provide time cues of any sort, the animals had managed to latch onto something that gave them regularity.
“I have written for years that experimental animals seem to be hungry for cues, or time signals, to keep on a regular cycle,” Folk said. “So we tried to figure out what cue the wild animals were using, and we could find only one thing that kept a 24 hour periodicity. At Barrow, the sun travels in a circle overhead for 82 days, but at midnight the circle is tipped to the north.
“We postulate that the animals are conscious of where the sun is in the sky and that the nearness of the sun to the horizon could be a clue to animals, and even plants, to keep on a 24-hour schedule.”

This is an interesting hypothesis: not just using the clock to orient by Sun, but also using the Sun posiiton to entrain the clock. I hope this gets tested and that this was not just a case of investigators missing an alternative environmental cue. Changes in the Earth’s magnetic field show daily oscillations and are potentially one of such alternative cues that animals could use. Just like Dr.Folk states in the article, I’d also like to see this study replicated in Arctic birds, as they are known to be sensitive to the magnetic field which they can use for migratory orientation.

The Lark-Mouse and the Prometheus-Mouse

Two interesting papers came out last week, both using transgenic mice to ask important questions about circadian organization in mammals. Interestingly, in both cases the gene inserted into the mouse was a human gene, though the method was different and the question was different:

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Greenwich time to remain Greenwich time

In light of my post earlier today about the discrepanices between ‘real time’ and ‘clock time’ (or ‘social time’), it is heartening that the Parliament in the U.K. wisely decided not to switch their clocks to the time the rest of Europe observes. If they did, they would be seriously out of whack. After all, at Zero Meridian in Greenwich (yup, I stood astride it, of course), midnight is really midnight – it is the middle of the time zone. Resetting it by one hour would put the Brits at the far Western edge of another time zone and they would always experience true midnight a long time (60-120 minutes!) after the clocks say it is midnight (the same goes for dawn, noon, dusk and any other time).
Now, if they (and us and everyone else) could only decide not to go through the twice-annual ritual of re-setting the official clocks by one hour (Spring forward, Fall back), that would save a lot of lives….

New Model for Interval Timing

While study of Time-Perception is, according to many, a sub-discipline of chronobiology, I personally know very little about it. Time perception is defined as interval timing, i.e., measuring duration of events (as opposed to counting, figuring which one of the two events happened first and which one second, or measuring time of day or year).
Still, since this blog is about all aspects of biological timing, I have to point you to a new paper in Neuron (press release) about a new computer model for human time-perception.

“If you toss a pebble into a lake,” he explained, “the ripples of water produced by the pebble’s impact act like a signature of the pebble’s entry time. The farther the ripples travel the more time has passed.
“We propose that a similar process takes place in the brain that allows it to track time,” he added. “Every time the brain processes a sensory event, such as a sound or flash of light, it triggers a cascade of reactions between brain cells and their connections. Each reaction leaves a signature that enables the brain-cell network to encode time.”

Of course, this is a little vague as far as neurophysiology goes, and we need to remember that even the most brilliant mathematical model may end up being wrong. Still, the model seems nifty and I hope they follow up with real lab work to test it.
Steve of Omni Brain has more and points to this 2005 review of the topic in Nature Review Neuroscience.

Sun Time is the Real Time

Blogging on Peer-Reviewed Research

If you really read this blog “for the articles”, especially the chronobiology articles, you are aware that the light-dark cycle is the most powerful environmental cue entraining circadian clocks. But it is not the only one. Clocks can also be entrained by a host of other (“non-photic”) cues, e.g., scheduled meals, scheduled exercise, daily dose of melatonin, etc.

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Mammalian SCN

TITLE If you are interested in the background and recent history of the research on mammalian SCN in line of Erik Herzog’s work I described in VIP synchronizes mammalian circadian pacemaker neurons and A Huge New Circadian Pacemaker Found In The Mammalian Brain, you may want to look at these old Circadiana posts as well:

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ClockNews

Memory Experts Show Sleeping Rats May Have Visual Dreams:

Matthew A. Wilson, professor of brain and cognitive sciences at MIT’s Picower Institute for Learning and Memory, and postdoctoral associate Daoyun Ji looked at what happens in rats’ brains when they dream about the mazes they ran while they were awake.
In a landmark 2001 study, Wilson showed that rats formed complex memories for sequences of events experienced while they were awake, and that these memories were replayed while they slept–perhaps reflecting the animal equivalent of dreaming.
Because these replayed memories were detected in the hippocampus, the memory center of the brain, the researchers were not able to determine whether they were accompanied by the type of sensory experience that we associate with dreams–in particular, the presence of visual imagery.
In the latest experiment, by recording brain activity simultaneously in the hippocampus and the visual cortex, Wilson and Ji demonstrated that replayed memories did, in fact, contain the visual images that were present during the running experience.
“This work brings us closer to an understanding of the nature of animal dreams and gives us important clues as to the role of sleep in processing memories of our past experiences,” Wilson said.

Sleepless in the Aquarium:

You’d think fish would not have that much on their minds to keep them up at night. But this week, Prober et al. describe transgenic zebrafish with a sleep disorder, a model system that may be useful in studies of sleep regulation. The authors first determined that hypocretin, the best characterized sleep wake regulator in mammals, is expressed in hypothalamic neurons of 5-d-old zebrafish in a pattern strikingly similar to that of mammals. The authors then engineered transgenic fish with a hypocretin promoter that could be induced by heat shock. Overexpression of the gene in zebrafish larvae promoted wakeful activity, hyperarousal, and inability to stay still, hallmarks of insomnia in humans. The effects of hypocretin overexpression were more dramatic in the absence of circadian cues, suggesting that the circadian system may normally antagonize hypocretin function.

First Biomarker For Human Sleepiness Identified In Fruit Flies:

Scientists have identified the first biochemical marker linked to sleep loss, an enzyme in saliva known as amylase, which increases in activity when sleep deprivation is prolonged. Researchers hope to make amylase the first of a panel of biomarkers that will aid diagnosis and treatment of sleep disorders and may one day help assess the risk of falling asleep at the wheel of a car or in other dangerous contexts.

A Huge New Circadian Pacemaker Found In The Mammalian Brain

If you really read this blog ‘for the articles’, you know some of my recurrent themes, e.g., that almost every biological function exhibits cycles and that almost every cell in every organism contains a more-or-less functioning clock. Here is a new paper that combines both of those themes very nicely, but I’ll start with a little bit of background first.

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New York Times Gets It Right, Just To Screw Up At The End In Blind Adherence To The He Said/She Said Journalism

New York Times Gets It Right, Just To Screw Up At The End In Blind Adherence To The He Said/She Said JournalismNow behind the Wall, but plenty of excerpts available in this March 26, 2005 post…

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Fetal Alcohol Syndrome Affects The Basic Properties Of The Circadian Clock

Fetal Alcohol Syndrome Affects The Basic Properties Of The Circadian ClockHow does that work? (April 03, 2005)

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VIP synchronizes mammalian circadian pacemaker neurons

Blogging on Peer-Reviewed Research

No other aspect of behavioral biology is as well understood at the molecular level as the mechanism that generates and sustains circadian rhythms. If you are following science in general, or this blog in particular, you are probably familiar with the names of circadian clock genes like per, tim, clk, frq, wc, cry, Bmal, kai, toc, doubletime, rev-erb etc.
The deep and detailed knowledge of the genes involved in circadian clock function has one unintended side-effect, especially for people outside the field. If one does not stop and think for a second, it is easy to fall under the impression that various aspects of the circadian oscillations, e.g., period, phase and amplitude, are determined by the clock genes. After all, most of these genes were discovered by the study of serendipitously occuring mutations, usually period-mutations.
If the circadian properties are really deteremined by clock genes, then the predictions from this hypothesis are that: 1) every cell in the body shows the same period (phase, amplitude, etc.), 2) every cell in the body has the same period throughout its life, 3) every cell removed from the body and placed in the dish continues to oscillate with the same period as it had inside the body, and 4) the properties of the circadian rhythms are not alterable by environmental influences.
Stated this bluntly, one has to recoil in horror: of course it is not determined by genes! But without such an exercise in thinking, much work and writing (especially by the press) tacitly assumes the strict genetic determination. However, the experimental data show this not to be true. Period (and other properties) of the whole organism’s rhythms are readily modified by environmental influences, e.g., light intensity (Aschoff Rule), heavy water, lithium, sex steroids and melatonin. They change with age and reproductive state. There is individual variation even in clonal species (or highly-inbred laboratory strains). The period of the rhythms measured in cells or cell-types in a dish is not always the same as exhibited by the same cells inside the organism. Finally, the occurrence of splitting (of one unified circadian output into two semi-independent components differing in period)suggests that two or more groups of circadian pacemakers simultaneously exhibit quite different periods within the same animal.
Several years ago, Dr. Eric Herzog (disclosure – a good friend) has shown that even the individual pacemaker cells within the same SCN (suprachiasmatic nucleus – the site of the main mammalian circadian clock in the brain) exhibit different periods. When dispersed in culture, pacemaker neurons (originally taken from a single animal) tend to show a broad variation in periods (amplitudes, etc…).
As they grow cellular processes, two neurons in a dish may touch and form connections. As soon as they do, their periods change and from then on the two cells show the SAME period, i.e., they are synchronized. As more and more cells connect, they build an entire network of neurons, all cycling in sync with each other – same period, same phase, same amplitude. This is assumed to happen inside the whole animal as well – the unconnected SCN neurons of the fetus start making connections just before (or immediately after, depending on the species) birth and as a result, an overt, whole-organism rhythm emerges out of arrhytmic background.
But, what molecules are involved in cell-cell communication that allows the pacemaker cells to synchronize their rhythms? For several years, the most likely candidate was thought to be GABA, an inhibitory neurotransmitter produced by all SCN cells. Sara Aton, a graduate student in Eric Herzog’s lab (now postdoc at UPenn), set out to test this hypothesis. Over a few years and several papers, a different story emerged, culminating in this months paper in PNAS:
GABA and Gi/o differentially control circadian rhythms and synchrony in clock neurons. (by Aton SJ, Huettner JE, Straume M and Herzog ED).
What the paper shows – and there is a lot of detail there, so you can read the paper for yourself if interested, or at least the media coverage (here, here and here) – is that various perturbations of the GABA system, either at the synthesis end or the reception end, have, at best, some mild effects on amplitude and phase. There was no effect of GABA on period of individual pacemaker neurons. Yet, effect on period is neccessary for mutual synchronization of cells into a network. Instead, VIP (vasoactive intestinal polypeptide) was shown to be the agent that, by modulating period, allowed spatially coupled cells to also temporally couple – to synchronize their circadian oscillations.
This is a much more important finding than you may think at the first glance. The naive idea of a single clock driving all the overt rhythms has been abandoned for more than half a century. Every important problem in chronobiology – coherence of rhythms, temperature compensation, communication between pacemakers and peripheral clocks, entrainment to environmental cycles, etc. – hinges on the properties of the multi-clock networks. Understanding the biochemical mechanism by which pacemaker cells syncronize with each other is thus a key finding that will allow us to study those phenomena at a cellular and molecular level. Right now, and due to Sara Aton’s work, VIP is the “handle” we will use to revisit those old problems and test our pet hypotheses about the coupling of circadian systems in various animals (the reasonable assumption being that mouse is not unique in using VIP and that this molecule is probably used for the same function in all vertebrates). We can now study exactly how two cells communicate by VIP to synchronize their clocks – is the pattern of VIP release, for instance, used as a kind of temporal “code”?
Probably the most important such phenomenon to study is splitting. Different kinds of spliting have been observed in lizards, starlings, tree-shrews (Tupaia), mice, rats, hamsters, marmosets and many other animals under various experimental conditions, e.g., constant light, constant darkness, removal of the pineal, infusion with testosterone, or exposure to skeleton photocycles. Splitting can be induced by highly artificial experimental protocols, e.g., alternate eye-patching, or they may appear spontaneusly in animals out in the wild, something that can be replicated in the laboratory.
In some cases, it has been shown that the splitting is lateral, i.e., left SCN drives one component and the right SCN drives the other. In the case of alternate eye-patching, it is reasonable to hypothesize that the same thing is happening. But in other cases, it is more likely that each SCN splits into two subsets of neurons, synchronized within but not between the two groups. Is VIP the synchronizer in both groups? In all cases? In all animals?
If, for instance, rhythms split into two componenets under the influence of testosterone, is VIP used for coupling within each of those two semi-independent “clocks”? Does one group of neurons, insensitive to testosterone, use VIP to synchronize its output, while the other group of neurons, under the influence of testosterone, changes its period and also uses VIP to synchronize its output?
Now that we know to use VIP and not GABA as an entry into the system, all of these questions will be much more amenable to future research – an exciting prospect for me and many others in the field.

Clock in the primate adrenal

Blogging on Peer-Reviewed Research

Clock in the primate adrenalOften a press release inflates the meaning of a research paper. Here is one example of it (from May 23, 2006):

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Eight Hours a Circadian Rhythm Do Not Make

Blogging on Peer-Reviewed Research

Eight Hours a Circadian Rhythm Do Not MakeThis post is a relatively recent (May 24, 2006) critique of a PLoS paper.

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Rotating Shift-Work can kill you

Chronic Jet-Lag Conditions Hasten Death in Aged Mice

Researchers at the University of Virginia have found that aged mice undergoing weekly light-cycle shifts – similar to those that humans experience with jet lag or rotating shift work – experienced significantly higher death rates than did old mice kept on a normal daylight schedule over the same eight-week period. The findings may not come as a great surprise to exhausted globetrotting business travellers, but the research nonetheless provides, in rather stark terms, new insight into how the disruption of circadian rhythms can impact well-being and physiology, and how those impacts might change with age.

Waking Experience Affects Sleep Need in Drosophila

Blogging on Peer-Reviewed Research

There is nothing easier than taking a bad paper – or a worse press release – and fisking it with gusto on a blog. If you happen also to know the author and keep him in contempt, the pleasure of destroying the article is even greater.
It is much, much harder to write (and to excite readers with) a blog post about an excellent paper published by your dear friends. But I’ll try to do this now anyway (after the cut).

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Entraining the clock by eating schedules

As the paper linked to in the previous post explains, everything is connected – clocks, sleep, hunger, obesity and diabetes.
An important part of understanding all these interconnections between clocks and food is to understand the food-entrainable clocks, i.e., how timing of meals affects the performance of the circadian clock.
A new paper provides a molecular link between scheduled meals and circadian timing, implicating our old friend PERIOD2 as part of the mechanisms by which timing of the meal entrains the brain clock (but not the mutual entrainment of peripheral clocks):
Circadian gene helps the brain predict mealtime:

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Estrogen, Aggression and Photoperiod

Randy Nelson is a wonderful person, an engaging speaker and the author of the best textbook on Behavioral Endocrinology. I heard that he is also a great teacher which does not surprise me and he has a talent for attracting some of the best students and postdocs to work in his lab. Oh, by the way, he also does some great research.
For decades, the study of seasonality and photoperiodism was a hustling bustling field, until everyone jumped on the clock-gene bandwagon. Randy Nelson is one of the rare birds to remain in the photoperiodism field, coming out every year with more and more exciting papers. Here is just the latest one – supercool! [excerpt under the fold]

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Circadian Rhythms, or Not, in Arctic Reindeer

Blogging on Peer-Reviewed Research

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.