A Blog Around The Clock

A very cool study that I could not help but comment on (January 18, 2006)…

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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:

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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.
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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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