August 2001

From Washington University in St. Louis

Sleepless aged rats show biological clock problems

One of the problems of the aged is getting a good night’s sleep. Often, the elderly sleep fitfully through the night only to be overcome by drowsiness during the day and nodding off then. A general feeling of tiredness and irritability goes hand-in-hand with this condition. Now a biologist at Washington University in St. Louis and colleagues from France and the University of Virginia have found this problem may be traced to a faulty biological clock — at least in aged rats.

Erik Herzog, Ph.D., assistant professor of biology at Washington University, examined cells involved in the generation of circadian rhythms — the 24-hour cycles in things like alertness and hormone levels. In collaboration with Fabienne Aujard, D.V.M., Ph.D., of France’s Centre National de la Recherche Scientifique, and Gene Block, Ph.D., professor of biology at the University of Virginia, Herzog found that the electrical activity of the clock cells in aged rats was not regular compared with that of young and middle-aged rats.

"In the case of the aged rats, many of them showed fragmented behavioral rhythms," Herzog explained. "They were still rhythmic, but showed bouts of activity when the rats normally would have rested and inactivity when the young animals were active. "So, the rats, like elderly humans, took naps when they would have normally been active. Remarkably, the cells in their biological clock reflected this behavior."

The research is supported by the National Institutes of Health and will be published in the forthcoming issue of Neuroscience. Herzog cannot surmise exactly what role aging is playing in this irregularity, but he doesn’t think it’s a result of the circadian rhythm network breaking down.

"The deterioration of rhythmicity would appear to be a single cell property," he said. "The individual pacemaker cells appear to be losing their ability to mark time. We could argue that this is evidence of aging acting at the level of single cells."

The hub of circadian rhythm in rats and humans and other mammals is found in the suprachiasmatic nucleus (SCN), a part of the hypothalamus that can be found on the bottom of the brain just above the roof of your mouth where your optic nerves cross. There are roughly 10,000 cells in this nucleus. The timekeeping mechanism in these cells depends on daily cycles in gene activity. The first of these genes identified in mammals was called CLOCK, for "circadian locomotor output cycles kaput."

The first thing that Herzog and his collaborators have established in studying this region is that SCN neurons can act as autonomous pacemakers, keeping time without input from other cells. While the SCN is required for circadian rhythmicity, there are other circadian oscillators in the body and in different parts of the brain. However, without the SCN, other circadian rhythms disappear. Herzog and his colleagues study rat SCN cells in vitro — outside the body — and hope to gain knowledge of how these cells normally work and what happens in cases of jet lag, shift work, blindness, fever, aging and other conditions that appear to alter our daily schedules.

"We think that there is a master clock in the SCN, and many ‘slave’ clocks in the brain and body," Herzog said. "The ‘slave’ clocks may receive daily synchronizing signals from the master, but when they get out of phase, it takes several days to catch up. That very well may be happening with jet lag. It’s not the SCN that gets out of whack in a different environment – for instance, after flying to Paris – but other structures inside and outside of the brain."












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