Researchers discover how body’s internal clock generates daily rhythms

Signals from retina and body clock received by same messenger

Establishing a clear link between light and the internal body clock

Boston, MA—Harvard Medical School researchers have gained one of the first glimpses of how the body’s circadian clock—a tiny cluster of nerve cells behind the eyes—sends out the signals that control natural daily rhythms. The newly discovered pathway, reported in the December 21 Science, opens a long-closed door to research that could ultimately lead to new treatments for circadian disturbances such as certain sleep disorders.

"If you could figure out the factors that are promoting wakefulness and sleep, that could in principle be turned into much better drugs for particular sleep disorders," said Chuck Weitz, HMS professor of neurobiology.

Circadian researchers have been remarkably successful in the past few years at identifying the molecular machinery—the genes and proteins—that make the circadian clock cells tick on a near 24-hour basis. But they were stymied when it came to figuring out how the machinery of these cells, located in the brain’s suprachiasmatic nucleus (SCN), actually drives such daily rhythms as the rise and fall of body temperature and the sleep–wake cycle. Researchers suspected that to achieve such rhythmic patterns, the clock must be switching molecular factors on and off, and even had an idea where in the brain the factors might reside, but no one had actually found any of them. Until now.

Weitz; Achim Kramer, HMS research fellow in neurobiology; and their HMS colleagues have identified the first of several factors controlling circadian locomotor patterns in a mammal, in this case the hamster. (Circadian movement patterns, which are characterized by periods of spontaneous physical activity occuring at the same time each day, exist in humans but are highly influenced by external factors.)

In addition, they have found that the factor, TGF-alpha, works through a middleman, the EGF receptor. Both proteins appear to be highly expressed in exactly the spots that had been predicted—TGF-alpha in the SCN and the EGF receptor in the nearby hypothalamus. Yet there are several unexpected aspects of the discovery. To begin, it appears that the duo regulate not just daily physical activity patterns but also the alternating pattern of wakefulness and sleep.

More surprising, perhaps, is the discovery that the EGF receptor middleman appears to receive information, in the form of TGF-alpha, not just from the clock but also from the eyes. The reason this is exciting is that circadian rhythms, though controlled by the clock, can be influenced by the outside world, particularly light, transmitted through the retina.

"In the real world it is both effects—the clock effect and some light effect that are really sculpting behavior," said Weitz. "No one had explicitly raised the possibility that the signal from the retina and the SCN might involve the same ligand or at least a ligand for the same receptor."

The group's discoveries made in hamsters are strengthened by their discovery that a strain of mutant mice with deficient quantities of EGF receptor do not display normal circadian movement patterns. "It all fits together," said Weitz.

This discovery illustrates how important flexible, private research funds are to opening new avenues of research. Weitz and colleagues were able to collect their data while supported solely through a grant from the Lefler Center for the Study of Neurodegenerative Disorders, which supports pilot research projects (http://neuro.med.harvard.edu/site/admin/Lefler/leflercenter.html). The Center’s grants make it possible for faculty and postdoctoral students to collect data in new scientific areas, and then apply for important federal grants using this vital pilot data.

Next, Weitz wants to explore whether the systems controlling other circadian behaviors are as elegant as the one controlling locomotion and sleep. "This is one step that gives us a way to look at these things that we did not have before," he said.

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