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NEUROBIOLOGY Link Found Between Body Rhythms and Circadian Clock, LightPathway Involves Input from Eyes as Well as Clock A recent study reveals one of the first glimpses of how the brain's circadian clock--a tiny cluster of neurons behind the eyes--sends out signals that control the body's daily rhythms. The newly discovered pathway opens a long-closed door in the field of circadian clock research and could ultimately lead to novel treatments for sleep disorders and other circadian disturbances.
"No one had any idea about the molecular pathway or the particular cells involved in these circadian behaviors," said Charles Weitz, speaking of daily locomotor activity and the sleep-wake cycle. "Now, we can mark which cells are involved and which pathway." Photo by Philip Farnsworth "If you could figure out the factors that promote wakefulness and sleep, that could in principle be turned into better drugs for particular sleep disorders," said Charles Weitz, HMS professor of neurobiology. His team's findings appear in the Dec. 21 Science. Circadian researchers have been remarkably successful in the past few years at identifying the molecular machinery that makes the clock cells of the suprachiasmatic nucleus (SCN) tick on a nearly 24-hour basis. But they were stymied when it came to figuring out how that machinery actually drives daily rhythms such as the rise and fall of body temperature and the sleep-wake cycle. They suspected that the rhythmic patterns were achieved by a turning on and off of behaviors and that this switching was produced by factors for activation and inhibition. They even had an idea where the factors might reside in the brain, but no one had yet found any.
Stop SignalsWeitz, Achim Kramer, and their colleagues have identified the first of what could be several inhibitory factors controlling the circadian rhythm of locomotion in a mammal, in this case, the hamster. (Circadian locomotor patterns, which are characterized by periods of spontaneous movement occurring 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 molecular duo regulates 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. This is exciting because circadian rhythms, though controlled by the clock, could be influenced by the outside world and, specifically, by 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." Out of ActionTo find the missing factors, Weitz, Kramer (who was then an HMS research fellow in neurobiology), and their colleagues introduced SCN-produced proteins into the brains of hamsters for a period of three weeks to see which might inhibit the normal locomotor activity pattern. Normally, the nocturnal hamsters are very predictable--jumping on a running wheel at almost exactly the same time each evening and for the same duration. The hamsters receiving TGF-alpha, however, refrained from this habit for the three-week experimental period. At the end of this time, they jumped right back on the wheel. But it was still not certain whether their laxity during the experiment had been due to some disruption in their circadian rhythm or to a more basic motor impairment.Once the researchers confirmed that TGF-alpha was working through the EGF receptor and that the pair was located in the expected regions, they conducted a series of physiological tests on the TGF-alpha animals to answer this question. The tests showed that the animals moved just fine around their cages, though not on the wheel, suggesting their motor systems were intact. Yet their sleep patterns were strange. "It appeared the high concentration of TGF-alpha was blocking some circadian input and removing them from the sleep-wake cycle," said Weitz. Since the animals had been experimentally manipulated, Weitz and his colleagues still wanted to know if TGF-alpha and the EGF receptor were regulating circadian patterns in the real world. Fortuitously, nature had produced a convenient experiment: a strain of mice with a defective version of the EGF receptor. "No one had ever looked at their locomotor patterns," said Weitz. It turned out that the mice--deprived of the full inhibitory activity of the receptor--were much more active than normal mice. Intriguingly, the disparity with normal mice was more marked in animals living under a normal light-dark regimen than those living in total darkness. Normal mice, when exposed to light, stop moving, perhaps as an adaptive response, which can result in less activity. The researchers found that this effect was impaired in the EGF receptor-deficient mice raised under light-dark conditions, which exaggerated their difference with normal mice raised similarly. Thinking that the EGF receptor might be receiving signals from the retina as well as the clock, the researchers looked for TGF-alpha in the retina. They found it, along with another receptor-stimulating protein, EGF. "So it all fits together," Weitz said. --Misia Landau |
