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How Does Anybody Really Know What Time it Is?

Circadian protein identified in brain, eye

FRIDAY, Dec. 21, 2001 (HealthDayNews) -- A protein linked to some cancers may serve a more useful purpose: helping the body keep time with the sun and stars.

The chemical, called transforming growth factor-alpha (TGF-a), signals mammals when to get active or go idle. But a new study says it also appears to be the first direct molecular connection between the eyes, the brain and circadian rhythm -- the internal clock that regulates cycles of sleeping and waking, movement and rest and other body functions.

Scientists have known that light helps organisms regulate their activity, and evidence has pointed to cells in the retina -- though not vision tissue -- as key to the process. Yet so far, they've identified few specific chemical agents for this mission.

Gianluca Tosini, a circadian rhythm expert at Morehouse School of Medicine, in Atlanta, says the findings "could be very, very important."

Modern society obeys the call of business, not the bed, working all hours of the night, when our ancestors were asleep in their caves. "This continuous phase shifting can have serious affects on the health of people," Tosini says, including cardiovascular complications and attention lapses that can lead to accidents. "By knowing the mechanism by which we can control our locomotor activity we can design [drugs] to avoid some of these problems."

Dr. Charles Weitz, a Harvard University brain biologist, led the new study, which appears this week in the journal Science.

Screening the brains of hamsters for clock regulating chemicals, the researchers hit on TGF-a, which is found in overabundance in people with head and neck cancers. They found it is produced cyclically in an area of the organ called the suprachiasmatic nucleus (SCN). This region is known to play a role in circadian rhythm, but its exact mechanics have remained elusive.

Near the SCN, TGF-a interacts with epidermal growth factor (EGF) receptors atop a bundle of neurons in the hypothalamus called the SPZ. The hypothalamus is a master regulator in charge of everything from body temperature to sex drives.

Normally, TGF-a levels peak when an animal is resting and ebb when it's time to be active. But Weitz and his colleagues found that hamsters whose brains were continuously infused with the protein quit running on their exercise wheels. When the infusion stopped, the animals quickly began to trot again at their normal times, suggesting that TGF-a was indeed inhibiting their locomotor "on" cycle.

EGF also blocked hamster locomotion, confirming that its receptors are the detectors for motor action signals, the researchers say. In addition to keeping hamsters lazy, TGF-a infusions also threw off their sleep-wake and body temperature cycles, say the researchers.

Mammals have twin clock systems: the built in metronome, which appears to be the SPZ, which responds to secreted chemicals; another system reacts to external stimuli such as light -- a process called masking.

In a separate experiment, the researchers showed that mutant mice with weak EGF receptors ran about three times as much during the day -- when they should have been relatively quiet -- as genetically normal mice. Mice and hamsters are nocturnal creatures, unlike day-active, or diurnal, humans.

The animals also had incomplete responses to light pulses that hushed the wheel-running of their normal cage mates. That, the researchers say, indicates EGF and its receptors are vital to masking.

Both TGF-a and EGF are present in human retina cells. Looking for these molecules in the eyes of mice, Weitz and his colleagues found both, and in areas of the retina that suggest they're involved in signaling to EGF receptors located back in the hypothalamus.

What seems to happen, they say, is that light signals, in the form of EGF or TGF-a, work their way from the retina to the hypothalamus, while TGF-a produced cyclically in the SCN does, too. Together they create circadian circuitry that keeps animals in rhythm.

What To Do: To learn more about sleep-wake cycles and how they can go awry, try Stanford University. You can also check the University of Chicago.

SOURCES: Interviews with Charles J. Weitz, M.D., Ph.D., associate professor of neurobiology, Harvard Medical School, Boston; Gianluca Tosini, Ph.D., associate professor of anatomy and neurobiology, Neuroscience Institute, Morehouse School of Medicine, Atlanta; Dec. 21, 2001, Science
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