Waking to the Idea that Our Timeclocks Are in Our Brain

TORONTO —  New evidence confirms that mankind’s daily cycles of sleeping and waking, so easily disrupted by travel through different time zones, are driven by an internal chemical mechanism rather than by environmental cycles of light and darkness, researchers say.

The new information results from a study of a recently discovered strain of hamsters whose daily rhythms, called circadian rhythms, are four hours shorter than normal. Biologists Michael Menaker and Martin Ralph of the University of Virginia have found that transplantation of a small section of the brain from those animals into normal hamsters gives the recipients an abnormal circadian rhythm identical to that of the donor.

Menaker believes that the newly discovered hamster strain may shed new light on certain human sleep disorders. A circadian cycle of abnormal length like that of the hamsters, he speculated, could be the cause of seasonal affective disorder, in which affected individuals enter deep depressions as the hours of daylight grow shorter in the autumn. Such a defect might also explain why some individuals have great difficulty functioning at the normal day-and-night pace of society.

The discovery also represents “one of the few demonstrations that transplanted brain tissues can alter specific behaviors in animals,” Menaker told a recent meeting of the Society for Neuroscience. All organisms except bacteria have circadian rhythms that govern both metabolic processes and behavior. In mammals, as many as 50 different rhythms exist, including those for sleeping and waking, body temperature, liver function, cell division and resistance to drugs.

If humans are placed in an environment without any external cues to day and night, they will become “free-running” and their circadian rhythms will return to their normal length, about 24 3/4 hours. In other words, they will go to sleep about an hour later each day.

Light synchronizes the circadian rhythm with a 24-hour day. But when an individual travels from one time zone to another, two or three days are required for resynchronization with the light-dark cycle at the new location. Different circadian cycles become synchronized at a different rate, producing the disorientation called jet lag.

Some had thought that it was actually the light and dark that set the rhythms, but this latest research confirms otherwise, the scientists say.

In animals, the circadian rhythms are thought to be produced by one of two organs. In most birds, research had shown that the source is the pineal gland, a light-sensitive organ in the brain.

In mammals, the situation was not as clear. A section of the brain called the supra-chiasmatic nucleus was thought to be the source of circadian rhythms, but that had not been proved. Surgical removal of the nucleus abolished circadian rhythms and transplants restored them. “But it was possible that the supra-chiasmatic nucleus was simply allowing rhythms to be expressed rather than creating them,” Ralph said.

Then Ralph, who was a graduate student at the time, discovered a hamster with an abnormal circadian rhythm in a shipment of new animals. While hamsters normally have a free-running period of 24.2 hours, the abnormal hamster had a period of only 20 hours.

The abnormality, they discovered, was tied to a specific gene because it could be passed on to progeny. Cross-breeding experiments showed that if a hamster had two copies of the defective gene, its free-running period was 20 hours; if it contained one copy, its period was 22 hours.

The discovery set the stage for proof that the supra-chiasmatic nucleus generates circadian rhythms. Transplant experiments showed that the recipient hamster always developed the free-running period of the donor, whether the donor’s period was 20, 22, or 24 hours. “They are very clean experiments with no ambiguities,” Menaker said.

Unfortunately, biologists still do not know how either the pineal gland or the supra-chiasmatic nucleus generates a circadian rhythm. “That is the $64 question,” Menaker said.

But the discovery of the mutant gene, he added, will make it possible for researchers to compare the supra-chiasmatic nuclei from hamsters with different periods to obtain hints about how the circadian period is generated. Isolation of the gene itself may also provide new insights.