Scientists Closer To Understanding How Internal Clock Resets

February 11, 1997

CHAMPAIGN, Ill. -- A five-minute flash of light in the night can reset an animal's biological clock, say scientists who report getting closer to understanding how that adjustment happens.

Two years ago, University of Illinois researchers reported in the journal Science that glutamate, a common neurotransmitter produced in nerve cells, was the messenger of light between the retina and the brain. Now, in the Jan. 15 issue of the Journal of Neuroscience, the U. of I. team details the earliest known molecular change that occurs in the time-shifting pathway.

Knowing how to adjust biological rhythms is of obvious interest to long-distance air travelers, night-shift workers and people suffering from winter depression.

In the new report, based on their work administering glutamate in rats, the researchers -- led by Martha U. Gillette, a professor of cell and structural biology and of physiology, and Jian M. Ding, a National Institutes of Health postdoctoral fellow -- propose a signaling pathway:

Light causes the retina to release glutamate, which binds to receptors in a portion of the brain's hypothalamus known as the suprachiastic nucleus. The receptor stimulates an enzyme that synthesizes nitric oxide, a gas that can freely flow through other cell membranes. The nitric oxide, the team discovered, activates additional enzymes that add phosphate to a nuclear protein called CREB.

Once CREB receives the phosphate, Ding said, the pivotal message is delivered to turn on genes that reset the clock. While additional steps may be involved, identifying the precise genes eventually may help scientists develop artificial techniques for readjusting daily rhythms.

As they reported two years ago, glutamate given during the day again did not alter the animals' biological clocks, suggesting strongly that the time of light treatment may be vitally important. The key to the sensitivity may lie in the so-far unidentified signaling elements that occur between the synthesis of nitric oxide and the phosphorous addition to CREB, the scientists conclude.

"When you give an animal a flash of light at night for just five minutes, you can permanently reset its clock," Ding said. "Such a long-lasting behavioral change requires an alteration in gene expression. Since P-CREB [the phosphate-containing form] is induced in five minutes after light exposure, it is the earliest possible molecular change we've caught in a complicated sequence of events.

"When you learn how to swim or ride a bicycle, you remember how for the rest of your life," he added. "To the eyes of a neurobiologist, the molecular mechanism mediating learning and memory is quite similar to that mediating circadian rhythm phase-shifting."

The research was funded by a Public Health Service grant and by the National Institute of Neurological Diseases and Stroke. Other U. of I. co-authors in the January report were Lia E. Faiman, a senior research scientist, and graduate students William J. Hurst and Liana R. Kuriashkina.

University of Illinois at Urbana-Champaign

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