Dec. 6, 1999 CHAMPAIGN, Ill. - Is your biological clock out of kilter? Researchers say they have identified an important molecule in the retina-brain pathway that is crucial to adjusting the clock.
In the Nov. 9 issue of the Proceedings of the National Academy of Sciences, the scientists point a finger at pituitary adenylyl cyclase-activating peptide (PACAP), whose function had been a mystery. In both animal and cellular studies, they found that PACAP works in concert with glutamate, another molecule in the nerve fibers between the retina and hypothalamus, home of the circadian clock.
"This study provides insight as to how the complex external signals that we encounter daily, such as the range of light intensities, are encoded and communicated to the brain," said Martha Gillette, the head of the department of cell and structural biology at the University of Illinois. "Light that you experience at night triggers the release of both glutamate and PACAP. The ratio probably depends on the intensity of the light stimulus."
Gillette's lab in 1994 reported that glutamate adjusts the clock in the presence of light at night. "PACAP fine tunes the glutamate signal," she said. "Together they convey more than just light is present. They encode information about light properties that is taken back to the clock, allowing it to adjust forward or backward appropriately."
The study - funded by the National Institute of Neurological Disorders and Stroke and the Danish Medical Research Council - focused on PACAP after a Danish group discovered that the molecule was localizing in the neural pathway. The question became what was PACAP doing?
"Adding exogenous PACAP together with glutamate had a negative effect on the amplitude of the clock-resetting effect of glutamate, which itself has the same effect on clock-resetting as light under laboratory conditions," Gillette said. "The surprise was that when we used fragments of the PACAP peptide as a control, the result was not that of glutamate alone. Rather, the effect was shifted in the opposite direction to increasing PACAP."
Applying antibodies to block the effect of PACAP that might be released from the optic nerve fibers in brain-slice preparations had the same effect. "This meant that PACAP was indeed released from the optic nerve when the glutamate was. It is a normal, silent component of the signal," she said.
This is likely the basis for why bright light at night keeps a person awake more effectively than dim light, Gillette said. Bright light delays clock time more and, thereby, makes it harder to awaken early the next morning. More PACAP in the light signal means a greater delay, she added.
Eventually, Gillette said, it may be possible to create drugs to selectively reset a person's sleep cycle, which would be welcome news for night-shift workers and for some people with sleep disorders.
The co-authors of the paper were Gillette, Dong Chen, Gordon F. Buchanan and Jian M. Ding, all of the U. of I., and Jens Hannibal, a professor of clinical biochemistry at the University of Copenhagen.
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