Researchers Discover Key Control Mechanism for an Area of the Brain That Regulates Sleep

03/15/99    Portland, Ore.

Much of what determines whether you sleep well or badly happens in a tiny area of the brain consisting of just a few thousand nerve cells, or neurons. Now, researchers at Oregon Health Sciences University have discovered that a chemical produced within the brain can slow the activity of those cells almost to a stop, affecting the body's reaction to light and darkness. The research, published in the March 15 issue of The Journal of Neuroscience, opens an entire new avenue of research toward understanding the molecular basis of sleep disorders and problems related to natural light cycles, such as seasonal affective disorder (SAD).

The research focuses on an area deep in the brain called the suprachiasmatic nucleus (SCN), which is about the size of the pinhead. The SCN is known to regulate the circadian rhythm--the 24-hour cycle of sleep and wakefulness. When neurons in the SCN are damaged, the sleep cycle is disrupted.

"The connection between these brain cells and the circadian cycle is clear," said Charles Allen, Ph.D., associate professor in OHSU's Center for Research on Occupational and Environmental Toxicology and lead author of the Journal of Neuroscience study. "Now we have powerful evidence that a substance we call orphanin alters the response of this area of the brain to light."

Orphanin (also known as nociceptin, or OFQ) is a peptide, or combination of amino acids that are the basic building blocks or proteins. This peptide is at work in several areas of the brain.

"The areas where orphanin is active, besides in the SCN, play a role in feeding, drinking behavior, nursing behavior, reproductive behavior, regulation of body temperature and reward, among other things," said David Grandy, Ph.D., associate professor of physiology and pharmacology at OHSU and senior author of the paper. Orphanin acts as a neurotransmitter, a kind of messenger that tells cells how to act. While its role elsewhere in the brain is still being studied, the OHSU research shows clearly that orphanin acts on all the cells in the SCN. "Everywhere we look orphanin directly inhibits cells," said Grandy. "It turns them off. It quiets them down. This is especially true in the SCN."

Collaborating with Grandy and Allen's teams, Dr. Michael Rea of the Biological Rhythms and Integrative Neurosciences Research Institute tested the effects of orphanin on the SCN in hamsters. First, normal hamsters were exposed to light before their normal waking time. The circadian clock adjusted to the light; in other words, the hamsters woke up earlier. Then, orphanin was injected into some of the animals. Even when consistently exposed to light before they would normally wake up, their circadian clock did not shift, suggesting orphanin was blocking the process that normally converts light into a brain signal telling the animal to wake up.

The most important signal you get to your biological clock is light," said Allen. "There's a direct connection between our eyes and the clock. In fact, the orphanin system is found in the retina as well as the SCN. We don't know the exact mechanism that keeps the clock adjusted to natural light cycles, but our latest research suggests that the light signal excited the neurons in the SCN, and orphanin will inhibit them."

The next step in this research is to determine the physiological mechanism by which orphanin modulates the circadian cycle. "Understanding that the system exists is the first step," said Grandy. "From that point we can better understand how it works. The ultimate hope is that these discoveries lead to better treatments for sleep disorders."

The OHSU research was funded by the National Institutes of Health and by the "Research for the Future" program of the Japan Society for the Promotion of Science.