Study identifies ‘visual system’ protein for circadian rhythm stability

Scientists from Johns Hopkins University School of Medicine and the National Institutes of Health have identified a protein in the visual system of mice that appears to play a key role in stabilizing the body’s circadian rhythms by buffering the brain’s response to the light. The discovery, published on December 5 in PLoS Biologyadvances efforts to better treat sleep disorders and jet lag, according to the study authors.

“If circadian rhythms adapted to every rapid change in lighting, for example an eclipse or a very dark, rainy day, they would not be very effective in regulating periodic behaviors such as sleep and hunger. The protein that “We have identified that helps wire the brain during neural development to enable stable responses to everyday circadian rhythm challenges,” says Alex Kolodkin, Ph.D., professor in the Department of Neuroscience at Johns Hopkins and deputy director of the Institute for Basic Biomedical Sciences.

Kolodkin co-led the study with Samer Hattar, Ph.D., head of the section on light and circadian rhythms at the National Institute of Mental Health.

Scientists have long known that most living things have a circadian “clock,” a set of biological rhythms that operate on a roughly 24-hour cycle and affect alertness, sleepiness, appetite, and body temperature. among other cyclical behaviors.

Upsetting this system – for example through shift work or long-distance travel across multiple time and light zones in humans – can have serious consequences. Previous studies link persistent circadian rhythm disruptions to increased risk of cancer, depression, and many other medical problems.

Circadian systems are essentially “entrained” by exposure to light. Although researchers have made significant progress in recent decades in defining the mechanisms responsible for circadian rhythms, how the brain adapts to these rhythms remains unclear.

To learn more, Kolodkin and Hattar, along with the study’s first authors, John Hunyara and Kat Daly, and their colleagues, searched a database for biological molecules present during development in the CCC. circadian rhythms of the mouse brain, the suprachiasmatic nucleus (SCN).

Located deep in the mouse and human brain, in the hypothalamus, the SCN sits near areas that control vision and makes connections with brain cells that lead to the retina, the part of the eye that detects light.

The research team quickly focused on a cell surface protein called contentin-3 (Tenm3), which is part of a larger family of proteins that play key roles in assembling circuits in the visual system and more generally in other circuits of the central nervous system.

When researchers genetically modified mice to prevent the production of Tenm3, the animals developed fewer connections between the retina and the SCN, compared to animals with intact Tenm3. However, mice lacking Tenm3 developed significantly more connectivity between core and shell cells of the SCN, where Tenm3 tends to localize.

To see how Tenm3 could stabilize circadian rhythms or subject them to disruption by even a tiny bit of light, the scientists designed a set of experiments.

First, they trained mice lacking Tenm3 on a 12-hour light/dark cycle, then moved the dark period forward by six hours. Mice with intact Tenm3 took about four days to readjust their circadian rhythms to the change, as measured by activity patterns diagnostic of normal sleep cycles. Animals without Tenm3, however, adapted much more quickly, about half the time.

When the researchers performed a similar experiment with light twice as dim as in the previous test, it took about eight days for the intact mice with Tenm3 to adjust their circadian cycles, but only about four days for the mice without Tenm3.

Even a simple 15-minute pulse of dim light caused mice lacking Tenm3 (but not mice with normal Tenm3 protein) to produce a brain chemical that serves as a proxy for light exposure, suggesting increased sensitivity to the light signals necessary for configuration. or reset the circadian clock.

These results suggest to the authors that Tenm3 helps the brain maintain stable circadian rhythms even when light exposure is variable. By learning more about this system and the role of Tenm3, Hattar says, researchers may eventually be able to diagnose and treat problems that lead to insomnia and other sleep disorders in people, or possibly to develop treatments for jet lag.

“There are very clear implications for human health,” he says.