Scientists at 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 be critical for stabilizing the body’s circadian rhythms by buffering the brain’s response to light. The discovery, published in the journal PLoS Biology, could help to better treat sleep disorders and jet lag. The study was led by Kolodkin Dr. Alex Kolodkin, professor in the Johns Hopkins Department of Neuroscience along with Dr. Samer Hattar, chief of the Division of Light and Circadian Rhythms at the National Institute of Mental Health.

Disruptions to the Circadian Rhythm Can Lead to Illness

Scientists have long known that most living things have a circadian clock, a series of biological rhythms that run in a 24-hour cycle and influence wakefulness, sleepiness, appetite and body temperature, among other things. Disruption to 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 have linked persistent disruption of the circadian rhythm to an increased risk of cancer, depression and a range of other medical problems. The circadian system is essentially “trained” by exposure to light. Although researchers have made significant progress in recent decades in describing the mechanisms responsible for circadian rhythms, it is still unclear how the brain is tuned to them.

To learn more, the scientists searched a database for biological molecules present during development in the circadian rhythm control center of the mouse brain – the suprachiasmatic nucleus (SCN). Located deep in the hypothalamus of both the mouse and human brain, the SCN is close to areas that control vision and makes connections to brain cells that lead to the retina, the light-sensitive part of the eye.

How a Specific Protein Maintains Stable Circadian Rhythms

The research team quickly identified a cell surface protein called teneurin-3 (Tenm3), which belongs to a larger family of proteins that play a key role in building the circuits of the visual system and more generally in other circuits of the central nervous system. When the researchers genetically modified mice to prevent Tenm3 production, the animals developed fewer connections between the retina and the SCN compared to animals with intact Tenm3. However, those mice lacking Tenm3 developed far more connections between cells in the nucleus and in the shell of the SCN, where Tenm3 is usually localized.

To find out to what extent Tenm3 stabilizes the circadian rhythm or disrupts it with a tiny bit of light, the scientists developed a series of experiments. First, they trained mice lacking Tenm3 to a 12-hour light-dark cycle and then shifted the dark period forward by six hours. Mice with intact Tenm3 took about four days to adapt their circadian rhythm to the shift, as measured by activity patterns indicative of normal sleep cycles. The animals without Tenm3, on the other hand, adapted much faster, in about half the time.

When the researchers conducted a similar experiment in which the light was twice as dim as in the earlier test, the mice with Tenm3 took about eight days to adjust their circadian cycle, while the mice without Tenm3 took only about four days. Even a 15-minute pulse of dim light triggered the production of a chemical in the brain that serves as an indicator of light exposure in the mice without Tenm3 – but not in the mice with normal Tenm3 protein – suggesting an increased sensitivity to light stimuli required to set or reset the circadian clock.

According to the authors, these results suggest that Tenm3 helps wire the brain to maintain stable circadian rhythms even when light exposure is variable. If circadian rhythms adapted to every rapid change in light conditions, such as an eclipse or a very dark and rainy day, they would not be very effective at regulating periodic behaviors such as sleep and hunger. The protein identified by the experts helps to wire the brain during neuronal development so that it can respond stably from day to day to the challenges of the circadian rhythm, and as researchers learn more about this system and the role of Tenm3, they may be able to diagnose and treat disorders that cause insomnia and other sleep disorders in people, or possibly develop treatments for jet lag.