Researchers from the 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 rhythm by buffering the brain’s response to light. Findings, published in PLoS Biology on December 5th, drive efforts to better treat sleep disorders and jet lag, say the study authors.
„If our circadian rhythms were to adapt to every rapid change in lighting, such as a solar eclipse or a very dark and rainy day, they wouldn’t be very effective in regulating periodic behaviors such as sleep and hunger. The protein we identified helps wire the brain during neuronal development to enable stable responses to circadian rhythm challenges from day to day.“
– Alex Kolodkin, Ph.D., Professor at the Johns Hopkins Department of Neuroscience and Deputy Director of the Institute for Basic Biomedical Sciences
Kolodkin led the study together 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 organisms have a circadian „clock,“ a set of biological rhythms that occur approximately within a 24-hour cycle, affecting alertness, sleepiness, appetite, and body temperature, among other cyclic behaviors. Disrupting this system, for example through shift work or long-haul travel across multiple time and light zones, can have serious consequences. Previous studies have linked sustained disruptions in the circadian rhythm to an increased risk of cancer, depression, and a variety of other medical issues.
Circadian systems are essentially „trained“ by light exposure. While researchers have made significant strides in understanding the mechanisms responsible for the circadian rhythm over the past few decades, it remains unclear how the brain becomes wired for this rhythm.
To learn more, Kolodkin and Hattar, along with the study’s lead authors John Hunyara and Kat Daly and their colleagues, combed a database for biological molecules present during development in the control center of the mouse brain for circadian rhythms – the suprachiasmatic nucleus (SCN).
The SCN is deep in the hypothalamus of both the mouse and human brain. It is located near areas that control vision and establishes connections with brain cells leading to the retina, the light-sensitive part of the eye.
The research team quickly focused on a cell-surface protein called Teneurin-3 (Tenm3), which belongs to a larger family of proteins that play a key role in building circuits of the visual system and more broadly in other circuits of the central nervous system.
When the researchers genetically altered mice to prevent Tenm3 production, the animals developed fewer connections between the retina and the SCN compared to animals with intact Tenm3. However, mice lacking Tenm3 developed far more connectivity between cells in the core and shell of the SCN, where Tenm3 tends to localize.
To see how Tenm3 could stabilize the circadian rhythm or even disrupt it by a tiny amount of light, the scientists developed a series of experiments.
First, they trained mice lacking Tenm3 on a 12-hour light-dark cycle and then shifted the dark period forward by six hours. Mice with intact Tenm3 needed about four days to adapt their circadian rhythm to the shift, as measured by activity patterns diagnosing normal sleep cycles. However, mice lacking Tenm3 adapted much more quickly, in about half the time.
When the researchers conducted a similar experiment with light that was only half as faint as the previous test, Tenm3-intact mice took about eight days to adjust their circadian cycles, whereas mice lacking Tenm3 only took about four days. A 15-minute weak light pulse triggered in mice lacking Tenm3 – but not in mice with normal Tenm3 protein –; to produce a brain chemical serving as a proxy for light exposure, indicating an increased sensitivity to light stimuli necessary for adjusting or resetting the circadian clock.
These results suggest to the authors that Tenm3 helps wire the brain to maintain stable circadian rhythms even when light exposure fluctuates. By learning more about this system and the role of Tenm3, researchers could potentially diagnose and treat disruptions that lead to insomnia and other sleep disorders, or possibly develop treatments for jet lag, according to Hattar.
„There are significant implications for human health,“ he says.
Other Johns Hopkins researchers contributing to this study include Katherine Torres.
This study was funded by grants from the NIH (R01EY032095) and the Intramural Research Program at NIMH (ZIAMH002964).
Hunyara, JL, et al. (2023). Teneurin-3 Regulates NIBS Generation and Light Response in the Suprachiasmatic Nucleus. PLOS Biology. doi.org/10.1371/journal.pbio.3002412.