Deep-brain imaging in awake mice reveals how light resets the circadian clock by activating complex SCN neuron networks.
The circadian clock is a powerful internal system that controls nearly every aspect of our daily lives—when we sleep and wake, when we feel hungry, how our immune system responds, and even how alert or focused we are at different times of the day.
An animal's internal (endogenous) clock runs close to 24 hours, but not exactly 24. Therefore, we need an oscillator and an orchestrator to adjust this internal clock to match the external light-dark cycle. In mammals, this orchestrator is a small but essential brain region called the suprachiasmatic nucleus (SCN), located deep inside the hypothalamus.
This cluster of about 20,000 to 40,000 neurons functions like a central watch, coordinating the timing of body functions to follow the 24-hour day.
When we cross time zones and experience jet lag, it happens because our internal clock remains set to the old time zone. Adjusting this clock to a new schedule—especially through exposure to light and darkness—is essential, but scientists still know very little about how this adjustment occurs within the SCN.
What is known is that special cells in the eye called intrinsically photosensitive retinal ganglion cells (ipRGCs) detect blue light and send signals to the SCN to reset the clock. But what happens inside the SCN after receiving this light signal has remained largely mysterious—until now.
In a study published in Nature Communications, led by researchers at National Taiwan University (NTU) and National Tsing Hua University (NTHU), scientists used the deepest-ever two-photon calcium imaging in awake mice to directly observe how individual SCN neurons respond to light.
This achievement is the result of an interdisciplinary collaboration among researchers in life science, physics, and computer science.
Dr. Po-Ting Yeh, the study's first author, explains the challenge: "It is difficult to study the basic physiological functions controlled by the hypothalamus, which lies deep inside the brain. This region governs essential behaviors like the circadian clock, sleep, energy balance, and feeding. But technical limitations have made it hard to understand how neurons in this area form functional circuits."
Until now, scientists believed that resetting the SCN was a simple, reflex-like process: light enters the eye, and the clock shifts accordingly. But the NTU team discovered that it is far more complex.
"Our findings were really surprising," says Dr. Yeh. "We thought adjusting the clock by light—like recovering from jet lag—would be straightforward since the SCN receives direct retinal input. The traditional model is simple: SCN neurons were believed to act like runners in a relay race, passing the light signal along in a linear chain. But what we observed was much more complicated."
"Some SCN neurons were activated by light, while others were inhibited. Interestingly, although the specific neurons that respond vary with each trial, the overall proportion of activated and inhibited neurons remains remarkably consistent. This suggests a population-level balance or computation, rather than a fixed pathway—more like a flexible network, similar to those seen in higher brain regions involved in decision-making."
Using genetic tools, the team identified a small group of SCN neurons that are normally activated by light in the early night and are specifically responsible for delaying the body clock—causing the animal to wake up and fall asleep later the next day.
"We were able to artificially activate these neurons at any time of day," says Ern-Pei Chua, a Ph.D. student at NTU and the study's third author, who led the behavioral experiments.
"This shifted the mouse's internal clock later—even during mid-day, when the circadian system normally ignores light. In the future, if we can precisely control these neurons, it could help people recover from jet lag faster—or even make it easier for late sleepers to wake up on time for class."
Senior author Professor Shih-Kuo Chen reflects on the broader implications of these findings: "Adjusting the circadian clock might seem as simple as sleeping in or waking up earlier, but the neuronal circuits involved may be as complex as deciding where to dine for an anniversary.
"By understanding how the hypothalamus integrates external cues like light to regulate basic functions, we're laying the groundwork for more precise ways to treat jet lag, insomnia, and other circadian-related disorders."
This research not only challenges long-standing assumptions about the brain's central clock—it also opens new possibilities for developing future therapies that align with our body's natural rhythms.
More information: Po-Ting Yeh et al, Discrete photoentrainment of mammalian central clock is regulated by bi-stable dynamic network in the suprachiasmatic nucleus, Nature Communications (2025). DOI: 10.1038/s41467-025-58661-1
Journal information: Nature Communications
Provided by National Taiwan University