Why are you active during the day and sleepy at night? This cycle happens due to a process called circadian photoreception, which is the way we synchronize the body’s internal, 24-h clock to the light and dark periods outside. Photoreception means that a biological system is sensing light. Circadian means a rhythm which is close to 24-h. So, circadian photoreception is how the biological clock of the brain, a special part of brain called the SCN, synchronizes its 24-h rhythm to the sunrise. The biological clock of the brain is in turn responsible for maintaining many circadian rhythms: mental, physical, and behavioral changes linked to the 24-h clock. Circadian photoreception is a part of the visual system, so it is related to processes happening in the eyes. Normally, when you think of the eyes, you think about vision. Photoreceptors are a special type of nerve cells in the eyes that respond to light. In the daytime, we use photoreceptors called cones. In the nighttime, when there is little light, we use another type of photoreceptors, called rods. Rods and cones contain photopigments, special pigments that change when they absorb light. Each photoreceptor cell contains only one type, or color, of photopigment.

Characteristics of Circadian Photoreception

Scientists learned that circadian photoreception requires the eyes. How did they test this? They used mice, since mice are similar to humans in terms of genetics and behaviors. Mice and humans have the same photopigments in the same types of cells. The cells even look the same and are the same size. Scientists removed the cells that connect the mice’s eyes to their brains. Then, they tested those mice to see if they still woke up at “sunrise.” They did not! However, the mice still had regular sleep cycles, but they went to sleep and woke up independent of the sunrise. As a result, scientists concluded that at least part of circadian photoreception must take place in the eye [1]. Later, scientists showed that some people who were completely blind still synchronized their sleep cycles with light cycles [2]! This was early evidence that humans, like mice, had extra photoreceptors in addition to the ones used for sight. Scientists also found a pathway that connects the eye to the biological clock in the brain, which is different from the part of the brain that allows us to see. This biological clock in the brain is called the SCN, which stands for the suprachiasmatic nucleus (Figure 1). Although the SCN is a small brain region, it is very important and is connected to multiple other brain regions [3].

To understand more about circadian photoreception, researchers placed mice in three different conditions. They placed some mice in conditions that corresponded to light in the daytime and dark in the nighttime and recorded their activity. The mice ran on their running wheels only at night. Then, they placed mice only in the dark. Even though there was no sunlight telling the mice what time it was, the mice followed their biological clock [4]. This means that they woke up and went to sleep with a daily rhythm, but that rhythm no longer matched the clock on the wall.

Last, the scientists flashed a small amount of light on the mice during the constant darkness. Then, they placed the mice in the dark again. They found that, the next day, the mice got up a few hours earlier and, for the rest of the experiment, the mice woke up at this new earlier time. They concluded that the mice’s sleep/wake cycles had been reset. The flashing light changed the time they woke up. Additionally, if they gave the same light flash at a different time of day, the mice woke up a few hours later the following day. Again, their internal clocks were reset [5].

Next, researchers wanted to test whether the strength of the light and the length of time they shined light on the mice influenced the results. They found that the circadian photoreception system in mice requires more light to get activated than rods do—rods become activated with very little light. The amount of light needed for circadian photoreception in mice is just above the strength of moonlight. This makes sense because mice are nocturnal animals (animals that wake up at night). When mice are awake in the moonlight, they do not want the moonlight to reset their internal clocks because they are already waking up at the right time (Figure 2). Instead, they use the little bit of light they see at sunset and sunrise to set their clocks.

The researchers also found that the circadian photoreception system seems to count the number of light flashes it detects over long periods. This is different from the way rods and cones work. The circadian photoreception system can measure the amount of light coming into the eyes. So, a bright light over a short time might have the same effect as a dimmer light shining over a long time [6].

Melanopsin: A New Photopigment

Scientists wanted to find out exactly where the photoreceptors responsible for circadian photoreception were located. Most scientists assumed the rods or cones were responsible, but they had to test this idea.

Clyde Keeler was one of the first researchers to find mice that did not have rods and cones, which means that those mice were blind. But Keeler found that these mice could still respond to the amount of light by changing the size of their pupils [7]. Later, Melanie Freedman and Russel Foster completed a similar experiment. They found that blind mice could still respond to the strength of light and change their bedtimes accordingly. They concluded that there must be another photopigment in the retina—but other scientists wanted more proof [8].

Foster’s student, Ignacio Provencio, helped find proof for a new photopigment. This new photopigment, called melanopsin, was different from the photopigments present in rods and cones. The discovery of this photopigment in frog skin helped prove that Foster was correct.

Provencio discovered that melanopsin was found in ganglion cells located in the innermost layer of the eye (Figure 3) [9]. Ganglion cells are special cells that send information to the brain. Normally, ganglion cells, which get information about light from rods and cones, do not directly respond to light. However, scientist David Berson found that ganglion cells containing melanopsin do directly respond to light. Scientists gave these ganglion cells a special name: intrinsically photosensitive retinal ganglion cells (ipRGCs). While this name sounds complicated, once we break it down, it is easy to understand. Intrinsically means “by nature.” Photosensitive means “sensitive to light.” Retinal refers to where the cells are found, in the retina. The last piece is the type of cell—ganglion cells [10].

How Do IpRGCs, Rods, and Cones Work Together?

Scientists found that ipRGCs use the same pathway from the eye to the brain that the circadian photoreception system uses [10, 11]. They also found that ipRGCs need about the same amount of light to get activated as humans and mice need to set their internal clocks [12]. Additionally, ipRGCs seem to count the number of light flashes they get over long periods. This means that ipRGCs count light flashes: For example, short, bright light and long, dim light would lead to the same number of light flashes. This was a really big deal in the visual science community because it challenged the persisting idea that photoreception occurs only in rods and cones!

Although we know that ipRGCs respond to light, they are also connected to the other photoreceptors, like rods and cones. The bottom of Figure 3 summarizes how these structures work together.

When researchers remove melanopsin, circadian photoreception still happens. This means that melanopsin is not necessary for circadian photoreception because the rods and cones can take over. When rods and cones are removed, circadian photoreception also still happens. This means that rods and cones are not necessary for circadian photoreception because melanopsin can take over. When melanopsin, rods, and cones are all removed, circadian photoreception does not happen [13]. So, those three photoreceptors are necessary parts of the circadian photoreception system. If ipRGCs themselves are removed, rather than just turning off their photopigments, there is also no circadian photoreception. This means that the melanopsin-expressing ipRGCs are the only pathway through which information from the eye gets to the brain’s biological clock. ipRGCs can catch light using any of the three photopigments: rods, cones, or melanopsin [14].

Conclusion

Circadian photoreception is the name for the process by which we match the body’s internal, 24-h clock to the light cycle outside, and it starts in the eyes. The discovery of circadian photoreception led to the discovery of a new photopigment, melanopsin, which was revolutionary for visual science. Before this, scientists thought that rods and cones were the only photopigments in humans. Circadian photoreception depends on melanopsin-containing cells called ipRGCs, which form the only pathway by which information moves from the eye to the biological clock in the brain. Because this is separate from our vision, this means that our brains are paying attention to light that we do not “see.” Our eyes are setting the alarm clocks in our SCN, and our SCN are waking us up at the right time.

Glossary

Circadian Photoreception: ↑ The way we synchronize the body’s internal, 24-h clock to the light cycle outside.

Biological Clock: ↑ An organism’s internal clock that maintains its circadian rhythm.

Photoreceptor: ↑ A special type of cell that responds to light. Photoreceptors include rods and cones.

Photopigment: ↑ Pigments that chemically change when they absorb light.

Suprachiasmatic Nucleus (SCN): ↑ A small brain region above the roof of the mouth that receives light information from the eye and controls circadian rhythms.

Melanopsin: ↑ A photopigment that is most sensitive to blue light and is important for circadian photoreception.

Ganglion Cells: ↑ Cells that make up the innermost part of retina. Branches from these cells form a nerve that goes into the brain to send information about light.

Intrinsically Photosensitive Retinal Ganglion Cells (ipRGCs): ↑ Ganglion cells that are sensitive to light because they contain the photopigment melanopsin.

Retina: ↑ The thin, light-sensitive tissue that lines the inside of the eye.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.