by Nicolai Pena
figures by Jasmin Joseph-Chazan

Toward the end of the 20th century, the intricate biology of how the eye produces visual information was thought to be well understood– a combination of sensors and circuits in the eye extract features of visual scenes. This information is conveyed from the eye to the brain by specialized neurons that physically connect the two structures (Figure 1, blue). Once information arrives at the master visual processing center of the brain – the visual cortex – simple colors, contrasts, and contours continue their transformation into a visual scene that is recognizable to us, like a rich set of hues and textures cast in the sky during a sunset.

Figure 1: How neurons of the eye connect to the brain. Both types of neurons in the eye (traditional vision neurons (blue)  & ipRGCs (yellow)) send information from the eye to the brain. However, instead of sending information to the visual cortex, ipRGCs  are wired to the suprachiasmatic nucleus (SCN). The SCN is the circadian pacemaker of the brain and orchestrates our daily sleep-wake cycles. Since the SCN is buried deep in the brain and cannot directly sense sunlight, it uses ipRGCs to know what time it is. 

Individuals with blindness can sense light

Yet there was a confusing exception to this traditional model: some people with complete blindness can still sense day-night cycles. While many blind individuals suffer from insomnia, the inability for sustained and regular sleep, some have healthy sleep patterns aligned to daily changes in sunlight. This suggested that, while unable to consciously perceive the scene of a sunset, for example, their brain is subconsciously aware of the receding light during dusk and prepares the body for sleep.

A 1995 study provided strong evidence that blind individuals could detect light. Researchers exposed blind patients to bright, artificial light for 90 minutes and then measured melatonin levels in the blood. Melatonin is a hormone that controls sleep cycles, naturally increasing at night to help us sleep. They found that bright light exposure strongly suppressed blood melatonin levels. Incredibly, while the patients did not report being able to see any light, their brains and bodies acted as if the sun had suddenly risen. 

Thus, scientists went searching for cells in the eye that could sense external light-dark cycles but not contribute to typical conscious vision – so called “time-of-day sensors.” 

Discovery of time-of-day sensors

Genetically blind mice have normal sleep cycles like the humans mentioned above. Moreover, mice have a visual system that shares key similarities with that of humans. Given these shared traits, researchers were confident that time-of-day sensors would be present in mice. In 2002, multiple teams of researchers converged on a small group of cells in the mouse eye: ipRGCs (intrinsically-photosensitive retinal ganglion cells). These microscopic time-of-day sensors make up only a tiny fraction of total eye tissue, which previously made them elusive to neuroscientists studying the eye.  

The newly identified ipRGCs looked familiar to scientists in some ways. Both ipRGCs and traditional vision detectors are neurons – specialized cells of the brain and body that communicate using electrical impulses. Additionally, each type sends thread-like projections spanning from the eye to the brain. But scientists quickly discovered biological properties of ipRGCs that support a unique role in sensing environmental sunlight vs. darkness. 

Three basic properties of ipRGCs

First, ipRGCs can directly sense light; they are intrinsically photosensitive (Figure 2). Traditional neurons of the retina, in contrast, cannot directly sense rays of light and need help from other parts of the eye. ipRGCs accomplish through a molecular sensor called melanopsin. Melanopsin is found on the surface of ipRGCs, can absorb individual particles of light, and can trigger ipRGCs to send electrical impulses to the brain. Imagine melanopsin as a light switch, and ipRGCs as a wire relaying electrical messages from the eye to the brain. When the switch is flipped on, ipRGCs tell the brain whether it is dim or sunny outside.

Figure 2: ipRGCs are directly activated by light. Left: Regular RGCs cannot directly sense light and need help from other parts of the eye. Right: ipRGCs can directly sense incoming light through a molecule called melanopsin. Once melanopsin is activated, ipRGCs send electrical impulses to the brain.

Second, ipRGCs have an unusual pattern of connectivity with the brain. Most neurons that originate from the eye are wired to brain centers meant for visual processing. ipRGCs, on the other hand, form connections with over a dozen non-visual brain regions. One region is the suprachiasmatic nucleus (SCN), a brain center known as the “circadian pacemaker(Figure 1, yellow). The SCN is a master regulator of the entire body’s light-dark rhythms, influencing daily changes in behavior. For example, this brain region causes drowsiness by stimulating the release of melatonin into the bloodstream. Since the brain is encased by a thick layer of skull bone and other tissues, the SCN receives little light. It must therefore use electrical signals from ipRGCs to align bodily processes according to a 24-hour clock. In this case, ipRGCs act as cellular messengers, keeping the brain aware of what time it is. 

Third, ipRGCs display unusually prolonged patterns of electrical activity. All neurons communicate with one another using electrical impulses. ipRGCs can discharge electrical impulses for extremely long periods of time. While most neurons only show heightened electrical activity for milliseconds, ipRGCs are activated for as long as they are exposed to light, and for several minutes even after a brief flash. 

In a human being, this means stepping outside for a daily commute to work, where the eyes are quickly immersed in a sunny morning, causes sustained activation of ipRGCs. This sort of prolonged activity is appropriate for a time-of-day sensor. They are not meant to detect the rapid succession of visual scenes after stepping out of the door: cars whirling down a nearby street, a row of brick-clad apartment buildings, a dachshund walking with its owner. Instead, the time-of-day sensor detects visual conditions that last minutes or hours at a time: morning, afternoon, evening. In sum, sustained electrical activity endows ipRGCs with the ability to detect a 24-hour light cycle.

Studying primate ipRGCs offers relevance to human biology

While much has been learned about ipRGC biology over the past 20 years, scientists could not be certain about the exact correspondence to human biology. Previous research focused on cells originating from mice, animals that, unlike humans, are not as reliant on vision and are nocturnal. Just this year, Liu, Milner, Do, and colleagues revealed key biological properties of primate ipRGCs in a pioneering set of experiments. This was the first study to focus on primate ipRGCs from macaque monkeys, whose visual system and evolutionary ancestry is strikingly similar to that of humans.

They found that a brief pulse of light can activate primate ipRGCs for several minutes, reinforcing the notion that these neurons mainly sense ambient light instead of details in a single visual scene. Take, for instance, someone reading a book in their living room. Primate ipRGCs will sense sunrays pouring through windows and reflecting off surfaces instead of the fine strings of text on a page.Notably, they also found that primate ipRGCs work together as a group to sense the 24-hour light cycle (Figure 3). Individual cells send electrical impulses to the brain in response to particular intensities of light: while one cell may prefer dim moonlight, another is activated by the searing intensities of a bright summer day. Thus, the primate brain, and likely the human brain, is kept informed on the time of day through a diverse population of ipRGCs.

Figure 3: Primate ipRGCs work as a group to sense the 24-hour light cycle. ipRGCs from the primate eye have different sensitivities to external light intensity (brightness). For example, some show their highest electrical activity to dim moonlight (ipRGC 1), while others are activated by intense midday sunlight (ipRGC 3). Human time-of-day sensors may similarly collaborate as a group to detect light conditions.

Finally, the research team learned, somewhat unexpectedly, that certain colors of light can inactivate ipRGC activity. After exposure to green light, as compared to the white light we normally see, they were able to electrically silence a previously active ipRGC. Such knowledge could contribute to the harnessing of artificial light as a therapeutic intervention. A light therapy approach may help individuals suffering from mood disorders like seasonal affective disorder or mitigate sleep-cycle disturbances common among shift workers.

ipRGCs: Looking at the big picture

Humans, compared to most other animals, have a highly developed visual system. Yet ipRGCs represent an ancient type of vision that our evolutionary ancestors likely possessed millions of years ago. Animals as evolutionarily distant as fish and chickens use ipRGC-like cells to inform their behavior. The former can use its time-of-day sensors to dart towards bright patches of water, while the latter uses similar sensors to spur wake-up choruses at the crack of dawn. In humans, knowledge of this visual system has revealed how our sleep patterns are aligned to 24-hour light cycles, including in people that are otherwise blind.

Beyond being a template for our sleep schedules, light sensed by ipRGCs has an immense impact on our physical and mental well-being. Essentially every tissue in the body is under the control of daily circadian rhythms. Regular disruption of circadian rhythms, which are kept on track by ambient light and ipRGCs, can increase susceptibility to cancer, cardiovascular dysfunction, and psychiatric disease. Moreover, time-of-day sensors in the eye connect to a diverse swath of brain structures involved in regulating our moods and cognition. Such knowledge is important in many contexts – from designing homes and workspaces to reforming daylight savings to treating episodes of seasonal depression. While work on ipRGCs is still in its early phases, future research promises to unveil biological secrets that currently lay just out of sight.

Nicolai Pena is a second year PhD student in the neuroscience program at Harvard University.

Jasmin Joseph-Chazan is a fourth year PhD student in the immunology program at Harvard University. 

For more information:

  • A profile of a man with retinal degeneration who can still sense day-night cycles may be found here (note ipRGCs are called “melanopsin cells”).
  • Click here for a more scientifically detailed summary of the Liu, Milner, and Do study.

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