Seeing the Eye’s Not-So-Simple Subtleties

By Amy Dusto

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Long referred to as the window to the soul, the eye also plays an important role in regulating the body’s internal clock, impacting everything from sleep to quality of life.

Now, new research from the lab of Samer Hattar, an associate professor of biology with a joint appointment in the Department of Neuroscience, gives scientists a clearer understanding of a little explored type of retinal cell—information that could eventually help redefine light‑related diagnoses for conditions like sleep problems and mood disorders. The paper appeared online in the July 17 issue of Nature.

Samer Hattar

Will Kirk / homewoodphoto.jhu.edu

The retinal cells, known as intrinsically photosensitive retinal ganglion cells (ipRGCs), were first discovered at Brown University in 2002. Since that time, researchers have assumed that all ipRGCs look and function alike, at once regulating both the light responses of pupil dilation and synchronization of the body’s internal clock to daylight hours, known as circadian rhythm.

It turns out that though the ipRGCs share fashion sense, they are not so susceptible to groupthink. The cells actually come in two physiologically alike—but functionally different—sub‑populations. This finding overturns previous data from other scientists that implied the ipRGC system was straightforward.

The genetic difference in ipRGC cell lines is small—and is differentiated by whether the cells are directed to regulate circadian rhythm or pupil dilation, Hattar found.

Given that each of these functions is completely different, says Hattar, when looking at the cells under many conditions, “to think they’d act the same was kind of naive.” Now he knows better. “I’ve learned not to take the system for granted.”

Previously, Hattar had shown that ipRGCs express small amounts of a light‑responsive pigment called melanopsin. ipRGCs are critical for both pupillary light response and circadian rhythm, which are in turn controlled by two different brain regions. In past experiments where all a mouse’s melanopsin cells were killed off, both functions were messed up.

Further work showed that melanopsin cells actually came in two flavors themselves, either with or without a certain protein called Brn3b. In his latest experiments, using mice, Hattar and colleagues wondered if they could disrupt the ipRGC functions individually another way: by genetically eliminating only the melanopsin cells that express Brn3b. (While it remains unknown whether Brn3b is found in humans, it is in mice, monkeys, and other mammals who often share brain physiology.)

This worked quite well, to the surprise of Hattar. “Somehow I didn’t expect [the cells] to be so cleanly separated,” he says. Without Brn3b positive melanopsin cells, one region of the brain got normal nerve action—circadian light response was intact, but pupillary light response was severely defective.

Usually, clinicians use melanopsin‑based responses in the pupil as a proxy for identifying patients with light‑related disorders affecting, for example, sleep or mood. “I think most of the time this is going to work,” says Hattar, “but our data gives a little cautionary tale.” A patient’s defective pupillary light response, as based on melanopsin, may not be the full story to her sleep disorder.

Light, and its myriad roles in our bodies, captivates Hattar. “You get used to it and forget it’s so important — even tree leaves measure day length.” He believes that more discoveries like these will tell us if, perhaps, it is better to take sleeping pills in a certain light environment, or how “light pollution” our exposure to various colors of light at all times of day, including a never‑quite‑dark nighttime associated with urban areas really affects our daily physiology.

“I think there’s a major influence of light in our behavior,” he says.