Researchers Identify Eye Signals That Prevent Circadian Rhythm Shifts

The eye not only has visual image-forming capabilities, but also regulates our behavior in response to light. Changes in light conditions regulate biological clocks, or circadian rhythms, in many living species. The mechanisms involved in this regulation are highly complex in humans, involving a multitude of communication signals between the eye and the brain.

While retinal neurons are known to induce excitatory signals, causing them to fire more, researchers at Northwestern University have identified a subpopulation of inhibitory signaling retinal neurons that are involved in non-image-forming, subconscious behaviors such as synchronization of circadian rhythms to light/dark cycles and pupil constriction to intense bright lights.

The study by the researchers, published in the journal Science, found that a specific subset of neurons sends inhibitory signals to the brain in conditions of dim light to prevent pupil constriction and changes to circadian rhythms in mice.

Dr. Tiffany Schmidt, Assistant Professor of Neurobiology at Northwestern’s Weinberg College of Arts and Sciences, and lead researcher on the study, explained that, “These inhibitory signals prevent our circadian clock from resetting to dim light and prevent pupil constriction in low light, both of which are adaptive for proper vision and daily function.” She added, “We think that our results provide a mechanism for understanding why our eye is so exquisitely sensitive to light, but our subconscious behaviors are comparatively insensitive to light.”

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Retinal ganglion cells (RGCs) transmit light signals from the retina to the brain and drive various light-stimulated behaviors that include conscious visual perception as well as subconscious, non-image-forming behaviors such as the pupillary light reflex.

It was previously thought that RGCs only release excitatory neurotransmitters such as glutamate to excite and activate neural activity. However, the study by Schmidt’s group has now revealed that a specific subset of intrinsically photosensitive RGCs (ipRGCs) also release the inhibitory neurotransmitter γ-aminobutyric acid (GABA), which decreases light sensitivity in mice.

The study found that inhibiting GABA signaling from ipRGCs in a mouse model led to heightened light sensitivity of the pupillary light reflex and of circadian photoentrainment in dim light. GABA release was found to shift the dynamic range of these non-image-forming behaviors to high light intensities.

In other words, normally, inhibitory GABA signaling reduces light sensitivity in low light conditions to prevent pupillary constriction and changes to the circadian rhythm.

Takuma Sonoda, first author of the paper, said that, “Our working hypothesis is that this mechanism keeps pupils from constricting in very low light.” He explained that, “This increases the amount of light hitting your retina, and makes it easier to see in low light conditions. This mechanism explains, in least part, why your pupils avoid constricting until bright light intensifies.”

Removing inhibitory GABA signaling from the neurons was shown to shift circadian rhythms in the mice in dim light.

Schmidt explained that, “This suggests that there is a signal from the eye that actively inhibits circadian rhythms realignment when environmental light changes, which was unexpected.” Schmidt said, “This makes some sense, however, because you do not want to adjust your body’s entire clock for minor perturbations in the environmental light/dark cycle, you only want this massive adjustment to take place if the change in lighting is robust.”

The study concluded that, “Our results identify an inhibitory RGC population in the retina and provide a circuit-level mechanism that contributes to the relative insensitivity of non-image-forming behaviors at low light levels.”

The study findings provide novel insights into the links between light sensitivity, non-visual behavior and circadian rhythms as governed by the eye’s ability to sense and communicate changes in light intensity.