Spectral Responses of the Human Circadian System Depend on the Irradiance and Duration of Exposure to Light

Light resets the circadian clock through a non–image-forming receptor system—or so it was thought; now, cone photoreceptors are shown to also participate. Retinal Receptors Conspire to Keep Us Awake Even without an intervening miracle, some blind people can see. When confronted by light, their pupils can constrict, their circadian clocks remain in rhythm, and their blood melatonin is suppressed. Although these people do not detect images of their surroundings—usually conveyed through their missing rods and cones—light still falls on their remaining retina, including special cells that contain a pigment (melanopsin) that receives and transfers blue light, allowing some light-regulated processes to function normally. But new evidence collected by Gooley et al. shows that the distinction between image-forming and non–image-forming sight is more complicated than we have appreciated. The authors carefully examined the light sensitivity of two functions: melatonin suppression and circadian phase control. To this end, they exposed normal individuals to two different wavelengths of light, one designed to be detected by the visual image-forming system and the other by the blue-light receptor melanopsin system. Rather than the expected result—that the non–image-forming responses were induced only by blue-light melanopsin cells—they saw that, at the beginning of the illumination period and at low light levels, the visual system could also drive the non–image-forming endpoints. These findings fit with neuroanatomy; cells that contain the blue-light receptors receive input from cones, which are integral parts of the image-forming system. Furthermore, these findings suggest that we have more to learn about how to optimally activate our light receptors. Indeed, advocates of blue-light therapy for sleep disorders or other ailments will need to rethink their views, as white light may work just as well. And technology addicts beware: The authors suggest that low-light exposure from our computers or indoor lighting late at night may be interfering with our circadian rhythms, making it even harder to get up in the morning. In humans, modulation of circadian rhythms by light is thought to be mediated primarily by melanopsin-containing retinal ganglion cells, not rods or cones. Melanopsin cells are intrinsically blue light–sensitive but also receive input from visual photoreceptors. We therefore tested in humans whether cone photoreceptors contribute to the regulation of circadian and neuroendocrine light responses. Dose-response curves for melatonin suppression and circadian phase resetting were constructed in subjects exposed to blue (460 nm) or green (555 nm) light near the onset of nocturnal melatonin secretion. At the beginning of the intervention, 555-nm light was equally effective as 460-nm light at suppressing melatonin, suggesting a significant contribution from the three-cone visual system (λmax = 555 nm). During the light exposure, however, the spectral sensitivity to 555-nm light decayed exponentially relative to 460-nm light. For phase-resetting responses, the effects of exposure to low-irradiance 555-nm light were too large relative to 460-nm light to be explained solely by the activation of melanopsin. Our findings suggest that cone photoreceptors contribute substantially to nonvisual responses at the beginning of a light exposure and at low irradiances, whereas melanopsin appears to be the primary circadian photopigment in response to long-duration light exposure and at high irradiances. These results suggest that light therapy for sleep disorders and other indications might be optimized by stimulating both photoreceptor systems.