PerspectiveCircadian Rhythms

Circadian Photoreception

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Science  10 Jan 2003:
Vol. 299, Issue 5604, pp. 213-214
DOI: 10.1126/science.1081112

The circadian rhythms of physiology and behavior are driven by autonomous cellular clocks. To be useful, these clocks must be synchronized to the day-night cycles of the real world. Not surprisingly, the primary environmental synchronizing cue is the natural cycle of light and dark. How that cue is perceived has been the subject of continuous investigation for more than 40 years. In fish, amphibians, reptiles, and birds—all the nonmammalian vertebrates—there are specialized circadian photoreceptor cells located in several places in the brain. These cells respond to light that penetrates the skin, skull, and overlying brain tissue, and their output signals act directly on clock centers in the brain. In these animals, eyes are not necessary for synchronization to the day-night cycle, although when present they increase the sensitivity of synchronization (1, 2).

Mammals are different. Perhaps because they originated from nocturnal ancestors, they have abandoned brain photoreceptor cells and use only their eyes for synchronization to the day-night cycle (3). However, mammals do have specialized circadian photoreceptors—but these are confined to the retina rather than being distributed throughout the brain (see the figure). The existence of retinal circadian photoreceptors in mammals was strongly inferred from experiments in which the classical visual photoreceptors of the retina—the rods and cones—were selectively eliminated in mice and rats without damaging the remainder of the retina and without altering circadian synchronization (4). Strong though this inference was, it was not accepted readily because the idea that there were retinal photoreceptors other than rods and cones was difficult to incorporate into existing models of retinal function.

In a recent groundbreaking paper, Berson and colleagues demonstrated that a small subset of retinal ganglion cells (RGCs) that project to the suprachiasmatic nucleus (SCN)—the brain's central circadian clock—are intrinsically photosensitive (5). These cells respond electrically to light in isolated retinal preparations in which synaptic transmission is chemically blocked. This finding converged with a parallel story developed earlier by Provencio and Rollag, who discovered a new putative photopigment called melanopsin in the intrinsically photosensitive melanocyte pigment cells in frog skin (6). They later cloned human melanopsin and localized its messenger RNA to the ganglion and amacrine cell layers of the mouse and primate retina (7). It was then a short (although technically difficult) step to demonstrate that the photoreceptive subset of RGCs contained melanopsin and projected to the SCN as well as to the intergeniculate leaflet (IGL) and the olivary pretectal nucleus (OPN) (8-11).

The third eye.

Retinal connections with the suprachiasmatic nucleus (SCN). Retinal ganglion cells (RGCs) send their axons to several brain nuclei. Most are involved in carrying visual information, but a small subset innervates the SCN and other circadian clock-related structures. Only these RCGs contain the putative photopigment melanopsin and are intrinsically light sensitive. Inset shows melanopsin-containing RGCs and their axons, labeled with a tau-lacZ marker, connecting with the SCN in mouse brain (11).


This exciting work identified the putative components of a new light-perceiving system, which was subsequently shown to influence the pupil's response to light (regulated in part by the OPN) as well as circadian entrainment and suppression of melatonin production by light. However, a direct link with physiology and behavior was still missing. That link is provided by a cluster of recent papers including two in this issue of Science (12-15). In three independent studies, light responses were measured in mice deficient in the photopigment melanopsin (12-14). Using different endpoints and different constructs to engineer the knockout mice, the three papers came to the same conclusion: Melanopsin is important in nonvisual responses to light, but it is not the whole story. Ruby et al. (12) showed that although their melanopsin-deficient mice could still be entrained to light cycles, still exhibited phase-shifting in response to pulses of bright white light, and responded with changes in period to alterations in constant light, these responses were attenuated by about 40%. In a companion paper, Panda and colleagues (13) used pulses of monochromatic light at 480 nm (the action spectrum peak for eliciting electrophysiological responses in melanopsin-positive RGCs) at three different irradiances. They observed in their melanopsin-deficient animals a roughly 45% attenuation of phase shifting at the two higher irradiances and considerably more attenuation at the lowest irradiance. They also found a change in the circadian period of these mice when they were switched from constant darkness to constant light. Finally, Lucas et al. (14) report on page 245 that mice in which the melanopsin gene was replaced by a tau-LacZ coding sequence had RGCs that were no longer photosensitive (although they remained unchanged in other ways). These animals had a diminished pupillary light reflex at high irradiances. The authors speculate (on the basis of other data) that the full dynamic range of the pupillary response could be accounted for by the rod/cone and melanopsin systems acting together.

Clearly, mammals possess a retinally based light-detection system that has components and performs functions separate and distinct from the visual system (which depends on rod and cone photoreception). Indeed, it is not unreasonable to think of this system as constituting a new sensory modality because it apparently has little in common with image formation. However, it is also likely that the rods and/or cones are somehow involved in this nonvisual photoreceptive modality and may account for the maintenance of nonvisual responses to light in melanopsin-deficient mice.

It is also possible that a photopigment other than melanopsin is involved. The cryptochromes Cry1 and Cry2 are important for circadian photoreception in Drosophila, and both are present in the mammalian retina and SCN. Because cryptochrome-deficient mice lose their circadian rhythms, it is difficult to assess photic effects on their behavior; however, their pupillary reflex remains intact and is the subject of a fourth paper on page 222 by Van Gelder and colleagues (15). These authors find that although the pupillary response of mCry1 and mCry2 mutant mice is unaffected, these mutations do reduce the pupillary response of rodless mice when all three defects are present in the same animals. Although these data suggest that cryptochromes may have “an important function in the mammalian nonvisual irradiance detection pathway,” they do not rule out the possibility that cryptochromes are important for other nonphotoreceptive processes.

Many questions remain about this exciting new sensory modality. Is melanopsin in fact the photopigment in photosensitive RGCs, or does it play a supporting role? How is the melanopsin (or other photopigment) in these cells, which are physically removed from the retinal pigment epithelium, re-isomerized (restored to a light-sensitive configuration) after photon capture? What part, if any, is played by rods and cones in nonvisual photoreception, and how do they interact with melanopsin-containing RGCs? What other aspects of physiology and behavior may be regulated by this sensory modality? Do some people lack photoreceptive RGCs in the same way as color-blind people lack particular classes of cones, and what would be the consequences of such a defect? Techniques and tools are now available to answer all of these questions.


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