Light is a potent stimulus for regulating circadian, hormonal, and behavioral systems. In addition, light therapy is effective for certain affective disorders, sleep problems, and circadian rhythm disruption. These biological and behavioral effects of light are influenced by a distinct photoreceptor in the eye, melanopsin containing intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to the conventional rods and cones. We summarize the neurophysiology of this newly described sensory pathway and consider implications for the measurement, production and application of light. A new light-measurement strategy taking account of the complex photoreceptive input to these non-visual responses is proposed for use by researchers, and simple suggestions for artificial/architectural lighting are provided for regulatory authorities, lighting manufacturers, designers and engineers.

In the mammalian retina, besides the conventional rod-cone system, a melanopsin-associated photoreceptive system exists that conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment [1][2][3][4][5][6][7] . On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive 8 . Furthermore, pupil reflex 8 , light-induced phase delays of the circadian clock 9,10 and period lengthening of the circadian rhythm in constant light 9,10 are all partially impaired. Here, we investigated whether additional photoreceptive systems participate in these responses. Using mice lacking rods and cones, we measured the action spectrum for phase-shifting the circadian rhythm of locomotor behaviour. This spectrum matches that for the pupillary light reflex in mice of the same genotype 11 , and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells 7 . We have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions. © 2003 Nature Publishing GroupCorrespondence and requests for materials should be addressed to K.-W.Y. (kwyau@mail.jhmi.edu). Supplementary Information accompanies the paper on www.nature.com/nature. Competing interests statementThe authors declare that they have no competing financial interests. 8 . In independently produced melanopsin-knockout mice, others have found that the ability of light to phase-delay and lengthen the period of the circadian rhythm is also diminished 9,10 . For the pupil reflex, this photic response can be quantitatively accounted for by a functional complementarity between the rod-cone system and the melanopsin system, without the need to invoke any additional light-detection system 8 . Nonetheless, the proposal has persisted that cryptochromes-flavoproteins reported to have a direct light-detecting role in Drosophila 12,13 -may have the same function in mammals [14][15][16] despite earlier evidence to the contrary 17 . To settle this question, we first examined the action spectrum for phase-shifting the circadian rhythm in mice lacking rod and cone photoreceptors (rd/rd cl) 18 . Next, we generated triple-knockout mice lacking all confirmed photodetection systems-Opn4 −/− Gnat1 −/− Cnga3 −/− (melanopsin (also known as opsin 4), guanine nucleotide-binding protein α-transducin 1 (also known as rod transducin α-subunit, or Trα) and cyclic GMP-gated channel A-subunit 3, respectively)-and tested these animals for pupil reflex, circadian photo-entrainment and the masking response to light. NIH Public AccessIrradiance-response relations for the light-induced phase shifting of the circadian rhythm of l...

In the mammalian retina, a small subset of retinal ganglion cells (RGCs) are intrinsically photosensitive, express the opsin-like protein melanopsin, and project to brain nuclei involved in non-image-forming visual functions such as pupillary light reflex and circadian photoentrainment. We report that in mice with the melanopsin gene ablated, RGCs retrograde-labeled from the suprachiasmatic nuclei were no longer intrinsically photosensitive, although their number, morphology, and projections were unchanged. These animals showed a pupillary light reflex indistinguishable from that of the wild type at low irradiances, but at high irradiances the reflex was incomplete, a pattern that suggests that the melanopsin-associated system and the classical rod/cone system are complementary in function.

Rod and cone photoreceptors detect light and relay this information through a multisynaptic pathway to the brain via retinal ganglion cells (RGCs) 1 . These retinal outputs support not only pattern vision, but also non-image forming (NIF) functions, which include circadian photoentrainment and pupillary light reflex (PLR). In mammals, NIF functions are mediated by rods, cones and the melanopsincontaining intrinsically photosensitive retinal ganglion cells (ipRGCs) 2, 3 . Rod/cone photoreceptors and ipRGCs are complementary in signalling light intensity for NIF functions 4-12 . The ipRGCs, in addition to being directly photosensitive, also receive synaptic input from rod/cone networks 13, 14 . To determine how the ipRGCs relay rod/cone light information for both image and non-image forming functions, we genetically ablated ipRGCs in mice. Here we show that animals lacking ipRGCs retain pattern vision, but have deficits in both PLR and circadian photoentrainment that are more extensive than those observed in melanopsin knockouts 8,10,11 . The defects in PLR and photoentrainment resemble those observed in animals that lack phototransduction in all three †To whom correspondence should be addressed.