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Melanopsin and rod–cone photoreceptive systems account for all major accessory visual functions in mice

Abstract

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-entrainment1,2,3,4,5,6,7. On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive8. Furthermore, pupil reflex8, light-induced phase delays of the circadian clock9,10 and period lengthening of the circadian rhythm in constant light9,10 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 genotype11, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells7. 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.

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Figure 1: Irradiance–response relations (a) and action spectrum (b) for circadian phase shifting in rd/rd cl mice by monochromatic light between 420 nm and 580 nm, assayed by wheel-running (n = 4–7 animals per irradiance at each wavelength).
Figure 2: Normal retinal morphology and presence and central connectivity of melanopsin-expressing RGCs in triple-knockout (Opn4-/- Gnat1-/- Cnga3-/-) mice.
Figure 3: Disabling of rods, cones and melanopsin-positive RGCs essentially eliminates the pupillary light reflex.
Figure 4: Actograms of wheel running for mice under a 16/8-h light/dark cycle, double-plotted on a 24-h timescale.
Figure 5: Actograms of wheel running plotted on a 7-h timescale.

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Acknowledgements

We thank H.-W. Liao and J. Lai for help in performing the immunocytochemical experiments with antibodies against cryptochromes; J. Butler for help with real-time RT–PCR; Y. Liang for help in genotyping the animals; P. Salmon for help in the wheel-running experiments; and D. M. Berson, H. R. Matthews, G. L. Fain and members of the Yau laboratory for scientific discussions. This work was supported by the US National Eye Institute (K.-W.Y.), the UK Biotechnology and Biological Sciences Research Council and the Wellcome Trust (R.J.L. and R.G.F.), and the Canadian Institutes of Health Research (N.M.).

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Correspondence to K.-W. Yau.

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Hattar, S., Lucas, R., Mrosovsky, N. et al. Melanopsin and rod–cone photoreceptive systems account for all major accessory visual functions in mice. Nature 424, 75–81 (2003). https://doi.org/10.1038/nature01761

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