Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Melanopsin cells are the principal conduits for rod–cone input to non-image-forming vision

Abstract

Rod and cone photoreceptors detect light and relay this information through a multisynaptic pathway to the brain by means of 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 melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs)2,3. Rod–cone photoreceptors and ipRGCs are complementary in signalling light intensity for NIF functions4,5,6,7,8,9,10,11,12. The ipRGCs, in addition to being directly photosensitive, also receive synaptic input from rod–cone networks13,14. To determine how the ipRGCs relay rod–cone light information for both image-forming 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 knockouts8,10,11. The defects in PLR and photoentrainment resemble those observed in animals that lack phototransduction in all three photoreceptor classes6. These results indicate that light signals for irradiance detection are dissociated from pattern vision at the retinal ganglion cell level, and animals that cannot detect light for NIF functions are still capable of image formation.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Elimination of ipRGCs in mouse retina.
Figure 2: The ipRGC fibres in the brain decrease in aDTA mice.
Figure 3: Opn4 aDTA mice have deficits in PLR.
Figure 4: Opn4 aDTA / aDTA mice do not photoentrain or mask.

References

  1. Hubel, D. H. Eye, Brain, and Vision (Freeman, New York, 1988)

    Google Scholar 

  2. Berson, D. M., Dunn, F. A. & Takao, M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 295, 1070–1073 (2002)

    ADS  CAS  Article  Google Scholar 

  3. Hattar, S., Liao, H. W., Takao, M., Berson, D. M. & Yau, K. W. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295, 1065–1070 (2002)

    ADS  CAS  Article  Google Scholar 

  4. Freedman, M. S. et al. Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 284, 502–504 (1999)

    ADS  CAS  Article  Google Scholar 

  5. Czeisler, C. A. et al. Suppression of melatonin secretion in some blind patients by exposure to bright light. N. Engl. J. Med. 332, 6–11 (1995)

    CAS  Article  Google Scholar 

  6. Hattar, S. et al. Melanopsin and rod–cone photoreceptive systems account for all major accessory visual functions in mice. Nature 424, 75–81 (2003)

    ADS  Article  Google Scholar 

  7. Panda, S. et al. Melanopsin is required for non-image-forming photic responses in blind mice. Science 301, 525–527 (2003)

    ADS  CAS  Article  Google Scholar 

  8. Lucas, R. J. et al. Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science 299, 245–247 (2003)

    ADS  CAS  Article  Google Scholar 

  9. Mrosovsky, N. & Hattar, S. Impaired masking responses to light in melanopsin-knockout mice. Chronobiol. Int. 20, 989–999 (2003)

    CAS  Article  Google Scholar 

  10. Panda, S. et al. Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 298, 2213–2216 (2002)

    ADS  CAS  Article  Google Scholar 

  11. Ruby, N. F. et al. Role of melanopsin in circadian responses to light. Science 298, 2211–2213 (2002)

    ADS  CAS  Article  Google Scholar 

  12. Lucas, R. J., Douglas, R. H. & Foster, R. G. Characterization of an ocular photopigment capable of driving pupillary constriction in mice. Nature Neurosci. 4, 621–626 (2001)

    CAS  Article  Google Scholar 

  13. Dacey, D. M. et al. Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN. Nature 433, 749–754 (2005)

    ADS  CAS  Article  Google Scholar 

  14. Wong, K. Y., Dunn, F. A., Graham, D. M. & Berson, D. M. Synaptic influences on rat ganglion-cell photoreceptors. J. Physiol. (Lond.) 582, 279–296 (2007)

    CAS  Article  Google Scholar 

  15. Hattar, S. et al. Central projections of melanopsin-expressing retinal ganglion cells in the mouse. J. Comp. Neurol. 497, 326–349 (2006)

    Article  Google Scholar 

  16. Gooley, J. J., Lu, J., Fischer, D. & Saper, C. B. A broad role for melanopsin in nonvisual photoreception. J. Neurosci. 23, 7093–7106 (2003)

    CAS  Article  Google Scholar 

  17. Hannibal, J. & Fahrenkrug, J. Target areas innervated by PACAP-immunoreactive retinal ganglion cells. Cell Tissue Res. 316, 99–113 (2004)

    CAS  Article  Google Scholar 

  18. Morin, L. P., Blanchard, J. H. & Provencio, I. Retinal ganglion cell projections to the hamster suprachiasmatic nucleus, intergeniculate leaflet, and visual midbrain: bifurcation and melanopsin immunoreactivity. J. Comp. Neurol. 465, 401–416 (2003)

    Article  Google Scholar 

  19. Sollars, P. J. et al. Melanopsin and non-melanopsin expressing retinal ganglion cells innervate the hypothalamic suprachiasmatic nucleus. Vis. Neurosci. 20, 601–610 (2003)

    Article  Google Scholar 

  20. Maxwell, F., Maxwell, I. H. & Glode, L. M. Cloning, sequence determination, and expression in transfected cells of the coding sequence for the tox 176 attenuated diphtheria toxin A chain. Mol. Cell. Biol. 7, 1576–1579 (1987)

    CAS  Article  Google Scholar 

  21. Wee, R., Castrucci, A. M., Provencio, I., Gan, L. & Van Gelder, R. N. Loss of photic entrainment and altered free-running circadian rhythms in math5-/- mice. J. Neurosci. 22, 10427–10433 (2002)

    CAS  Article  Google Scholar 

  22. Gooley, J. J., Lu, J., Chou, T. C., Scammell, T. E. & Saper, C. B. Melanopsin in cells of origin of the retinohypothalamic tract. Nature Neurosci. 4, 1165 (2001)

    CAS  Article  Google Scholar 

  23. Barnard, A. R., Hattar, S., Hankins, M. W. & Lucas, R. J. Melanopsin regulates visual processing in the mouse retina. Curr. Biol. 16, 389–395 (2006)

    CAS  Article  Google Scholar 

  24. Iwakabe, H., Katsuura, G., Ishibashi, C. & Nakanishi, S. Impairment of pupillary responses and optokinetic nystagmus in the mGluR6-deficient mouse. Neuropharmacology 36, 135–143 (1997)

    CAS  Article  Google Scholar 

  25. Prusky, G. T., Alam, N. M., Beekman, S. & Douglas, R. M. Rapid quantification of adult and developing mouse spatial vision using a virtual optomotor system. Invest. Ophthalmol. Vis. Sci. 45, 4611–4616 (2004)

    Article  Google Scholar 

  26. Vorhees, C. V. & Williams, M. T. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nature Protocols 1, 848–858 (2006)

    Article  Google Scholar 

Download references

Acknowledgements

We thank J. Mackes and G. Harrison for help in genotyping the animals; R. Kuruvilla, M. Van Doren, B. Wendland, M. Halpern, M. Caterina, C.-Y. Su, J. Bradley and laboratory members in the Biology Department at the Johns Hopkins University for scientific discussions and comments on the manuscript. This work was supported by grants from the National Institutes of Health (to S. Hattar and K.-W.Y.), the Biotechnology and Biological Sciences Research Council (to R.J.L.) and the David and Lucile Packard and Alfred P. Sloan Foundations (to S. Hattar).

Author Contributions A.D.G. and S. Hattar wrote the paper. J.L.E., R.J.L., D.M.B. and T.C.B. gave helpful comments on the manuscript. A.D.G., J.L.E. and C.M.A. in S. Hattar’s laboratory performed all the behavioural studies on the aDTA homozygous animals, as well as the X-gal staining of the Opn4aDTA/tau-LacZ and Opn4tau-LacZ/+ animals, the morphology of the retina, the cholera toxin injections, the water maze and the optomotor studies. D.M.B. helped in analysing the brains of the Opn4aDTA/tau-lacZ and the cholera-toxin-injected animals. G.S.L. and A.R.B. in R.J.L.’s laboratory conducted all the behavioural studies on the aDTA heterozygous animals, and the electroretinogram studies. T.C.B. provided the construct and suggestions for the aDTA targeting strategy. H.C. made the optokinetic nystagmus recordings. H.-W.L. in K.-W.Y.’s laboratory performed the melanopsin immunostaining on aDTA heterozygous mice. Animals were first conceived in K.-W.Y.’s laboratory and produced by S. Hattar and S. Haq to the chimeric stage. Germline transmission was obtained independently in the laboratories of S. Hattar (with help from H.Z.) and K.-W.Y. All other authors helped in the planning, technical support and discussions of experiments.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Robert J. Lucas or Samer Hattar.

Supplementary information

Supplementary information

The file contains Supplementary Figures 1-7 with Legends and Supplementary Tables 1-2. (PDF 6821 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Güler, A., Ecker, J., Lall, G. et al. Melanopsin cells are the principal conduits for rod–cone input to non-image-forming vision. Nature 453, 102–105 (2008). https://doi.org/10.1038/nature06829

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06829

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing