Article | Published:

Rod photoreceptors drive circadian photoentrainment across a wide range of light intensities

Nature Neuroscience 13, 1107–1112 (2010) | Download Citation

Subjects

Abstract

In mammals, synchronization of the circadian pacemaker in the hypothalamus is achieved through direct input from the eyes conveyed by intrinsically photosensitive retinal ganglion cells (ipRGCs). Circadian photoentrainment can be maintained by rod and cone photoreceptors, but their functional contributions and their retinal circuits that impinge on ipRGCs are not well understood. Using mice that lack functional rods or in which rods are the only functional photoreceptors, we found that rods were solely responsible for photoentrainment at scotopic light intensities. Rods were also capable of driving circadian photoentrainment at photopic intensities at which they were incapable of supporting a visually guided behavior. Using mice in which cone photoreceptors were ablated, we found that rods signal through cones at high light intensities, but not at low light intensities. Thus, rods use two distinct retinal circuits to drive ipRGC function to support circadian photoentrainment across a wide range of light intensities.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

References

  1. 1.

    et al. Melanopsin cells are the principal conduits for rod-cone input to non–image forming vision. Nature 453, 102–105 (2008).

  2. 2.

    et al. Inducible ablation of melanopsin-expressing retinal ganglion cells reveals their central role in non-image forming visual responses. PLoS ONE 3, e2451 (2008).

  3. 3.

    , , , & Melanopsin-containing retinal ganglion cells: architecture, projections and intrinsic photosensitivity. Science 295, 1065–1070 (2002).

  4. 4.

    et al. Targeted destruction of photosensitive retinal ganglion cells with a saporin conjugate alters the effects of light on mouse circadian rhythms. PLoS ONE 3, e3153 (2008).

  5. 5.

    , & Phototransduction by retinal ganglion cells that set the circadian clock. Science 295, 1070–1073 (2002).

  6. 6.

    et al. A novel human opsin in the inner retina. J. Neurosci. 20, 600–605 (2000).

  7. 7.

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

  8. 8.

    , , & Synaptic influences on rat ganglion-cell photoreceptors. J. Physiol. (Lond.) 582, 279–296 (2007).

  9. 9.

    et al. Photon capture and signalling by melanopsin retinal ganglion cells. Nature 457, 281–287 (2009).

  10. 10.

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

  11. 11.

    et al. Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice. Nature 424, 76–81 (2003).

  12. 12.

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

  13. 13.

    , , , & Modeling the role of mid-wavelength cones in circadian responses to light. Neuron 53, 677–687 (2007).

  14. 14.

    et al. Circadian photoreception in the retinally degenerate mouse (rd/rd). J. Comp. Physiol. [A] 169, 39–50 (1991).

  15. 15.

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

  16. 16.

    & Circadian rhythms in mice can be regulated by photoreceptors with cone-like characteristics. Brain Res. 694, 183–190 (1995).

  17. 17.

    et al. Spectral responses of the human circadian system depend on the irradiance and duration of exposure to light. Sci. Transl. Med. 2, 31–33 (2010).

  18. 18.

    et al. Distinct contributions of rod, cone and melanopsin photoreceptors to encoding irradiance. Neuron 66, 417–428 (2010).

  19. 19.

    et al. Phototransduction in transgenic mice after targeted deletion of the rod transducin alpha-subunit. Proc. Natl. Acad. Sci. USA 97, 13913–13918 (2000).

  20. 20.

    , , , & Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. Science 284, 505–507 (1999).

  21. 21.

    Contribution of classic photoreceptors to entrainment. J. Comp. Physiol. A Neuroethol. Sens. Neural Behav. Physiol. 189, 69–73 (2003).

  22. 22.

    & Entrainment of the circadian activity rhythm to the light cycle: effective light intensity for a Zeitgeber in the retinal degenerate C3H mouse and the normal C57BL mouse. Physiol. Behav. 24, 523–527 (1980).

  23. 23.

    et al. Selective loss of cone function in mice lacking the cyclic nucleotide–gated channel CNG3. Proc. Natl. Acad. Sci. USA 96, 7553–7557 (1999).

  24. 24.

    et al. Cone photoreceptor function loss-3, a novel mouse model of achromatopsia due to a mutation in Gnat2. Invest. Ophthalmol. Vis. Sci. 47, 5017–5021 (2006).

  25. 25.

    & Rod pathways: the importance of seeing nothing. Trends Neurosci. 22, 497–504 (1999).

  26. 26.

    & The rod pathway in the rabbit retina: a depolarizing bipolar and amacrine cell. J. Neurosci. 6, 331–345 (1986).

  27. 27.

    , & Microcircuitry of the dark-adapted cat retina: functional architecture of the rod-cone network. J. Neurosci. 6, 3505–3517 (1986).

  28. 28.

    , , , & A novel signaling pathway from rod photoreceptors to ganglion cells in mammalian retina. Neuron 21, 481–493 (1998).

  29. 29.

    , , & Rapid quantification of adult and developing mouse spatial vision using a virtual optomotor system. Invest. Ophthalmol. Vis. Sci. 45, 4611–4616 (2004).

  30. 30.

    , & Speed, spatial and temporal tuning of rod and cone vision in mouse. J. Neurosci. 28, 189–198 (2008).

  31. 31.

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

  32. 32.

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

  33. 33.

    , & Analysis of sleep-wakefulness rhythms in male rats after suprachiasmatic nucleus lesions and ocular enucleation. Brain Res. 122, 33–47 (1977).

  34. 34.

    , , & Multiple photoreceptors contribute to nonimage-forming visual functions predominantly through melanopsin-containing retinal ganglion cells. Cold Spring Harb. Symp. Quant. Biol. 72, 509–515 (2007).

  35. 35.

    et al. Identifying the photoreceptive inputs to the mammalian circadian system using transgenic and retinally degenerate mice. Behav. Brain Res. 125, 97–102 (2001).

  36. 36.

    & Diurnal mice (Mus musculus) and other examples of temporal niche switching. J. Comp. Physiol. A Neuroethol. Sens. Neural Behav. Physiol. 191, 1011–1024 (2005).

  37. 37.

    , & Differential effects of light wavelength in phase advancing the melatonin rhythm. J. Pineal Res. 36, 140–144 (2004).

  38. 38.

    et al. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J. Neurosci. 21, 6405–6412 (2001).

  39. 39.

    , & High sensitivity of the human circadian melatonin rhythm to resetting by short wavelength light. J. Clin. Endocrinol. Metab. 88, 4502–4505 (2003).

  40. 40.

    , , & Spectral sensitivity of a novel photoreceptive system mediating entrainment of mammalian circadian rhythms. Nature 308, 186–188 (1984).

  41. 41.

    , , , & Nonvisual light responses in the Rpe65 knockout mouse: rod loss restores sensitivity to the melanopsin system. Proc. Natl. Acad. Sci. USA 103, 10432–10437 (2006).

  42. 42.

    , & An alternative pathway for rod signals in the rodent retina: rod photoreceptors, cone bipolar cells and the localization of glutamate receptors. Proc. Natl. Acad. Sci. USA 96, 14130–14135 (1999).

  43. 43.

    , , , & Light signaling in scotopic conditions in the rabbit, mouse and rat retina: a physiological and anatomical study. J. Neurophysiol. 93, 3479–3488 (2005).

  44. 44.

    & Spectral sensitivity of photoreceptors mediating phase-shifts of circadian rhythms in retinally degenerate CBA/J (rd/rd) and normal CBA/N (+/+) mice. J. Comp. Physiol. [A] 178, 797–802 (1996).

  45. 45.

    & Bleached pigment activates transduction in isolated rods of the salamander retina. J. Physiol. (Lond.) 480, 261–279 (1994).

  46. 46.

    , & Cellular mechanisms that underlie bleaching and background adaptation. J. Gen. Physiol. 96, 345–372 (1990).

  47. 47.

    & Comparison of the responses of AII amacrine cells in the dark- and light-adapted rabbit retina. Vis. Neurosci. 16, 653–665 (1999).

  48. 48.

    & Bandpass filtering at the rod to second-order cell synapse in salamander (Ambystoma tigrinum) retina. J. Neurosci. 23, 3796–3806 (2003).

  49. 49.

    et al. Recoverin improves rod-mediated vision by enhancing signal transmission in the mouse retina. Neuron 46, 413–420 (2005).

  50. 50.

    & Recovery phase of the murine rod photoresponse reconstructed from electroretinographic recordings. J. Neurosci. 16, 563–571 (1996).

Download references

Acknowledgements

We would like to thank J. Nathans for the h.red DTA mice. We also want to thank R. Kuruvilla, H. Zhao and M. Halpern for their careful reading of the manuscript and helpful suggestions and the Johns Hopkins University Mouse Tri-Lab for its support. This work was supported by US National Institutes of Health grants GM076430 (S.H.) and EY017606 (A.P.S.), the David and Lucile Packard Foundation (S.H.), the Alfred P. Sloan Foundation (S.H.) and the McKnight Endowment Fund for Neurosciences (A.P.S.).

Author information

Affiliations

  1. Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Cara M Altimus
    • , Ali D Güler
    •  & Samer Hattar

  2. Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA.

    • Nazia M Alam
    •  & Glen T Prusky

  3. Zilkha Neurogenetic Institute, Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California, USA.

    • A Cyrus Arman
    •  & Alapakkam P Sampath

  4. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Samer Hattar

Authors

  1. Search for Cara M Altimus in:

  2. Search for Ali D Güler in:

  3. Search for Nazia M Alam in:

  4. Search for A Cyrus Arman in:

  5. Search for Glen T Prusky in:

  6. Search for Alapakkam P Sampath in:

  7. Search for Samer Hattar in:

Contributions

The experiments were conceived and designed by C.M.A., A.D.G., A.P.S. and S.H. Wheel-running experiments were carried out by C.M.A. A.C.A. performed current-clamp recordings of retinal cells. N.M.A., C.M.A. and G.T.P. carried out virtual optomotor system experiments. C.M.A., A.D.G., A.P.S. and S.H. wrote the manuscript, which was reviewed and edited by all of the authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Alapakkam P Sampath or Samer Hattar.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–3

To obtain permission to re-use content from this article visit RightsLink.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nn.2617

Further reading Further reading