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

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.

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Figure 1: Rods drive circadian photoentrainment across a wide range of light intensities.
Figure 2: The rod-cone pathway is important for mesopic light signaling.
Figure 3: Rods contribution to phase shifts and period lengthening in constant light is dependent on cone state.

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References

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

    Article  Google Scholar 

  2. Hatori, M. 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).

    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).

    Article  CAS  Google Scholar 

  4. Göz, D. 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).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. Dkhissi-Benyahya, O., Gronfier, C., De Vanssay, W., Flamant, F. & Cooper, H.M. Modeling the role of mid-wavelength cones in circadian responses to light. Neuron 53, 677–687 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Gooley, J.J. 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).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Lucas, R.J., Freedman, M.S., Munoz, M., Garcia-Fernandez, J.M. & Foster, R.G. Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. Science 284, 505–507 (1999).

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  22. Ebihara, S. & Tsuji, K. 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).

    Article  CAS  Google Scholar 

  23. Biel, M. 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).

    Article  CAS  Google Scholar 

  24. Chang, B. 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).

    Article  Google Scholar 

  25. Sharpe, L.T. & Stockman, A. Rod pathways: the importance of seeing nothing. Trends Neurosci. 22, 497–504 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Smith, R.G., Freed, M.A. & Sterling, P. Microcircuitry of the dark-adapted cat retina: functional architecture of the rod-cone network. J. Neurosci. 6, 3505–3517 (1986).

    Article  CAS  Google Scholar 

  28. Soucy, E., Wang, Y., Nirenberg, S., Nathans, J. & Meister, M. A novel signaling pathway from rod photoreceptors to ganglion cells in mammalian retina. Neuron 21, 481–493 (1998).

    Article  CAS  Google Scholar 

  29. 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 

  30. Umino, Y., Solessio, E. & Barlow, R.B. Speed, spatial and temporal tuning of rod and cone vision in mouse. J. Neurosci. 28, 189–198 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  34. Güler, A.D., Altimus, C.M., Ecker, J.L. & Hattar, S. 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).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Wright, H.R., Lack, L.C. & Kennaway, D.J. Differential effects of light wavelength in phase advancing the melatonin rhythm. J. Pineal Res. 36, 140–144 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  39. Lockley, S.W., Brainard, G.C. & Czeisler, C.A. High sensitivity of the human circadian melatonin rhythm to resetting by short wavelength light. J. Clin. Endocrinol. Metab. 88, 4502–4505 (2003).

    Article  CAS  Google Scholar 

  40. Takahashi, J.S., DeCoursey, P.J., Bauman, L. & Menaker, M. Spectral sensitivity of a novel photoreceptive system mediating entrainment of mammalian circadian rhythms. Nature 308, 186–188 (1984).

    Article  CAS  Google Scholar 

  41. Doyle, S.E., Castrucci, A.M., McCall, M., Provencio, I. & Menaker, M. 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).

    Article  CAS  Google Scholar 

  42. Hack, I., Peichl, L. & Brandstatter, J.H. 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).

    Article  CAS  Google Scholar 

  43. Protti, D.A., Flores-Herr, N., Li, W., Massey, S.C. & Wassle, H. Light signaling in scotopic conditions in the rabbit, mouse and rat retina: a physiological and anatomical study. J. Neurophysiol. 93, 3479–3488 (2005).

    Article  Google Scholar 

  44. Yoshimura, T. & Ebihara, S. 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).

    Article  CAS  Google Scholar 

  45. Cornwall, M.C. & Fain, G.L. Bleached pigment activates transduction in isolated rods of the salamander retina. J. Physiol. (Lond.) 480, 261–279 (1994).

    Article  CAS  Google Scholar 

  46. Cornwall, M.C., Fein, A. & MacNichol, E.F., Jr. Cellular mechanisms that underlie bleaching and background adaptation. J. Gen. Physiol. 96, 345–372 (1990).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  50. Lyubarsky, A.L. & Pugh, E.N. Jr. Recovery phase of the murine rod photoresponse reconstructed from electroretinographic recordings. J. Neurosci. 16, 563–571 (1996).

    Article  CAS  Google Scholar 

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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.).

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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.

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Correspondence to Alapakkam P Sampath or Samer Hattar.

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Altimus, C., Güler, A., Alam, N. et al. Rod photoreceptors drive circadian photoentrainment across a wide range of light intensities. Nat Neurosci 13, 1107–1112 (2010). https://doi.org/10.1038/nn.2617

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