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The role of retinal photoreceptors in the regulation of circadian rhythms

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Abstract

The circadian clock is an evolutionarily, highly conserved feature of most organisms. This internal timing mechanism coordinates biochemical, physiological and behavioral processes to maintain synchrony with the environmental cycles of light, temperature and nutrients. Several studies have shown that light is the most potent cue used by most organisms (humans included) to synchronize daily activities. In mammals, light perception occurs only in the retina; three different types of photoreceptors are present within this tissue: cones, rods and the newly discovered intrinsically photosensitive retinal ganglion cells (ipRGCs). Researchers believe that the classical photoreceptors (e.g., the rods and the cones) are responsible for the image-forming vision, whereas the ipRGCs play a key role in the non-image forming vision. This non-image-forming photoreceptive system communicates not only with the master circadian pacemaker located in the suprachiasmatic nuclei of the hypothalamus, but also with many other brain areas that are known to be involved in the regulation of several functions; thus, this non-image forming system may also affect several aspects of mammalian health independently from the circadian system.

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References

  1. Daan S, Aschoff J. Circadian contribution to survival. In: Aschoff J, Daan S, Groos G, editors. Vertebrate Circadian System. Berlin: Springer-Verlag; 1982. p. 305–21.

    Google Scholar 

  2. Pittendrigh CS. Temporal organization: reflections of a Darwinian clock-watcher. Annu Rev Physiol. 1993;55:16–54.

    Article  PubMed  CAS  Google Scholar 

  3. Yamazaki S, Numano R, Abe M, Hida A, Takahashi R, Ueda M, et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science. 2000;288:682–5.

    Article  PubMed  CAS  Google Scholar 

  4. Yoo SH, Yamazaki S, Lowrey PL, Shimomura K, Ko CH, Buhr ED, et al. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci USA. 2004;101:5339–6.

    Article  PubMed  CAS  Google Scholar 

  5. Yamazaki S, Goto M, Menaker M. No evidence for extraocular photoreceptors in the circadian system of the Syrian hamster. J Biol Rhythms. 1999;14:197–201.

    Article  PubMed  CAS  Google Scholar 

  6. Foster RG, Provencio I, Hudson D, Fiske S, DeGrip WJ, Menaker M. Circadian photoreception in the retinally degenerate mouse (rd/rd). J Comp Physiol A. 1991;169:39–50.

    Article  PubMed  CAS  Google Scholar 

  7. Freedman MS, Lucas RJ, Soni B, von Schantz M, Muñoz M, David-Gray Z, et al. Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science. 1999;284:502–4.

    Article  PubMed  CAS  Google Scholar 

  8. 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]. 1996;178:797–2.

    CAS  Google Scholar 

  9. Provencio I, Jiang G, De Grip WJ, Hayes WP, Rollag MD. Melanopsin: an opsin in melanophores, brain, and eye. Proc Natl Acad Sci USA. 1998;95:340–5.

    Article  PubMed  CAS  Google Scholar 

  10. Chaurasia SS, Rollag MD, Jiang G, Haynes WP, Haque R, Natesan A, et al. Molecular cloning, localization and circadian expression of melanopsin (Opn4): differential regulation of expression in pineal and retinal cell types. J Neurochemistry. 2005;92:158–70.

    Article  CAS  Google Scholar 

  11. Grone BP, Zhao S, Chen CC, Fernald RD. Localization and diurnal expression of melanopsin, vertebrate ancient opsin, and pituitary adenylate cyclase-activating peptide mRNA in a teleost retina. J Biol Rhythms. 2007;22:558–61.

    Article  PubMed  Google Scholar 

  12. Koyanagi M, Kubokawa K, Tsukamoto H, Shichida Y, Terakita A. Cephalochordate melanopsin: evolutionary linkage between invertebrate visual cells and vertebrate photosensitive retinal ganglion cells. Curr Biol. 2005;15:1065–9.

    Article  PubMed  CAS  Google Scholar 

  13. Bellingham J, Chaurasia SS, Melyan Z, Liu C, Cameron MA, Tarttelin EE, et al. Evolution of melanopsin photoreceptors: discovery and characterization of a new melanopsin gene in non-mammalian vertebrates. PLos Biology. 2007;4:e254.

    Article  Google Scholar 

  14. Provencio I, Rodriguez IR, Jiang G, Hayes WP, Moreira EF, Rollag MD. A novel human opsin in the inner retina. J Neurosci. 2000;20:600–5.

    PubMed  CAS  Google Scholar 

  15. Hannibal J, Hindersson P, Knudsen SM, Georg B, Fahrenkrug J. The photopigment melanopsin is exclusively present in pituitary adenylate cyclase-activating polypeptide-containing retinal ganglion cells of the retinohypothalamic tract. J Neurosci. 2002;22:RC191.

    PubMed  Google Scholar 

  16. Gooley JJ, Lu J, Chou TC, Scammell TE. Saper CB Melanopsin in cells of origin of the retinohypothalamic tract. Nature Neurosci. 2001;4:1165.

    Article  PubMed  CAS  Google Scholar 

  17. Hattar S, Liao HW, Takao M, Berson DM, Yau KW. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science. 2002;295:1065.

    Article  PubMed  CAS  Google Scholar 

  18. Berson DM, Dunn FA, Takao M. Phototransduction by ganglion cells innervating the circadian pacemaker. Science. 2002;295:1070–3.

    Article  PubMed  CAS  Google Scholar 

  19. Warren EJ, Allen CN, Brown RL, Robinson DW. Intrinsic light responses of retinal ganglion cells projecting to the circadian system. Eur J Neurosci. 2003;17:1727–35.

    Article  PubMed  Google Scholar 

  20. Hattar S, Lucas RJ, Mrosovsky N, Thompson S, Douglas RH, Hankins MW, et al. Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice. Nature. 2003;424:76–81.

    Article  PubMed  CAS  Google Scholar 

  21. Hannibal J, Fahrenkrug J. Melanopsin containing retinal ganglion cells are light responsive from birth. NeuroReport. 2004;15:2317–20.

    Article  PubMed  CAS  Google Scholar 

  22. Sekaran S, Lupi D, Jones SL, Sheely CJ, Hattar S, Yau KW, et al. Melanopsin-dependent photoreception provides earliest light detection in the mammalian retina. Curr Biol. 2005;15:1099–107.

    Article  PubMed  CAS  Google Scholar 

  23. Hannibal J, Georg B, Hindersson P, Fahrenkrug J. Light and darkness regulate melanopsin in the retinal ganglion cells of the albino Wistar rat. J Mol Neurosci. 2005;27:147–55.

    Article  PubMed  CAS  Google Scholar 

  24. Sakamoto K, Liu C, Tosini G. Classical photoreceptors regulate melanopsin mRNA levels in the rat retina. J Neuroscience. 2004;24:9693–7.

    Article  CAS  Google Scholar 

  25. Mathes A, Engel L, Holthues H, Wolloscheck T, Spessert R. Daily profile in melanopsin transcripts depends on seasonal lighting conditions in the rat retina. J Neuroendocrinol. 2007;19:952–7.

    Article  PubMed  CAS  Google Scholar 

  26. Qiu X, Kumbalasiri T, Carlson SM, Wong KY, Krishna V, Provencio I, et al. Induction of photosensitivity by heterologous expression of melanopsin. Nature. 2005;433:745–9.

    Article  PubMed  CAS  Google Scholar 

  27. Melyan Z, Tarttelin EE, Bellingham J, Lucas RJ, Hankins MW. Addition of human melanopsin renders mammalian cells photoresponsive. Nature. 2005;433:741–5.

    Article  PubMed  CAS  Google Scholar 

  28. Panda S, Nayak SK, Campo B, Walker JR, Hogenesch JB, Jegla T. Illumination of the melanopsin signaling pathway. Science. 2005;307:600–4.

    Article  PubMed  CAS  Google Scholar 

  29. Panda S, Sato TK, Castrucci AM, Rollag MD, DeGrip WJ, Hogenesch JB, et al. Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science. 2002;298:2213–6.

    Article  PubMed  CAS  Google Scholar 

  30. Ruby NF, Brennan TJ, Xie X, Cao V, Franken P, Heller HC, et al. Role of melanopsin in circadian responses to light. Science. 2002;298:2211–3.

    Article  PubMed  CAS  Google Scholar 

  31. Sakamoto K, Liu C, Tosini G. Classical photoreceptors regulate melanopsin mRNA levels in the rat retina. J Neuroscience. 2004;24:9693–7.

    Article  CAS  Google Scholar 

  32. Tosini G, Aguzzi J, Bullock NM. Effect of photoreceptor degeneration on circadian photoreception and free-running period in the Royal College of Surgeons rat. Brain Res. 2007;1148:76–82.

    Article  PubMed  CAS  Google Scholar 

  33. Lucas RJ, Douglas RH, Foster RG. Characterization of an ocular photopigment capable of driving pupillary constriction in mice. Nat Neurosci. 2001;4:621–6.

    Article  PubMed  CAS  Google Scholar 

  34. Lucas RJ, Hattar S, Takao M, Berson DM, Foster RG, Yau KW. Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science. 2003;299:245–7.

    Article  PubMed  CAS  Google Scholar 

  35. Lucas RJ, Freedman MS, Muñoz M, Garcia-Fernández JM, Foster RG. Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. Science. 1999;284:505–7.

    Article  PubMed  CAS  Google Scholar 

  36. Panda S, Provencio I, Tu DC, Pires SS, Rollag MD, Castrucci AM, et al. Melanopsin is required for non-image-forming photic responses in blind mice. Science. 2003;301:525–7.

    Article  PubMed  CAS  Google Scholar 

  37. Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, et al. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J Neurosci. 2001;21:6405–12.

    PubMed  CAS  Google Scholar 

  38. Brainard GC, Sliney D, Hanifin JP, Glickman G, Byrne B, Greeson JM, et al. Sensitivity of the human circadian system to short-wavelength (420-nm) light. J Biol Rhythms. 2008;23:379–86.

    Article  PubMed  Google Scholar 

  39. Benca RM, Gilliland MA, Obermeyer WH. Effects of lighting conditions on sleep and wakefulness in albino Lewis and pigmented Brown Norway rats. Sleep. 1998;21:451–60.

    PubMed  CAS  Google Scholar 

  40. Hattar S, Kumar M, Park A, Tong P, Tung J, Yau KW, et al. Central projections of melanopsin-expressing retinal ganglion cells in the mouse. J Comp Neurol. 2006;497:326–49.

    Article  PubMed  Google Scholar 

  41. Lupi D, Oster H, Thompson S, Foster RG. The acute light-induction of sleep is mediated by OPN4-based photoreception. Nat Neurosci. 2008;11:1068–73.

    Article  PubMed  CAS  Google Scholar 

  42. Altimus CM, Güler AD, Villa KL, McNeill DS, Legates TA, Hattar S. Rods-cones and melanopsin detect light and dark to modulate sleep independent of image formation. Proc Natl Acad Sci U S A. 2008;105:19998–20003.

    Article  PubMed  Google Scholar 

  43. Thompson S, Lupi D, Hankins MW, Peirson SN, Foster RG. The effects of rod and cone loss on the photic regulation of locomotor activity and heart rate. Eur J NeuroSci. 2008;28:724–9.

    Article  PubMed  Google Scholar 

  44. Glickman G, Byrne B, Pineda C, Hauck WW, Brainard GC. Light therapy for Seasonal Affective Disorder with blue narrow-band light-emitting diodes (LED). Biol Psychiatry. 2006;59:502–7.

    Article  PubMed  Google Scholar 

  45. Lockley SW, Gooley JJ. Circadian photoreception: spotlight on the brain. Curr Biol. 2006;16:R795–7.

    Article  PubMed  CAS  Google Scholar 

  46. Roecklein KA, Rohan KJ, Duncan WC, Rollag MD, Rosenthal NE, Lipsky RH, et al. A missense variant (P10L) of the melanopsin (OPN4) gene in seasonal affective disorder. J Affect Disord. 2009;114:279–85.

    Article  PubMed  CAS  Google Scholar 

  47. Morin LP, Blanchard JH, Provencio I. Retinal ganglion cell projections to the hamster suprachiasmatic nucleus, intergeniculate leaflet, and visual midbrain: bifurcation and melanopsin immunoreactivity. J Comp Neurol. 2003;465:401–16.

    Article  PubMed  Google Scholar 

  48. Dacey DM, Liao HW, Peterson BB, Robinson FR, Smith VC, Pokorny J, et al. Melanopsin-expressing ganglion cells in primate retina signal color and irradiance and project to the LGN. Nature. 2005;433:749–54.

    Article  PubMed  CAS  Google Scholar 

  49. Zaidi FH, Hull JT, Peirson SN, Wulff K, Aeschbach D, Gooley JJ, et al. Short-wavelength light sensitivity of circadian, pupillary, and visual awareness in humans lacking an outer retina. Curr Biol. 2007;17:2122–8.

    Article  PubMed  CAS  Google Scholar 

  50. Schmidt TM, Kofuji P. Functional and morphological differences among intrinsically photosensitive retinal ganglion cells. J Neurosci. 2009;29:476–82.

    Article  PubMed  CAS  Google Scholar 

  51. Green CB, Besharse JC. Retinal circadian clocks and control of retinal physiology. J Biol Rhythms. 2004;19:91–102.

    Article  PubMed  CAS  Google Scholar 

  52. Iuvone PM, Tosini G, Haque R, Klein DC, Chaurasia SS. Circadian clocks, clock-controlled genes and melatonin biosynthesis in the retina. Prog Retin Eye Res. 2005;24:433–56.

    Article  PubMed  CAS  Google Scholar 

  53. Tosini G, Pozdeyev N, Sakamoto K, Iuvone PM. The circadian clock system in mammalian retina. BioEssays. 2008;30:624–33.

    Article  PubMed  CAS  Google Scholar 

  54. Tosini G, Menaker M. Circadian rhythms in cultured mammalian retina. Science. 1996;272:419–21.

    Article  PubMed  CAS  Google Scholar 

  55. Sakamoto K, Oishi K, Shiraishi M, Hamano S, Otsuka H, Miyake Y, et al. Two circadian oscillatory mechanisms in the mammalian retina. NeuroReport. 2000;11:3995–7.

    Article  PubMed  CAS  Google Scholar 

  56. Doyle SE, McIvor WE, Menaker M. Circadian rhythmicity in dopamine content of mammalian retina: role of the photoreceptors. J Neurochem. 2002;83:211–9.

    Article  PubMed  CAS  Google Scholar 

  57. Pozdeyev NK, Tosini G, Ali F, Rozov S, Lee RH, Iuvone PM. Dopamine modulates diurnal and circadian rhythms of protein phosphorylation in photoreceptor cells of mouse retina. Eur J Neurosci. 2008;27:26691.

    Article  Google Scholar 

  58. Ruan GX, Allen GC, Yamazaki S, McMahon DG. An autonomous circadian clock in the inner mouse retina regulated by dopamine and GABA. PLoS Biol. 2008;6:e249.

    Article  PubMed  CAS  Google Scholar 

  59. Zhang DQ, Wong KY, Sollars PJ, Berson DM, Pickard GE, McMahon DG. Intraretinal signaling by ganglion cell photoreceptors to dopaminergic amacrine neurons. Proc Natl Acad Sci U S A. 2008;105:14181–6.

    Article  PubMed  Google Scholar 

  60. Cameron MA, Pozdeyev N, Vugler AA, Cooper H, Iuvone PM, Lucas RJ. Light regulation of retinal dopamine that is independent of melanopsin phototransduction. Eur J NeuroSci. 2009;29:761–7.

    Article  PubMed  CAS  Google Scholar 

  61. Barnard AR, Hattar S, Hankins MW, Lucas RJ. Melanopsin regulates visual processing in the mouse retina. Curr Biol. 2006;16:389–95.

    Article  PubMed  CAS  Google Scholar 

  62. Lupi D, Cooper HM, Froehlich A, Standford L, McCall MA, Foster RG. Transgenic ablation of rod photoreceptors alters the circadian phenotype of mice. Neurosci. 1999;89:363–74.

    Article  CAS  Google Scholar 

  63. Yamazaki S, Alones V, Menaker M. Interaction of the retina with suprachiasmatic pacemakers in the control of circadian behavior. J Biol Rhythms. 2002;17:315–29.

    Article  PubMed  Google Scholar 

  64. Lee HS, Nelms JL, Nguyen M, Silver R, Lehman MN. The eye is necessary for a circadian rhythm in the suprachiasmatic nucleus. Nat Neurosci. 2003;6:111–2.

    Article  PubMed  CAS  Google Scholar 

  65. Sakamoto K, Liu C, Tosini G. Circadian rhythms in the retina of rats with photoreceptor degeneration. J Neurochemistry. 2004;90:1019–24.

    Article  CAS  Google Scholar 

  66. Ruan GX, Zhang DQ, Zhou T, Yamazaki S, McMahon DG. Circadian organization of the mammalian retina. Proc Natl Acad Sci U S A. 2006;103:9703–8.

    Article  PubMed  CAS  Google Scholar 

  67. Mrosovsky N, Hattar S. Diurnal mice (Mus musculus) and other examples of temporal niche switching. J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2005;191:1011–24.

    Article  PubMed  CAS  Google Scholar 

  68. Doyle SE, Yoshikawa T, Hillson H, Menaker M. Retinal pathways influence temporal niche. Proc Natl Acad Sci U S A. 2008;105:13133–8.

    Article  PubMed  Google Scholar 

  69. Cahill GM, Menaker M. Effects of excitatory amino acid receptor antagonists and agonists on suprachiasmatic nucleus responses to retinohypothalamic tract volleys. Brain Res. 1989;479:76–82.

    Article  PubMed  CAS  Google Scholar 

  70. Colwell CS, Menaker M. NMDA as well as non-NMDA receptor antagonists can prevent the phase-shifting effects of light on the circadian system of the golden hamster. J Biol Rhythms. 1992;7:125–36.

    Article  PubMed  CAS  Google Scholar 

  71. Huhman KL, Marvel CL, Gillespie CF, Mintz EM, Albers HE. Tetrodotoxin blocks NPY-induced but not muscimol-induced phase advances of wheel-running activity in Syrian hamsters. Brain Res. 1997;772:176–80.

    Article  PubMed  CAS  Google Scholar 

  72. Gastel JA, Roseboom PH, Rinaldi PA, Weller JL, Klein DC. Melatonin production: proteasomal proteolysis in serotonin N-acetyltransferase regulation. Science. 1998;279:1358–60.

    Article  PubMed  CAS  Google Scholar 

  73. Paul KN, Fukuhara C, Tosini G, Albers HE. Transduction of light in the suprachiasmatic nucleus: evidence for two different neurochemical cascades regulating the levels of Per1 mRNA and Pineal Melatonin. Neuroscience. 2003;119:137–44.

    Article  PubMed  CAS  Google Scholar 

  74. Paul KN, Gamble KL, Novak C, Fukuhara C, Tosini G, Albers HE. TTX blocks the transduction of light information from the SCN to the pineal gland without influencing Per1 and Per2 expression in the SCN cells. Eur J Neurosci. 2004;19:2808–14.

    Article  PubMed  Google Scholar 

  75. Gamble KL, Paul KN, Karom MC, Tosini G, Albers HE. Paradoxical effects of NPY in the suprachiasmatic nucleus. Eur J Neurosci. 2007;23:2488–94.

    Article  Google Scholar 

  76. Larsen PJ, Enquist LW, Card JP. Characterization of the multisynaptic neuronal control of the rat pineal gland using viral transneuronal tracing. Eur J NeuroSci. 1998;10:128–45.

    Article  PubMed  CAS  Google Scholar 

  77. Teclemariam-Mesbah R, Ter Horst GJ, Postema F, Wortel J, Buijs RM. Anatomical demonstration of the suprachiasmatic nucleus-pineal pathway. J Comp Neurol. 1999;406:171–82.

    Article  PubMed  CAS  Google Scholar 

  78. Card JP. Pseudorabies virus and the functional architecture of the circadian timing system. J Biol Rhythms. 2000;15:453–61.

    PubMed  CAS  Google Scholar 

  79. Scheer FA, Ter Horst GJ, van Der Vliet J, Buijs RM. Physiological and anatomic evidence for regulation of the heart by suprachiasmatic nucleus in rats. Am J Physiol Heart Circ Physiol. 2001;280:H1391–9.

    PubMed  CAS  Google Scholar 

  80. Mutoh T, Shibata S, Korf HW, Okamura H. Melatonin modulates the light-induced sympathoexcitation and vagal suppression with participation of the suprachiasmatic nucleus in mice. J Physiol. 2003;547:317–32.

    Article  PubMed  CAS  Google Scholar 

  81. Scheer FA, Pirovano C, Van Someren EJ. Buijs RM Environmental light and suprachiasmatic nucleus interact in the regulation of body temperature. Neuroscience. 2005;132:465–77.

    Article  PubMed  CAS  Google Scholar 

  82. Ishida A, et al. Light activates the adrenal gland: timing of gene expression and glucocorticoid release. Cell Metab. 2005;2:297–307.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Supported by NIH grants NS 43459 to G.T., NS060659 to K.N.P., and T32MH65740 T.B.S.

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  1. Circadian Rhythms and Sleep Disorders Program, Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA

    Ketema N. Paul, Talib B. Saafir & Gianluca Tosini

  2. Neuroscience Institute, Morehouse School of Medicine, 720 Westview Dr, Atlanta, GA, 30310, USA

    Gianluca Tosini

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  1. Ketema N. Paul
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Paul, K.N., Saafir, T.B. & Tosini, G. The role of retinal photoreceptors in the regulation of circadian rhythms. Rev Endocr Metab Disord 10, 271–278 (2009). https://doi.org/10.1007/s11154-009-9120-x

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