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The acute light-induction of sleep is mediated by OPN4-based photoreception

Abstract

Sleep is regulated by both homeostatic and circadian mechanisms. The latter, termed 'process c', helps synchronize sleep-wake patterns to the appropriate time of the day. However, in the absence of a circadian clock, overall sleep-wake rhythmicity is preserved and remains synchronized to the external light-dark cycle, indicating that there is an additional, clock-independent photic input to sleep. We found that the direct photic regulation of sleep in mice is predominantly mediated by melanopsin (OPN4)-based photoreception of photosensitive retinal ganglion cells (pRGCs). Moreover, OPN4-dependent sleep regulation was correlated with the activation of sleep-promoting neurons in the ventrolateral preoptic area and the superior colliculus. Collectively, our findings describe a previously unknown pathway in sleep regulation and identify the pRGC/OPN4 signaling system as a potentially new pharmacological target for the selective manipulation of sleep and arousal states.

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Figure 1: Rods/cones alone or pRGCs alone are sufficient to entrain the circadian clock and sleep-wake rhythms.
Figure 2: OPN4, but not rods and cones, regulates the acute light-induced sleep response in mice.
Figure 3: Masking responses to light are preserved in Opn4−/− mice.
Figure 4: Light-induced Fos transcription is abolished in the VLPO and superior colliculus of Opn4−/−.

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References

  1. Foster, R.G. et al. Non-rod, non-cone photoreception in rodents and teleost fish. Novartis Found. Symp. 253, 3–23; discussion 23–30, 52–55, 102–109 (2003).

    CAS  PubMed  Google Scholar 

  2. 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 

  3. 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 

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

    Article  CAS  Google Scholar 

  5. Provencio, I., Rollag, M.D. & Castrucci, A.M. Photoreceptive net in the mammalian retina. This mesh of cells may explain how some blind mice can still tell day from night. Nature 415, 493 (2002).

    Article  CAS  Google Scholar 

  6. 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 

  7. Sekaran, S., Foster, R.G., Lucas, R.J. & Hankins, M.W. Calcium imaging reveals a network of intrinsically light-sensitive inner-retinal neurons. Curr. Biol. 13, 1290–1298 (2003).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. 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 

  12. Peirson, S.N. et al. Microarray analysis and functional genomics identify novel components of melanopsin signaling. Curr. Biol. 17, 1363–1372 (2007).

    Article  CAS  Google Scholar 

  13. Borbely, A.A. Effects of light on sleep and activity rhythms. Prog. Neurobiol. 10, 1–31 (1978).

    Article  CAS  Google Scholar 

  14. Saper, C.B., Scammell, T.E. & Lu, J. Hypothalamic regulation of sleep and circadian rhythms. Nature 437, 1257–1263 (2005).

    Article  CAS  Google Scholar 

  15. Lockley, S.W. et al. Short-wavelength sensitivity for the direct effects of light on alertness, vigilance and the waking electroencephalogram in humans. Sleep 29, 161–168 (2006).

    PubMed  Google Scholar 

  16. Benca, R.M., Gilliland, M.A. & Obermeyer, W.H. Effects of lighting conditions on sleep and wakefulness in albino Lewis and pigmented Brown Norway rats. Sleep 21, 451–460 (1998).

    Article  CAS  Google Scholar 

  17. Borbely, A.A. Sleep and motor activity of the rat during ultra-short light-dark cycles. Brain Res. 114, 305–317 (1976).

    Article  CAS  Google Scholar 

  18. Borbely, A.A. A two process model of sleep regulation. Hum. Neurobiol. 1, 195–204 (1982).

    CAS  PubMed  Google Scholar 

  19. David-Gray, Z.K., Janssen, J.W., DeGrip, W.J., Nevo, E. & Foster, R.G. Light detection in a 'blind' mammal. Nat. Neurosci. 1, 655–656 (1998).

    Article  CAS  Google Scholar 

  20. Provencio, I., Wong, S., Lederman, A.B., Argamaso, S.M. & Foster, R.G. Visual and circadian responses to light in aged retinally degenerate mice. Vision Res. 34, 1799–1806 (1994).

    Article  CAS  Google Scholar 

  21. 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 

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

    Article  CAS  Google Scholar 

  23. Fuller, P.M., Gooley, J.J. & Saper, C.B. Neurobiology of the sleep-wake cycle: sleep architecture, circadian regulation and regulatory feedback. J. Biol. Rhythms 21, 482–493 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. 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 

  26. Gaus, S.E., Strecker, R.E., Tate, B.A., Parker, R.A. & Saper, C.B. Ventrolateral preoptic nucleus contains sleep-active, galaninergic neurons in multiple mammalian species. Neuroscience 115, 285–294 (2002).

    Article  CAS  Google Scholar 

  27. Conte, I., Morcillo, J. & Bovolenta, P. Comparative analysis of Six3 and Six6 distribution in the developing and adult mouse brain. Dev. Dyn. 234, 718–725 (2005).

    Article  CAS  Google Scholar 

  28. Stoykova, A. & Gruss, P. Roles of Pax genes in developing and adult brain as suggested by expression patterns. J. Neurosci. 14, 1395–1412 (1994).

    Article  CAS  Google Scholar 

  29. Guler, 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 

  30. Peirson, S. & Foster, R.G. Melanopsin: another way of signaling light. Neuron 49, 331–339 (2006).

    Article  CAS  Google Scholar 

  31. Bae, K., Lee, C., Hardin, P.E. & Edery, I. dCLOCK is present in limiting amounts and likely mediates daily interactions between the dCLOCK-CYC transcription factor and the PER-TIM complex. J. Neurosci. 20, 1746–1753 (2000).

    Article  CAS  Google Scholar 

  32. Kume, K. et al. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98, 193–205 (1999).

    Article  CAS  Google Scholar 

  33. van der Horst, G.T. et al. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398, 627–630 (1999).

    Article  CAS  Google Scholar 

  34. Zheng, B. et al. Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell 105, 683–694 (2001).

    Article  CAS  Google Scholar 

  35. Bunger, M.K. et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009–1017 (2000).

    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. Miller, A.M., Obermeyer, W.H., Behan, M. & Benca, R.M. The superior colliculus pretectum mediates the direct effects of light on sleep. Proc. Natl. Acad. Sci. USA 95, 8957–8962 (1998).

    Article  CAS  Google Scholar 

  38. Holt, C.E. & Harris, W.A. Position, guidance and mapping in the developing visual system. J. Neurobiol. 24, 1400–1422 (1993).

    Article  CAS  Google Scholar 

  39. 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 

  40. Hankins, M.W. & Lucas, R.J. The primary visual pathway in humans is regulated according to long-term light exposure through the action of a nonclassical photopigment. Curr. Biol. 12, 191–198 (2002).

    Article  CAS  Google Scholar 

  41. Albrecht, U. & Foster, R.G. Placing ocular mutants into a functional context: a chronobiological approach. Methods 28, 465–477 (2002).

    Article  CAS  Google Scholar 

  42. Jud, C., Schmutz, I., Hampp, G., Oster, H. & Albrecht, U. A guideline for analyzing circadian wheel-running behavior in rodents under different lighting conditions. Biol. Proced. Online 7, 101–116 (2005).

    Article  Google Scholar 

  43. Rieux, C. et al. Analysis of immunohistochemical label of Fos protein in the suprachiasmatic nucleus: comparison of different methods of quantification. J. Biol. Rhythms 17, 121–136 (2002).

    Article  CAS  Google Scholar 

  44. Abraham, D., Oster, H., Huber, M. & Leitges, M. The expression pattern of three mast cell–specific proteases during mouse development. Mol. Immunol. 44, 732–740 (2007).

    Article  CAS  Google Scholar 

  45. Peirson, S.N., Butler, J.N. & Foster, R.G. Experimental validation of novel and conventional approaches to quantitative real-time PCR data analysis. Nucleic Acids Res. 31, e73 (2003).

    Article  Google Scholar 

  46. Oster, H. et al. The circadian rhythm of glucocorticoids is regulated by a gating mechanism residing in the adrenal cortical clock. Cell Metab. 4, 163–173 (2006).

    Article  CAS  Google Scholar 

  47. Paxinos, G. et al. In vitro autoradiographic localization of calcitonin and amylin binding sites in monkey brain. J. Chem. Neuroanat. 27, 217–236 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Hattar (Johns Hopkins University) for generously donating the Opn4−/− mice, N. Naujokat for technical assistance and S.N. Peirson for helpful comments on this manuscript. This work was supported by a Wellcome Trust Program grant and a European Commission grant (EuClock) to R.G.F. H.O. was supported by an Otto Hahn fellowship of the Max Planck Society and an Emmy Noether fellowship of the Deutsche Forschungsgemeinschaft.

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R.G.F. conceived the project. D.L. conducted the sleep and immunohistochemical analyses. H.O. undertook the wheel running, the in situ and the qPCR analyses. S.T. set up and contributed to the sleep experiments. R.G.F., H.O. and D.L. wrote the paper, with advice from S.T.

Corresponding author

Correspondence to Russell G Foster.

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Lupi, D., Oster, H., Thompson, S. et al. The acute light-induction of sleep is mediated by OPN4-based photoreception. Nat Neurosci 11, 1068–1073 (2008). https://doi.org/10.1038/nn.2179

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