All known eukaryotic organisms exhibit physiological and behavioral rhythms termed circadian rhythms that cycle with a near-24-hour period; in mammals, light is the most potent stimulus for entraining endogenous rhythms to the daily light cycle. Photic information is transmitted via the retinohypothalamic tract (RHT) to the suprachiasmatic nucleus (SCN) in the hypothalamus, where circadian rhythms are generated, but the retinal photopigment that mediates circadian entrainment has remained elusive. Here we show that most retinal ganglion cells (RGCs) that project to the SCN express the photopigment melanopsin.
The phase of circadian rhythms in rodents is shifted most effectively by light ranging from 480–511 nm, consistent with an opsin-based photopigment1,2,3. However, mice lacking rods and cones have normal circadian entrainment, suggesting that a novel photopigment mediates phase-shifting in response to light4. Recently, melanopsin, an opsin-based photopigment, was localized to the RGC layer of rodents and primates5. We therefore tested whether RGCs that express melanopsin project to the SCN.
We injected the right SCN of 10 rats with FluoroGold (FG) to retrogradely label the retinohypothalamic RGCs. Four of the injections were confined to the SCN and did not include the optic chiasm or optic tract (Fig. 1a). In these animals, FG labeled a distinct subset of widely distributed RGCs, corresponding to type III or W cells, as previously reported6.
For in situ hybridization, we used a 957-base-pair mouse melanopsin riboprobe5. Melanopsin transcript occurred in a pattern similar to that previously described5, with a scattered population of cells showing intense hybridization, predominantly in the RGC layer (Fig. 1b).
In doubly labeled sections, 74.2 ± 0.3% (mean ± s.e.m.) of retrogradely labeled RGCs also expressed melanopsin mRNA (Fig. 1c), with a similar percentage of double labeling in eyes ipsilateral and contralateral to the FG injection. Although the extent of retrograde labeling differed between cases, approximately 70% of RGCs that were intensely labeled for melanopsin mRNA were also retrogradely labeled. Both calculations are likely to underestimate the actual percentage of colocalization, because technical factors limit the efficiency of the combined labels. Therefore, most RGCs that project to the SCN express melanopsin, and a majority of melanopsin-containing RGCs project to the SCN.
These observations suggest that RGCs that contain melanopsin are particularly well poised to provide photic information to the SCN. Melanopsin in these retinohypothalamic RGCs may therefore mediate the photic entrainment of circadian rhythms in mice lacking rods and cones. Although a high percentage of RHT RGCs express melanopsin, RHT cells may also receive other photic signals through rods and cones in intact animals. In addition, the photopigments cryptochrome 1 and 2 have been localized to RGCs of the mouse retina7. Further experiments will be necessary to determine whether cryptochromes are involved in circadian photic entrainment. However, melanopsin may now be considered a primary candidate photopigment for mediating circadian entrainment.
Takahashi, J. S., DeCoursey, P. J., Bauman, L. & Menaker, M. Nature 308, 186–188 (1984).
Provencio, I. & Foster, R. G. Brain Res. 694, 183–190 (1995).
Yoshimura, T. & Ebihara, S. J. Comp. Physiol. A 178, 797–802 (1996).
Freedman, M. S. et al. Science 284, 502–504 (1999).
Provencio, I. et al. J. Neurosci. 20, 600–605 (2000).
Moore, R. Y., Speh, J. C. & Card, J. P. J. Comp. Neurol. 352, 351–366 (1995).
Miyamoto, Y. & Sancar, A. Proc. Natl. Acad. Sci. USA 95, 6097–6102 (1998).
This work was supported by USPHS grants HL60292, MH62589 and HL07901.
The authors declare no competing financial interests.
About this article
Cite this article
Gooley, J., Lu, J., Chou, T. et al. Melanopsin in cells of origin of the retinohypothalamic tract. Nat Neurosci 4, 1165 (2001). https://doi.org/10.1038/nn768
Rhodopsin and melanopsin coexist in mammalian sperm cells and activate different signaling pathways for thermotaxis
Scientific Reports (2020)
The Circadian Clock, the Immune System, and Viral Infections: The Intricate Relationship Between Biological Time and Host-Virus Interaction
Scientific Reports (2020)
Crosstalk: The diversity of melanopsin ganglion cell types has begun to challenge the canonical divide between image‐forming and non‐image‐forming vision
Journal of Comparative Neurology (2020)
Relationship between Indoor Daytime Light Exposure and Circadian Phase Response under Laboratory Free-Living Conditions
Biological Rhythm Research (2020)