Skip to main content
    • Aa
    • Aa

Melanopsin and non-melanopsin expressing retinal ganglion cells innervate the hypothalamic suprachiasmatic nucleus


Retinal input to the hypothalamic suprachiasmatic nucleus (SCN) synchronizes the SCN circadian oscillator to the external day/night cycle. Retinal ganglion cells that innervate the SCN via the retinohypothalamic tract are intrinsically light sensitive and express melanopsin. In this study, we provide data indicating that not all SCN-projecting retinal ganglion cells express melanopsin. To determine the proportion of ganglion cells afferent to the SCN that express melanopsin, ganglion cells were labeled following transsynaptic retrograde transport of a recombinant of the Bartha strain of pseudorabies virus (PRV152) constructed to express the enhanced green fluorescent protein (EGFP). PRV152 injected into the anterior chamber of the eye retrogradely infects four retinorecipient nuclei in the brain via autonomic circuits to the eye, resulting in transneuronally labeled ganglion cells in the contralateral retina 96 h after intraocular infection. In animals with large bilateral lesions of the lateral geniculate body/optic tract, ganglion cells labeled with PRV152 are retrogradely infected from only the SCN. In these animals, most PRV152-infected ganglion cells were immunoreactive for melanopsin. However, a significant percentage (10–20%) of EGFP-labeled ganglion cells did not express melanopsin. These data suggest that in addition to the intrinsically light-sensitive melanopsin-expressing ganglion cells, conventional ganglion cells also innervate the SCN. Thus, it appears that the rod/cone system of photoreceptors may provide signals to the SCN circadian system independent of intrinsically light-sensitive melanopsin ganglion cells.

Corresponding author
Address correspondence and reprint requests to: Gary E. Pickard, Department of Biomedical Sciences, Section of Anatomy and Neurobiology, Colorado State University, Fort Collins, CO 80523-1670, USA. E-mail:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

Belenky, M.A., Smeraski, C.A., Provencio, I., Sollars, P.J., & Pickard, G.E. (2003). Melanopsin retinal ganglion cells receive bipolar and amacrine cell synapses. Journal of Comparative Neurology460, 380393.

Berson, D.M. (2003). Strange vision: Ganglion cells as circadian photoreceptors. Trends in Neuroscience26, 314320.

Berson, D.M., Dunn, F.A., & Takao, M. (2002). Phototransduction by retinal ganglion cells that set the circadian clock. Science295, 10701073.

Brideau, A.D., Eldridge, M.G., & Enquist, L.W. (2000). Directional transneuronal infection by pseudorabies virus is dependent on an acidic internalization motif in the Us9 cytoplasmic tail. Journal of Virology74, 45494561.

Card, J.P., Whealy, M.E., Robbins, A.K., Moore, R.Y., & Enquist, L.W. (1991). Two alpha-herpevirus strains are transported differentially in the rodent visual system. Neuron6, 957969.

Chao, T.I., Grosche, J., Friedrich, K.J., Biedermann, B., Francke, M., Pannicke, T., Reichelt, W., Wulst, M., Mühle, C., Pritz-Hohmeier, S., Kuhrt, H., Faude, F., Drommer, W., Kasper, M., Buse, E., & Reichenbach, A. (1997). Comparative studies on mammalian Müller (retinal glial) cells. Journal of Neurocytology26, 439454.

Famiglietti, E.V. & Kolb, H. (1976). Structural basis of “ON”- and “OFF”-center responses in retinal ganglion cells. Science194, 193195.

Freedman, M.S., Lucas, R.J., Soni, B., von Schantz, M., Munoz, M., David-Gray, Z., & Foster, R. (1999). Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science284, 502504.

Gooley, J.J., Lu, J., Chou, T.C., Scammell, T.E., & Saper, C.B. (2001). Melanopsin in cells of origin of the retinohypothalamic tract. Nature Neuroscience4, 1165.

Hannibal, J., Vrang, N., Card, J.P., & Fahrenkrug, J. (2001). Light-dependent induction of cFos during subjective day and night in PACAP-containing ganglion cells of the retinohypothalamic tract. Journal of Biological Rhythms16, 457470.

Hannibal, J., Hindersson, P., Nevo, E., & Fahrehkrug, J. (2002b). The circadian photopigment melanopsin is expressed in the blind subterranean mole rat, Spalax. NeuroReport13, 14111414.

Hattar, S., Liao, H.-W., Takao, M., Berson, D.M., & Yau, K.-W. (2002). Melanopsin-containing retinal ganglion cells: Architecture, projections, and intrinsic photosensitivity. Science295, 10651070.

Hattar, S., Lucas, R.J., Mrosovsky, N., Thompson, S., Douglas, R.H., Hankins, M.W., Lem, J., Biel, M., Hofmann, F., Foster, R.G., & Yau, K.-W. (2003). Melanopsin and rod–cone photoreceptive systems account for all major accessory visual functions in mice. Nature424, 7581.

Husak, P.J., Kuo, T., & Enquist, L.W. (2000). Pseudorabies virus membrane proteins gI and gE facilitate anterograde spread of infection in projection-specific neurons in the rat. Journal of Virology74, 1097510983.

Johnson, R.F., Moore, R.Y., & Morin, L.P. (1988). Loss of entrainment and anatomical plasticity after lesions of the hamster retinohypothalamic tract. Brain Research460, 297313.

Lu, J., Shiromani, P., & Saper, C.B. (1999). Retinal input to the sleep-active ventrolateral preoptic nucleus in the rat. Neuroscience93, 209214.

Lucas, R.J., Freedman, M.S., Munoz, M., Garcia-Fernandez, J.M., & Foster, R.G. (1999). Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. Science284, 505507.

Moore, R.Y., Speh, J.C., & Card, J.P. (1995). The retinohypothalamic tract originates from a distinct subset of retinal ganglion cells. Journal of Comparative Neurology352, 351366.

Morin, L.P. & Blanchard, J.H. (1998). Interconnections among nuclei of the subcortical visual shell: The intergeniculate leaflet is a major constituent of the hamster subcortical visual system. Journal of Comparative Neurology396, 288309.

Morin, L.P., Goodless-Sanchez, N., Smale, L., & Moore, R.Y. (1994). Projections of the suprachiasmatic nuclei, subparaventricular zone and retrochiasmatic area in the golden hamster. Neuroscience61, 391410.

Morin, L.P., Blanchard, J.H., & Provencio, I. (2003). Retinal ganglion cell projections to the hamster suprachiasmatic nucleus, intergeniculate leaflet, and visual midbrain: Bifurcation and melanopsin immunoreactivity. Journal of Comparative Neurology465, 401416.

Panda, S., Sato, T.K., Castrucci, A.M., Rollag, M.D., DeGrip, W.J., Hogenesch, J.B., Provencio, I., & Kay, S.A. (2002). Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science298, 22132216.

Panda, S., Provencio, I., Tu, D.C., Pires, S.S., Rollag, M.D., Castrucci, A.M., Pletcher, M.T., Sato, T.K., Wiltshire, T., Andahazy, M., Kay, S.A., Van Gelder, R.N., & Hogenesch, J.B. (2003). Melanopsin is required for non-image forming photic responses in blind mice. Science301, 525527.

Pickard, G.E. (1982). The afferent connections of the suprachiasmatic nucleus of the golden hamster with emphasis on the retinohypothalamic projection. Journal of Comparative Neurology211, 6583.

Pickard, G.E. (1985). Bifurcating axons of retinal ganglion cells terminate in the hypothalamic suprachiasmatic nucleus and the intergeniculate leaflet of the thalamus. Neuroscience Letters55, 211217.

Pickard, G.E. & Silverman, A.J. (1981). Direct retinal projections to the hypothalamus, piriform cortex and accessory optic nuclei in the golden hamster as demonstrated by a sensitive anterograde horseradish peroxidase technique. Journal of Comparative Neurology196, 155172.

Pickard, G.E., Ralph, M., & Menaker, M. (1987). The intergeniculate leaflet partially mediates the effects of light on circadian rhythms. Journal of Biological Rhythms2, 3556.

Provencio, I., Jiang, G., DeGrip, W.J., Hayes, W.P., & Rollag, M.D. (1998). Melanopsin: An opsin in melanophores, brain, and eye. Proceedings of the National Academy of Sciences of the U.S.A.95, 340345.

Provencio, I., Rollag, M.D., & Castrucci, A.M. (2002). Photoreceptive net in the mammalian retina. Nature415, 493.

Pu, M. (1999) Dendritic morphology of cat retinal ganglion cells projecting to suprachiasmatic nucleus. Journal of Comparative Neurology414, 267274.

Ruby, N.F., Brennan, T.J., Xie, X., Cao, V., Franken, P., Heller, H.C., & O'Hara, B.F. (2002). Role of melanopsin in circadian responses to light. Science298, 22112213.

Sancar, A. (2000). Cryptochrome: The second photoactive pigment in the eye and its role in circadian photoreception. Annual Review of Biochemistry69, 3167.

Smeraski, C.A., Sollars, P.J., Ogilvie, M.D., Enquist, L.W., & Pickard, G.E. (2004). Suprachiasmatic nucleus input to autonomic circuits identified by retrograde transsynaptic transport of pseudorabies virus from the rat eye. Journal of Comparative Neurology471, 298313.

Smith, B.N., Banfield, B.W., Smeraski, C.A., Wilcox, C.L., Dudek, F.E., Enquist, L.W., & Pickard, G.E. (2000). Pseudorabies virus expressing enhanced green fluorescent protein: A tool for in vitro electrophysiological analysis of transsynaptically labeled neurons in identified CNS circuits. Proceedings of the National Academy of Sciences of the U.S.A.97, 92649269.

Tomishima, M.J. & Enquist, L.W. (2001). A conserved α-herpesvirus protein necessary for axonal localization of viral membrane proteins. Journal of Cell Biology154, 741752.

Warren, E.J., Allen, C.N., Brown, R.L., & Robinson, D.W. (2003). Intrinsic light responses of retinal ganglion cells projecting to the circadian system. European Journal of Neuroscience17, 17271735.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Visual Neuroscience
  • ISSN: 0952-5238
  • EISSN: 1469-8714
  • URL: /core/journals/visual-neuroscience
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 3
Total number of PDF views: 23 *
Loading metrics...

Abstract views

Total abstract views: 175 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 23rd May 2017. This data will be updated every 24 hours.