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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:
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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 Neurology 460, 380393.
Berson, D.M. (2003). Strange vision: Ganglion cells as circadian photoreceptors. Trends in Neuroscience 26, 314320.
Berson, D.M., Dunn, F.A., & Takao, M. (2002). Phototransduction by retinal ganglion cells that set the circadian clock. Science 295, 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 Virology 74, 45494561.
Card, J.P. (1995). Pseudorabies virus replication and assembly in the rodent central nervous system. In Viral Vectors. Gene Therapy and Neuroscience Applications, ed. Kaplitt, M.G. & Loewy, A.D., pp. 319345. San Diego, California: Academic Press.
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. Neuron 6, 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 Neurocytology 26, 439454.
Dunn, F.A. & Berson, D.M. (2002). Are intrinsically photosensitive retinal ganglion cells influenced by rods or cones? [ARVO Abstract] Investigative Ophthalmology and Visual Science 43(4), Abstract nr 2982.
Famiglietti, E.V. & Kolb, H. (1976). Structural basis of “ON”- and “OFF”-center responses in retinal ganglion cells. Science 194, 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. Science 284, 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 Neuroscience 4, 1165.
Gooley, J.J., Lu, J., Fischer, D., & Saper, C.B. (2003). A broad role for melanopsin in non-visual photoreception. Journal of Neuroscience, 23, 70937106.
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 Rhythms 16, 457470.
Hannibal, J., Hindersson, P., Knudsen, S.M., Georg, B., & Fahrenkrug, J. (2002a). The photopigment melanopsin is exclusively present in pituitary adenylate cyclase-activating polypeptide-containing retinal ganglion cells of the retinohypothalamic tract. Journal of Neuroscience 22, RC191 (17).
Hannibal, J., Hindersson, P., Nevo, E., & Fahrehkrug, J. (2002b). The circadian photopigment melanopsin is expressed in the blind subterranean mole rat, Spalax. NeuroReport 13, 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. Science 295, 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. Nature 424, 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 Virology 74, 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 Research 460, 297313.
Lu, J., Shiromani, P., & Saper, C.B. (1999). Retinal input to the sleep-active ventrolateral preoptic nucleus in the rat. Neuroscience 93, 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. Science 284, 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 Neurology 352, 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 Neurology 396, 288309.
Morin, L.P. & Wood, R.I. (2001). A Stereotaxic Atlas of the Golden Hamster Brain. New York: Academic Press.
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. Neuroscience 61, 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 Neurology 465, 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. Science 298, 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. Science 301, 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 Neurology 211, 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 Letters 55, 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 Neurology 196, 155172.
Pickard, G.E., Ralph, M., & Menaker, M. (1987). The intergeniculate leaflet partially mediates the effects of light on circadian rhythms. Journal of Biological Rhythms 2, 3556.
Pickard, G.E., Smeraski, C.A., Tomlinson, C.C., Banfield, B.W., Kaufman, J., Wilcox, C.L., Enquist, L.W., & Sollars, P.J. (2002). Intravitreal injection of the attenuated pseudorabies virus, PRV-Bartha, results in infection of the hamster suprachiasmatic nucleus only by retrograde transsynaptic transport via autonomic circuits. Journal of Neuroscience 22, 27012710.
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., Rodriguez, I.R., Jiang, G., Hayes, W.P., Moreira, E.F., & Rollag, M.D. (2000). A novel human opsin in the inner retina. Journal of Neuroscience 20, 600605.
Provencio, I., Rollag, M.D., & Castrucci, A.M. (2002). Photoreceptive net in the mammalian retina. Nature 415, 493.
Pu, M. (1999) Dendritic morphology of cat retinal ganglion cells projecting to suprachiasmatic nucleus. Journal of Comparative Neurology 414, 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. Science 298, 22112213.
Sancar, A. (2000). Cryptochrome: The second photoactive pigment in the eye and its role in circadian photoreception. Annual Review of Biochemistry 69, 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 Neurology 471, 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.
Strack, A.M. & Loewy, A.D. (1990). Pseudorabies virus: A highly specific transneuronal cell body marker in the sympathetic nervous system. Journal of Neuroscience 10, 21392147.
Tiao, Y-C. & Blakemore, C. (1976). Regional specialization in the golden hamster's retina. Journal of Comparative Neurology 168, 439458.
Tomishima, M.J. & Enquist, L.W. (2001). A conserved α-herpesvirus protein necessary for axonal localization of viral membrane proteins. Journal of Cell Biology 154, 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 Neuroscience 17, 17271735.
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Visual Neuroscience
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