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Central Projections of Melanopsin-Expressing Retinal THE JOURNAL OF COMPARATIVE NEUROLOGY 497:326–349 (2006) Central Projections of Melanopsin- Expressing Retinal Ganglion Cells in the Mouse SAMER HATTAR,1 MONICA KUMAR,3 ALEXANDER PARK,1 PATRICK TONG,2 JONATHAN TUNG,3 KING-WAI YAU,1,2 AND DAVID M. BERSON3* 1Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2105 2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2105 3Department of Neuroscience, Brown University, Providence, Rhode Island 02912 ABSTRACT A rare type of ganglion cell in mammalian retina is directly photosensitive. These novel retinal photoreceptors express the photopigment melanopsin. They send axons directly to the suprachiasmatic nucleus (SCN), intergeniculate leaflet (IGL), and olivary pretectal nucleus (OPN), thereby contributing to photic synchronization of circadian rhythms and the pupillary light reflex. Here, we sought to characterize more fully the projections of these cells to the brain. By targeting tau-lacZ to the melanopsin gene locus in mice, ganglion cells that would normally express melanopsin were induced to express, instead, the marker enzyme ␤-galactosidase. Their axons were visualized by X-gal histochemistry or anti-␤-galactosidase immunofluorescence. Es- tablished targets were confirmed, including the SCN, IGL, OPN, ventral division of the lateral geniculate nucleus (LGv), and preoptic area, but the overall projections were more widespread than previously recognized. Targets included the lateral nucleus, peri-supraoptic nucleus, and subparaventricular zone of the hypothalamus, medial amygdala, margin of the lateral habenula, posterior limitans nucleus, superior colliculus, and periaqueductal gray. There were also weak projections to the margins of the dorsal lateral geniculate nucleus. Co-staining with the cholera toxin B subunit to label all retinal afferents showed that melanopsin ganglion cells provide most of the retinal input to the SCN, IGL, and lateral habenula and much of that to the OPN, but that other ganglion cells do contribute at least some retinal input to these targets. Staining patterns after monocular enucleation revealed that the projections of these cells are overwhelmingly crossed except for the projection to the SCN, which is bilaterally symmetrical. J. Comp. Neurol. 497:326–349, 2006. © 2006 Wiley-Liss, Inc. Indexing terms: melanopsin; circadian; retinofugal; pupil; suprachiasmatic nucleus; retinal ganglion cell; retinohypothalamic tract; pretectum; superior colliculus Melanopsin is an opsin protein originally identified in frog dermal melanophores (Provencio et al., 1998, 2000) and now firmly established as a functional sensory pho- topigment (Newman et al., 2003; Melyan et al., 2005; Grant sponsor: the National Eye Institute; Grant number: 5R01 Panda et al., 2005; Qiu et al., 2005; Fu et al., 2005). In EY014596 (to K.-W.Y.); Grant number: 5 R01 EY012793 (to D.B.). mammals, it is expressed in the eye, almost exclusively in Dr. Hattar’s current address: Department of Biology, Johns Hopkins a small percentage of retinal ganglion cells (RGCs; Prov- University, Baltimore, MD 21218-2685. encio et al., 2000, 2002; Hannibal et al., 2002; Hattar et *Correspondence to: David M. Berson, Department of Neuroscience, Box al., 2002). These melanopsin-expressing RGCs (mRGCs) 1953, Brown University, Providence, RI 02912. E-mail: David_Berson@ Brown.edu are directly sensitive to light and thus constitute a third Received 1 June 2005; Revised 6 December 2005; Accepted 11 January class of mammalian retinal photoreceptors, in addition to 2005 the rods and cones (Berson et al., 2002; Berson, 2003; DOI 10.1002/cne.20970 Warren et al., 2003). Published online in Wiley InterScience (www.interscience.wiley.com). © 2006 WILEY-LISS, INC. The Journal of Comparative Neurology. DOI 10.1002/cne PROJECTIONS OF MELANOPSIN GANGLION CELLS 327 Among their many striking structural and functional ganglion cells may also have unusually robust ipsilateral differences from the classical photoreceptors is that, as projections to their other targets. To pursue this issue, we ganglion cells, they project directly to the brain. One tar- examined in the same knock-in mice the effects of monoc- get of these projections is the suprachiasmatic nucleus of ular enucleation on the relative density of ␤-galactosidase- the hypothalamus (Gooley et al., 2001; Berson et al., 2002; positive fibers on the two sides of the brain. Hannibal et al., 2002; Hattar et al., 2002), a link that We also sought further evidence on the degree to which helps to synchronize this master pacemaker of circadian inputs from mRGCs converged with those of other RGCs rhythms to the solar cycle (Berson, 2003; Hirota and (non-mRGCs) in specific target nuclei. All photic re- Fukada, 2004). A second target, the intergeniculate leaflet sponses to which mRGCs are known to contribute persist (Hattar et al., 2002, Morin et al., 2003), also participates in some form when the melanopsin gene is knocked out in circadian photoentrainment (Harrington, 1997). A third (Panda et al., 2002; Ruby et al., 2002; Lucas et al., 2003; output reaches the olivary pretectal nucleus (Hattar et al., Mrosovsky and Hattar, 2003). Because direct photosensi- 2002; Morin et al., 2003), a key element in the circuit tivity is lost in mRGCs when melanopsin is deleted (Lucas mediating the pupillary light reflex (Trejo and Cicerone, et al., 2003), the residual responses presumably reflect the 1984; Clarke and Ikeda, 1985; Young and Lund, 1994). influences of rods and/or cones (Hattar et al., 2003; Panda Other targets of the mRGCs have begun to emerge, et al., 2003). Indeed, there is electrophysiological evidence implying their participation in diverse functions. These for rod and cone input to the SCN (Aggelopoulos and targets include the preoptic region, hypothalamic sub- Meissl, 2000). The routes by which these rod/cone signals paraventricular zone, ventral lateral geniculate nucleus, reach the critical brain nuclei are unknown. The mRGCs and superior colliculus (Hattar et al., 2002; Gooley et al., themselves are a likely conduit, because these cells are 2003; Morin et al., 2003; Hannibal and Fahrenkrug, 2004). known to be excited by rod- or cone-driven synaptic net- Past studies of these projections have relied mainly on works (Dunn and Berson, 2002; Belenky et al., 2003; retrograde transport of tracers injected into candidate Dacey et al., 2005) and because they retain their normal targets combined with immunohistochemistry or in situ axonal outputs in the face of melanopsin deletion (Lucas hybridization to identify retinal cells expressing melanop- et al., 2003). Alternatively, conventional (non-melanopsin) sin. This has limited the number of possible targets ganglion cells may relay rod and cone signals to these probed, and little information has been available about brain regions (Gooley et al., 2001; Morin et al., 2003; the form, trajectory, or distribution of the axons. In this Sollars et al., 2003; Hannibal and Fahrenkrug, 2004). study, we set out to describe the full extent of central We assessed the relative contribution of mRGCs and projections of mRGCs, exploiting a gene-targeted mouse non-mRGCs to the retinal input to individual nuclei by strain engineered to express the ␤-galactosidase marker double-immunofluorescence experiments in which antero- enzyme selectively in mRGCs (Hattar et al., 2002). grade transport labeled all retinal afferents while A second goal of the present study was to characterize ␤-galactosidase marked the axons of melanopsin RGCs. the relative strength of ipsilateral and contralateral pro- jections from the mRGCs. A striking feature of the retino- hypothalamic projection in the mouse is that the crossed MATERIALS AND METHODS and uncrossed components are about equally strong (Youngstrom and Nunez, 1986; Cassone et al., 1988; Animals Miura et al., 1997; Abrahamson and Moore, 2001), All procedures were conducted in accordance with NIH whereas more than 95% of retinal fibers are crossed in the guidelines and approved by the Institutional Animal Care rest of the visual system (Drager and Olsen, 1980; Miura and Use Committees of Brown University and Johns Hop- et al., 1997). Because most retinal afferents to the SCN kins University. The studies used 24 male and female are derived from mRGCs, we wondered whether these adult mice of the B6/129 strain genetically modified to Abbreviations AH anterior hypothalamic nucleus MPO medial preoptic area AHP anterior hypothalamic area, posterior OPN olivary pretectal nucleus AP anterior pretectal nucleus ot optic tract AV anteroventral thalamic nucleus ox optic chiasm BST bed nucleus of the stria terminalis PAG periaqueductal gray CL central lateral thalamic nucleus pc posterior commissure CP cerebral peduncle PO preoptic area f fornix pSON peri-supraoptic nucleus fr fasciculus retroflexus SC superior colliculus hc habenular commissure SCN suprachiasmatic nucleus ic internal capsule SGS stratum griseum superficiale of the superior colliculus IGL intergeniculate leaflet SI substantia innominata LD lateral dorsal thalamic nucleus sm stria medullaris LGd lateral geniculate nucleus, dorsal division SO stratum opticum of the superior colliculus LGv lateral geniculate nucleus, ventral division st stria terminalis LH lateral hypothalamus SPZ subparaventricular zone LHb lateral habenula SZ stratum zonale of the superior colliculus LP lateral posterior thalamic nucleus st stria terminalis LPO lateral preoptic area VLPO ventrolateral preoptic
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