Melanopsin-Containing Retinal Ganglion Cells: Architecture, Projections, and Intrinsic Photosensitivity

Abstract

The primary circadian pacemaker, in the suprachiasmatic nucleus (SCN) of the mammalian brain, is photoentrained by light signals from the eyes through the retinohypothalamic tract. Retinal rod and cone cells are not required for photoentrainment. Recent evidence suggests that the entraining photoreceptors are retinal ganglion cells (RGCs) that project to the SCN. The visual pigment for this photoreceptor may be melanopsin, an opsin-like protein whose coding messenger RNA is found in a subset of mammalian RGCs. By cloning rat melanopsin and generating specific antibodies, we show that melanopsin is present in cell bodies, dendrites, and proximal axonal segments of a subset of rat RGCs. In mice heterozygous for tau-lacZ targeted to the melanopsin gene locus, β-galactosidase-positive RGC axons projected to the SCN and other brain nuclei involved in circadian photoentrainment or the pupillary light reflex. Rat RGCs that exhibited intrinsic photosensitivity invariably expressed melanopsin. Hence, melanopsin is most likely the visual pigment of phototransducing RGCs that set the circadian clock and initiate other non-image-forming visual functions.Retinal rods and cones, with their light-sensitive, opsin-based pigments, are the primary photoreceptors for vertebrate vision. Visual signals are transmitted to the brain through RGCs, the output neurons whose axons form the optic nerve. This system, through its projections to the lateral geniculate nucleus and the midbrain, is responsible for interpreting and tracking visual objects and patterns. A separate visual circuit, running in parallel with this imageforming visual system, encodes the general level of environmental illumination and drives certain photic responses, including synchronization of the biological clock with the light-dark cycle (1), control of pupil size (2), acute suppression of locomotor behavior (3), melatonin release (4), and others (5-7). Surprisingly, this non-image-forming system does not appear to originate from rods and cones. For example, rods and cones are not required for photoentrainment of circadian rhythms (8), a function mediated by the retinohypothalamic tract (9,10) and its target, the SCN, the brain's circadian pacemaker (1). Nor are rods and cones necessary for the pupillary light reflex, mediated by the retinal projection to the pretectal region of the brainstem (2). At present, the best candidate for a photopigment is an opsin-like protein † To whom correspondence should be addressed. kwyau@mail.jhmi.edu. * These authors contributed equally to this work. called melanopsin, which is expressed by a subset of mouse and human RGCs (11). The accompanying report (12) shows that RGCs projecting to the SCN are directly sensitive to light. Thus, melanopsin may be the photopigment responsible for this intrinsic photosensitivity, and it may also trigger other non-image-forming visual functions. NIH Public AccessWe cloned the full-length cDNA for rat melanopsin (13), on the basis of homology to mouse melanopsin (11). The predicted amino...

Intrinsic light responses of retinal ganglion cells projecting to the circadian system

“…Moreover, octopus rhodopsin bears an evolutionary similarity to melanopsin (Oshima, 2001), which is expressed in SCN-projecting RGCs in the rat (Gooley et al, 2001;Hattar et al, 2002;Hannibal et al, 2002). Melanopsin is thought to form a retinal-based photopigment, and its sequence displays several hallmarks of invertebrate opsins, including a tyrosine counter-ion for the retinal Schiff's base, instead of the glutamate that is characteristic of vertebrate opsins (Provencio et al, 1998).…”

“…In striking contrast to their counterparts projecting to the primary visual targets (the dorsal lateral geniculate nucleus and the superior colliculus), SCN-projecting RGCs exhibit light responses independent of rod-and cone-driven synaptic input . Furthermore, the majority of these neurons express the novel photopigment melanopsin (Provencio et al, 2000;Gooley et al, 2001;Hattar et al, 2002;Hannibal et al, 2002). As an essential part of the neural pathway from the retina to the SCN, these RGCs play a critical role in generating and shaping retinal output to the circadian system.…”

“…This morphology would seem ideal for the circadian system because it could survey the light intensity over a large sector of the retina. The most striking and novel property of SCN-projecting RGCs is an intrinsic sensitivity to light Hattar et al, 2002). Using whole-cell patch-clamp techniques, Berson et al, (2002) recorded intrinsic light responses from RGCs that were labelled with retrograde tracers following stereotaxic injection of the SCN.…”

Age-related changes in neurochemical components and retinal projections of rat intergeniculate leaflet

“…Comparing wildtype mice with ocular mutants lacking rods and cones, Lupi et al (2012) showed a higher impact of the intrinsic aging effects, rather than degeneration of photoreceptors, on IGL and SCN activation. However, they did not study this relationship with melanopsin-based photosensitive retinal ganglion cells (pRGCs), which forms RHT (Gooley et al 2001;Hattar et al 2002). It should be noted that we used an albino rat animal model, which has an abnormally increased predominance of contralateral retinofugal projections (Fleming et al 2006).…”

Vision science: Seeing without seeing

“…Samer Hattar, a neuroscientist at Johns Hopkins University in Baltimore, Maryland, and his colleagues found that as many as 1% of the cells in the mouse ganglion layer express melanopsin, which is most sensitive to blue light 6 . David Berson, a neuroscientist at Brown University in Providence, Rhode Island, and his lab showed that these cells, ipRGCs, detect light on their own and reach into the brain's pacemaker, the suprachiasmatic nucleus 7 .…”