Melanopsin and the Intrinsically Photosensitive Retinal Ganglion Cells: Biophysics to Behavior
2019; Cell Press; Volume: 104; Issue: 2 Linguagem: Inglês
10.1016/j.neuron.2019.07.016
ISSN1097-4199
Autores Tópico(s)Retinal Development and Disorders
ResumoThe mammalian visual system encodes information over a remarkable breadth of spatiotemporal scales and light intensities. This performance originates with its complement of photoreceptors: the classic rods and cones, as well as the intrinsically photosensitive retinal ganglion cells (ipRGCs). IpRGCs capture light with a G-protein-coupled receptor called melanopsin, depolarize like photoreceptors of invertebrates such as Drosophila, discharge electrical spikes, and innervate dozens of brain areas to influence physiology, behavior, perception, and mood. Several visual responses rely on melanopsin to be sustained and maximal. Some require ipRGCs to occur at all. IpRGCs fulfill their roles using mechanisms that include an unusual conformation of the melanopsin protein, an extraordinarily slow phototransduction cascade, divisions of labor even among cells of a morphological type, and unorthodox configurations of circuitry. The study of ipRGCs has yielded insight into general topics that include photoreceptor evolution, cellular diversity, and the steps from biophysical mechanisms to behavior. The mammalian visual system encodes information over a remarkable breadth of spatiotemporal scales and light intensities. This performance originates with its complement of photoreceptors: the classic rods and cones, as well as the intrinsically photosensitive retinal ganglion cells (ipRGCs). IpRGCs capture light with a G-protein-coupled receptor called melanopsin, depolarize like photoreceptors of invertebrates such as Drosophila, discharge electrical spikes, and innervate dozens of brain areas to influence physiology, behavior, perception, and mood. Several visual responses rely on melanopsin to be sustained and maximal. Some require ipRGCs to occur at all. IpRGCs fulfill their roles using mechanisms that include an unusual conformation of the melanopsin protein, an extraordinarily slow phototransduction cascade, divisions of labor even among cells of a morphological type, and unorthodox configurations of circuitry. The study of ipRGCs has yielded insight into general topics that include photoreceptor evolution, cellular diversity, and the steps from biophysical mechanisms to behavior. Mammals sense light for diverse purposes. Resolving spatial and temporal detail supports object recognition and action guidance, such as during a chase through the woods. On the other hand, integrating over space and time blurs details together to provide a representation of ambient light intensity. This representation is used to synchronize the circadian clock with the solar day and to drive seasonal rhythms in physiology. Thus, the visual system encodes information over a variety of spatiotemporal scales and does so across the billion-fold change in light intensity that accompanies the earth’s rotation. Mechanisms that serve these needs are found in the first steps in vision, where photoreceptors convert light into a biological response. Until about twenty years ago, it was believed that the mammalian retina was duplex, possessing two types of photoreceptors: rods and cones (Figure 1A). An early fissure in this belief stemmed from observations of individuals who had profound degeneration of these neurons and lacked visual awareness. Light suppressed their melatonin level, much as it did in the normally sighted (Czeisler et al., 1995Czeisler C.A. Shanahan T.L. Klerman E.B. Martens H. Brotman D.J. Emens J.S. Klein T. Rizzo 3rd, J.F. Suppression of melatonin secretion in some blind patients by exposure to bright light.N. Engl. J. Med. 1995; 332: 6-11Crossref PubMed Scopus (457) Google Scholar). Some “blind” individuals also woke and slept as if their circadian clocks maintained synchrony with the environmental cycle of illumination and darkness. A potential explanation was that enough rods and cones survived to support basic functions but not conscious perception. However, light also suppressed melatonin and set the circadian clocks of mice that were engineered to entirely lack these photoreceptors—provided that the eyes were intact (Freedman et al., 1999Freedman M.S. Lucas R.J. Soni B. von Schantz M. Muñoz M. David-Gray Z. Foster R. Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors.Science. 1999; 284: 502-504Crossref PubMed Scopus (570) Google Scholar, Lucas et al., 1999Lucas R.J. Freedman M.S. Muñoz M. Garcia-Fernández J.M. Foster R.G. Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors.Science. 1999; 284: 505-507Crossref PubMed Scopus (377) Google Scholar). Moreover, even in normal animals, certain responses exhibited dependencies on the wavelength, intensity, and duration of illumination that were poorly explained by the properties of rods and cones (e.g., Brainard et al., 2001Brainard G.C. Hanifin J.P. Greeson J.M. Byrne B. Glickman G. Gerner E. Rollag M.D. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor.J. Neurosci. 2001; 21: 6405-6412Crossref PubMed Google Scholar, Lucas et al., 2001Lucas R.J. Douglas R.H. Foster R.G. Characterization of an ocular photopigment capable of driving pupillary constriction in mice.Nat. Neurosci. 2001; 4: 621-626Crossref PubMed Scopus (430) Google Scholar, Takahashi et al., 1984Takahashi J.S. DeCoursey P.J. Bauman L. Menaker M. Spectral sensitivity of a novel photoreceptive system mediating entrainment of mammalian circadian rhythms.Nature. 1984; 308: 186-188Crossref PubMed Google Scholar). It appeared that an ocular source of photoreception awaited discovery (see Do and Yau, 2010Do M.T.H. Yau K.-W. Intrinsically photosensitive retinal ganglion cells.Physiol. Rev. 2010; 90: 1547-1581Crossref PubMed Scopus (202) Google Scholar for additional historical perspective). This source was found in an unlikely place within the eye. Rods and cones are part of the outer retina, which lies farthest from the incoming light. On the other side, in the inner retina, are retinal ganglion cells (RGCs). These neurons convey information from the eye to the brain. A small fraction of RGCs is distinguished by expression of a visual pigment called melanopsin (Opn4; see Box 1 as well as Figures 1B and 2; Hattar et al., 2002Hattar S. Liao H.W. Takao M. Berson D.M. Yau K.-W. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity.Science. 2002; 295: 1065-1070Crossref PubMed Scopus (1569) Google Scholar, Provencio et al., 1998Provencio I. Jiang G. De Grip W.J. Hayes W.P. Rollag M.D. Melanopsin: an opsin in melanophores, brain, and eye.Proc. Natl. Acad. Sci. USA. 1998; 95: 340-345Crossref PubMed Scopus (642) Google Scholar, Provencio et al., 2002Provencio I. Rollag M.D. Castrucci A.M. Photoreceptive net in the mammalian retina. This mesh of cells may explain how some blind mice can still tell day from night.Nature. 2002; 415: 493Crossref PubMed Google Scholar). These are the intrinsically photosensitive RGCs (ipRGCs; Berson et al., 2002Berson D.M. Dunn F.A. Takao M. Phototransduction by retinal ganglion cells that set the circadian clock.Science. 2002; 295: 1070-1073Crossref PubMed Scopus (2008) Google Scholar). Light activates melanopsin to trigger a G protein cascade that causes membrane depolarization. This response is opposite to that of rods and cones, which hyperpolarize, but resembles that of photoreceptors found in invertebrates like fruit flies and horseshoe crabs. IpRGCs fire spikes. They are understood to use glutamate as their primary neurotransmitter; uniquely among RGCs, they also express a peptide neurotransmitter called PACAP (pituitary adenylate cyclase activating peptide; Hannibal et al., 2002aHannibal J. Hindersson P. Knudsen S.M. Georg B. Fahrenkrug J. The photopigment melanopsin is exclusively present in pituitary adenylate cyclase-activating polypeptide-containing retinal ganglion cells of the retinohypothalamic tract.J. Neurosci. 2002; 22: RC191Crossref PubMed Google Scholar). IpRGCs have a widespread influence, innervating dozens of regions throughout the brain (Figures 1C and 3). Among them are the suprachiasmatic nucleus (SCN, master circadian clock), olivary pretectal nucleus (OPN, pupillary constriction), and dorsal lateral geniculate nucleus (dLGN, visual perception; Brown et al., 2010Brown T.M. Gias C. Hatori M. Keding S.R. Semo M. Coffey P.J. Gigg J. Piggins H.D. Panda S. Lucas R.J. Melanopsin contributions to irradiance coding in the thalamo-cortical visual system.PLoS Biol. 2010; 8: e1000558Crossref PubMed Scopus (149) Google Scholar, Delwig et al., 2016Delwig A. Larsen D.D. Yasumura D. Yang C.F. Shah N.M. Copenhagen D.R. Retinofugal projections from melanopsin-expressing retinal ganglion cells revealed by intraocular injections of cre-dependent virus.PLoS ONE. 2016; 11: e0149501Crossref PubMed Google Scholar, Ecker et al., 2010Ecker J.L. Dumitrescu O.N. Wong K.Y. Alam N.M. Chen S.K. LeGates T. Renna J.M. Prusky G.T. Berson D.M. Hattar S. Melanopsin-expressing retinal ganglion-cell photoreceptors: cellular diversity and role in pattern vision.Neuron. 2010; 67: 49-60Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar, Gooley et al., 2003Gooley J.J. Lu J. Fischer D. Saper C.B. A broad role for melanopsin in nonvisual photoreception.J. Neurosci. 2003; 23: 7093-7106Crossref PubMed Google Scholar, Hattar et al., 2006Hattar S. Kumar M. Park A. Tong P. Tung J. Yau K.-W. Berson D.M. Central projections of melanopsin-expressing retinal ganglion cells in the mouse.J. Comp. Neurol. 2006; 497: 326-349Crossref PubMed Scopus (529) Google Scholar, Morin and Studholme, 2014Morin L.P. Studholme K.M. Retinofugal projections in the mouse.J. Comp. Neurol. 2014; 522: 3733-3753Crossref PubMed Scopus (79) Google Scholar, Quattrochi et al., 2019Quattrochi L.E. Stabio M.E. Kim I. Ilardi M.C. Michelle Fogerson P. Leyrer M.L. Berson D.M. The M6 cell: a small-field bistratified photosensitive retinal ganglion cell.J. Comp. Neurol. 2019; (Published online January 1, 2019)https://doi.org/10.1002/cne.24556Crossref PubMed Scopus (9) Google Scholar). Known influences of ipRGCs extend well beyond their direct targets. Examples are regulation of melatonin synthesis in the pineal gland and of synaptic plasticity in the hippocampus (LeGates et al., 2012LeGates T.A. Altimus C.M. Wang H. Lee H.K. Yang S. Zhao H. Kirkwood A. Weber E.T. Hattar S. Aberrant light directly impairs mood and learning through melanopsin-expressing neurons.Nature. 2012; 491: 594-598Crossref PubMed Scopus (224) Google Scholar). IpRGCs themselves are diverse, with six types identified in the mouse (called M1–M6; see below and Figure 2). The mammalian retina is not duplex but multiplex.Box 1A Primer on Animal Visual PigmentsAn animal visual pigment has two parts, opsin (a G-protein-coupled receptor) and chromophore (the photosensitive ligand, a covalently linked derivative of vitamin A called retinaldehyde or, simply, retinal). Upon photon absorption, the chromophore has an opportunity to isomerize and drive a conformational change of the opsin. For activation, this isomerization is typically from 11-cis retinal to all-trans retinal.Activated pigments take one of two principal paths. In the first, opsin and isomerized chromophore dissociate. This process is called bleaching because visible light is absorbed well by pigment but poorly by its separate parts (Fein and Szuts, 1982Fein A. Szuts E.Z. Photoreceptors: Their Role in Vision. Volume 5. Cambridge University Press, 1982Google Scholar). Opsin must combine with new chromophore to regenerate functional pigment. In the second path, absorption of a subsequent photon drives pigment from the active state. Pigments whose active states are long lived tend to deactivate in this manner. Such pigments have an intrinsic capacity to be activated repeatedly during illumination. They are classified as bistable or, more generally, multistable. Bleaching and multistability are not mutually exclusive. Illumination of sufficient intensity may cause bleachable pigments to absorb photons in quick succession, switching them between active and inactive states (Ritter et al., 2008Ritter E. Elgeti M. Bartl F.J. Activity switches of rhodopsin.Photochem. Photobiol. 2008; 84: 911-920Crossref PubMed Scopus (0) Google Scholar). Moreover, pigments with stable active states may bleach on occasion.Two types of visual pigment are recognized in the animal kingdom, ciliary and rhabdomeric, which are typically found in the primary photoreceptors of vertebrates and invertebrates, respectively (Fain et al., 2010Fain G.L. Hardie R. Laughlin S.B. Phototransduction and the evolution of photoreceptors.Curr. Biol. 2010; 20: R114-R124Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, Shichida and Matsuyama, 2009Shichida Y. Matsuyama T. Evolution of opsins and phototransduction.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2009; 364: 2881-2895Crossref PubMed Scopus (183) Google Scholar). They are recognized by their protein sequence and genomic structure. Ciliary pigments tend to be bleachable and rhabdomeric pigments bistable.The spectra of all vitamin A-based pigments have shapes that are virtually identical (when plotted on a frequency or reciprocal-wavelength axis; Lamb, 1995Lamb T.D. Photoreceptor spectral sensitivities: common shape in the long-wavelength region.Vision Res. 1995; 35: 3083-3091Crossref PubMed Scopus (143) Google Scholar). Given only the peak wavelength sensitivity (λmax) of a pigment, its entire spectrum can be reconstructed using an empirical function that is referred to as the nomogram (Govardovskii et al., 2000Govardovskii V.I. Fyhrquist N. Reuter T. Kuzmin D.G. Donner K. In search of the visual pigment template.Vis. Neurosci. 2000; 17: 509-528Crossref PubMed Scopus (644) Google Scholar). The uncommon exceptions are pigments that use accessory chromophores and therefore exhibit more complex spectral sensitivities (Kirschfeld et al., 1977Kirschfeld K. Franceschini N. Minke B. Evidence for a sensitising pigment in fly photoreceptors.Nature. 1977; 269: 386-390Crossref PubMed Google Scholar).Often, the conformational states of a pigment have distinct spectra, each defined by its λmax and the nomogram (Hillman et al., 1983Hillman P. Hochstein S. Minke B. Transduction in invertebrate photoreceptors: role of pigment bistability.Physiol. Rev. 1983; 63: 668-772Crossref PubMed Scopus (101) Google Scholar). Delivering wavelengths that are preferentially absorbed by one state will drive it to an adjoining state. If two states are close in spectral sensitivity, light will always produce a mixture of both states. On the other hand, if two states are well separated, light can drive practically all pigment molecules into one state or the other depending on wavelength. Pigment states and their interconversions underlie the spectral sensitivity of the cell’s response (the “action spectrum”).An important note is that wavelength and intensity are interchangeable in determining the probability that a pigment absorbs a photon. For example, even if a pigment has a λmax in the visible range, infrared or ultraviolet light can cause activation if sufficiently intense.Figure 3Major Brain Targets of Mouse IpRGCsShow full captionA sample of ipRGC brain targets is depicted in a quasi-sagittal schematic of the mouse brain. Below is a plot of innervation densities across ipRGC types, drawn after Berson and colleagues (Quattrochi et al., 2019Quattrochi L.E. Stabio M.E. Kim I. Ilardi M.C. Michelle Fogerson P. Leyrer M.L. Berson D.M. The M6 cell: a small-field bistratified photosensitive retinal ganglion cell.J. Comp. Neurol. 2019; (Published online January 1, 2019)https://doi.org/10.1002/cne.24556Crossref PubMed Scopus (9) Google Scholar) and incorporating additional information (Ecker et al., 2010Ecker J.L. Dumitrescu O.N. Wong K.Y. Alam N.M. Chen S.K. LeGates T. Renna J.M. Prusky G.T. Berson D.M. Hattar S. Melanopsin-expressing retinal ganglion-cell photoreceptors: cellular diversity and role in pattern vision.Neuron. 2010; 67: 49-60Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar, Hattar et al., 2006Hattar S. Kumar M. Park A. Tong P. Tung J. Yau K.-W. Berson D.M. Central projections of melanopsin-expressing retinal ganglion cells in the mouse.J. Comp. Neurol. 2006; 497: 326-349Crossref PubMed Scopus (529) Google Scholar, Huang et al., 2019Huang L. Xi Y. Peng Y. Yang Y. Huang X. Fu Y. Tao Q. Xiao J. Yuan T. An K. et al.A visual circuit related to habenula underlies the antidepressive effects of light therapy.Neuron. 2019; 102: 128-142.e8Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Morin and Studholme, 2014Morin L.P. Studholme K.M. Retinofugal projections in the mouse.J. Comp. Neurol. 2014; 522: 3733-3753Crossref PubMed Scopus (79) Google Scholar, Zhao et al., 2014Zhao X. Stafford B.K. Godin A.L. King W.M. Wong K.Y. Photoresponse diversity among the five types of intrinsically photosensitive retinal ganglion cells.J. Physiol. 2014; 592: 1619-1636Crossref PubMed Scopus (73) Google Scholar). Each blue dot indicates the approximate density of innervation by its size, a white dot indicates undetectable innervation, and lack of a dot indicates an absence of information. M5s and M6s are pooled because their projections were examined together for technical reasons. AH, anterior hypothalamus; BST, bed nucleus of the stria terminalis; dLGN, dorsal lateral geniculate nucleus; IGL, intergeniculate leaflet; LH, lateral hypothalamus; MA, medial amygdala; OPN, olivary pretectal nucleus (with shell, s, and core, c, regions); PA, preoptic area, which includes the VLPO (ventrolateral preoptic area); PAG, periaqueductal gray; PHb, perihabenular zone; pSON, peri-supraoptic nucleus; SC, superior colliculus; SCN, suprachiasmatic nucleus; sPa, subparaventricular zone; and vLGN, ventral lateral geniculate nucleus.View Large Image Figure ViewerDownload Hi-res image Download (PPT) An animal visual pigment has two parts, opsin (a G-protein-coupled receptor) and chromophore (the photosensitive ligand, a covalently linked derivative of vitamin A called retinaldehyde or, simply, retinal). Upon photon absorption, the chromophore has an opportunity to isomerize and drive a conformational change of the opsin. For activation, this isomerization is typically from 11-cis retinal to all-trans retinal. Activated pigments take one of two principal paths. In the first, opsin and isomerized chromophore dissociate. This process is called bleaching because visible light is absorbed well by pigment but poorly by its separate parts (Fein and Szuts, 1982Fein A. Szuts E.Z. Photoreceptors: Their Role in Vision. Volume 5. Cambridge University Press, 1982Google Scholar). Opsin must combine with new chromophore to regenerate functional pigment. In the second path, absorption of a subsequent photon drives pigment from the active state. Pigments whose active states are long lived tend to deactivate in this manner. Such pigments have an intrinsic capacity to be activated repeatedly during illumination. They are classified as bistable or, more generally, multistable. Bleaching and multistability are not mutually exclusive. Illumination of sufficient intensity may cause bleachable pigments to absorb photons in quick succession, switching them between active and inactive states (Ritter et al., 2008Ritter E. Elgeti M. Bartl F.J. Activity switches of rhodopsin.Photochem. Photobiol. 2008; 84: 911-920Crossref PubMed Scopus (0) Google Scholar). Moreover, pigments with stable active states may bleach on occasion. Two types of visual pigment are recognized in the animal kingdom, ciliary and rhabdomeric, which are typically found in the primary photoreceptors of vertebrates and invertebrates, respectively (Fain et al., 2010Fain G.L. Hardie R. Laughlin S.B. Phototransduction and the evolution of photoreceptors.Curr. Biol. 2010; 20: R114-R124Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, Shichida and Matsuyama, 2009Shichida Y. Matsuyama T. Evolution of opsins and phototransduction.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2009; 364: 2881-2895Crossref PubMed Scopus (183) Google Scholar). They are recognized by their protein sequence and genomic structure. Ciliary pigments tend to be bleachable and rhabdomeric pigments bistable. The spectra of all vitamin A-based pigments have shapes that are virtually identical (when plotted on a frequency or reciprocal-wavelength axis; Lamb, 1995Lamb T.D. Photoreceptor spectral sensitivities: common shape in the long-wavelength region.Vision Res. 1995; 35: 3083-3091Crossref PubMed Scopus (143) Google Scholar). Given only the peak wavelength sensitivity (λmax) of a pigment, its entire spectrum can be reconstructed using an empirical function that is referred to as the nomogram (Govardovskii et al., 2000Govardovskii V.I. Fyhrquist N. Reuter T. Kuzmin D.G. Donner K. In search of the visual pigment template.Vis. Neurosci. 2000; 17: 509-528Crossref PubMed Scopus (644) Google Scholar). The uncommon exceptions are pigments that use accessory chromophores and therefore exhibit more complex spectral sensitivities (Kirschfeld et al., 1977Kirschfeld K. Franceschini N. Minke B. Evidence for a sensitising pigment in fly photoreceptors.Nature. 1977; 269: 386-390Crossref PubMed Google Scholar). Often, the conformational states of a pigment have distinct spectra, each defined by its λmax and the nomogram (Hillman et al., 1983Hillman P. Hochstein S. Minke B. Transduction in invertebrate photoreceptors: role of pigment bistability.Physiol. Rev. 1983; 63: 668-772Crossref PubMed Scopus (101) Google Scholar). Delivering wavelengths that are preferentially absorbed by one state will drive it to an adjoining state. If two states are close in spectral sensitivity, light will always produce a mixture of both states. On the other hand, if two states are well separated, light can drive practically all pigment molecules into one state or the other depending on wavelength. Pigment states and their interconversions underlie the spectral sensitivity of the cell’s response (the “action spectrum”). An important note is that wavelength and intensity are interchangeable in determining the probability that a pigment absorbs a photon. For example, even if a pigment has a λmax in the visible range, infrared or ultraviolet light can cause activation if sufficiently intense. A sample of ipRGC brain targets is depicted in a quasi-sagittal schematic of the mouse brain. Below is a plot of innervation densities across ipRGC types, drawn after Berson and colleagues (Quattrochi et al., 2019Quattrochi L.E. Stabio M.E. Kim I. Ilardi M.C. Michelle Fogerson P. Leyrer M.L. Berson D.M. The M6 cell: a small-field bistratified photosensitive retinal ganglion cell.J. Comp. Neurol. 2019; (Published online January 1, 2019)https://doi.org/10.1002/cne.24556Crossref PubMed Scopus (9) Google Scholar) and incorporating additional information (Ecker et al., 2010Ecker J.L. Dumitrescu O.N. Wong K.Y. Alam N.M. Chen S.K. LeGates T. Renna J.M. Prusky G.T. Berson D.M. Hattar S. Melanopsin-expressing retinal ganglion-cell photoreceptors: cellular diversity and role in pattern vision.Neuron. 2010; 67: 49-60Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar, Hattar et al., 2006Hattar S. Kumar M. Park A. Tong P. Tung J. Yau K.-W. Berson D.M. Central projections of melanopsin-expressing retinal ganglion cells in the mouse.J. Comp. Neurol. 2006; 497: 326-349Crossref PubMed Scopus (529) Google Scholar, Huang et al., 2019Huang L. Xi Y. Peng Y. Yang Y. Huang X. Fu Y. Tao Q. Xiao J. Yuan T. An K. et al.A visual circuit related to habenula underlies the antidepressive effects of light therapy.Neuron. 2019; 102: 128-142.e8Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Morin and Studholme, 2014Morin L.P. Studholme K.M. Retinofugal projections in the mouse.J. Comp. Neurol. 2014; 522: 3733-3753Crossref PubMed Scopus (79) Google Scholar, Zhao et al., 2014Zhao X. Stafford B.K. Godin A.L. King W.M. Wong K.Y. Photoresponse diversity among the five types of intrinsically photosensitive retinal ganglion cells.J. Physiol. 2014; 592: 1619-1636Crossref PubMed Scopus (73) Google Scholar). Each blue dot indicates the approximate density of innervation by its size, a white dot indicates undetectable innervation, and lack of a dot indicates an absence of information. M5s and M6s are pooled because their projections were examined together for technical reasons. AH, anterior hypothalamus; BST, bed nucleus of the stria terminalis; dLGN, dorsal lateral geniculate nucleus; IGL, intergeniculate leaflet; LH, lateral hypothalamus; MA, medial amygdala; OPN, olivary pretectal nucleus (with shell, s, and core, c, regions); PA, preoptic area, which includes the VLPO (ventrolateral preoptic area); PAG, periaqueductal gray; PHb, perihabenular zone; pSON, peri-supraoptic nucleus; SC, superior colliculus; SCN, suprachiasmatic nucleus; sPa, subparaventricular zone; and vLGN, ventral lateral geniculate nucleus. Rods, cones, and ipRGCs are presently the only mammalian cells known to convert light into electrical signals (Hattar et al., 2003Hattar 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. Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice.Nature. 2003; 424: 76-81Crossref PubMed Google Scholar, Panda et al., 2003Panda 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. et al.Melanopsin is required for non-image-forming photic responses in blind mice.Science. 2003; 301: 525-527Crossref PubMed Scopus (499) Google Scholar). Rods are sensitive enough to support sight even in starlight, while cones are equipped for color vision in daylight (Ingram et al., 2016Ingram N.T. Sampath A.P. Fain G.L. Why are rods more sensitive than cones?.J. Physiol. 2016; 594: 5415-5426Crossref PubMed Scopus (23) Google Scholar, Naarendorp et al., 2010Naarendorp F. Esdaille T.M. Banden S.M. Andrews-Labenski J. Gross O.P. Pugh Jr., E.N. Dark light, rod saturation, and the absolute and incremental sensitivity of mouse cone vision.J. Neurosci. 2010; 30: 12495-12507Crossref PubMed Scopus (84) Google Scholar); downstream of these outer photoreceptors are numerous RGC types that convey distinct features of the visual image to the brain (Gollisch and Meister, 2010Gollisch T. Meister M. Eye smarter than scientists believed: neural computations in circuits of the retina.Neuron. 2010; 65: 150-164Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, Sanes and Masland, 2015Sanes J.R. Masland R.H. The types of retinal ganglion cells: current status and implications for neuronal classification.Annu. Rev. Neurosci. 2015; 38: 221-246Crossref PubMed Scopus (409) Google Scholar). This review is concerned with the roles that ipRGCs play, both as photoreceptors and retinal output neurons, and the mechanisms that support those roles. IpRGCs of the M1 type are examined most deeply because they are the best understood, allowing connections to be drawn from biophysics to behavior. A broad sweep will be made through additional topics, including the other ipRGC types, influences of melanopsin on development, potential roles of melanopsin in health, and challenges for future research. Nevertheless, aspects of this large and rapidly expanding field will be missed or only glimpsed. Expert reviews are cited along the way to help fill these gaps. Finally, the information given will concern common laboratory rodents unless noted; other species are discussed toward the end. The part played by ipRGCs is most obvious for non-image vision, a set of functions that respond more to irradiance (the overall intensity of illumination) than to contrast (local, spatiotemporal differences in illumination; reviewed by Warthen and Provencio, 2012Warthen D.M. Provencio I. The role of intrinsically photosensitive retinal ganglion cells in nonimage-forming responses to light.Eye Brain. 2012; 4: 43-48PubMed Google Scholar). Irradiance governs important parameters such as visibility, temperature, and the types of species that are active. Unsurprisingly, many functions that use irradiance information are essential. For example, irradiance is the principal regulator of the circadian clock, which establishes normal patterns of gene expression throughout the body. The clock encodes irradiance by pooling light over large portions of the visual scene and broad intervals of time (Dobb et al., 2017Dobb R. Martial F. Elijah D. Storchi R. Brown T.M. Lucas R.J. The impact of temporal modulations in irradiance under light adapted conditions on the mouse suprachiasmatic nuclei (SCN).Sci. Rep. 2017; 7: 10582Crossref PubMed Scopus (4) Google Scholar, Mouland et al., 2017Mouland J.W. Stinchcombe A.R. Forger D.B. Brown T.M. Lucas R.J. Responses to spatial contrast in the mouse suprachiasmatic nuclei.Curr Biol. 2017; 27: 1633-1640Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, Nelson and Takahashi, 1991Nelson D.E. Takahashi J.S. Sensitivity and integration in a visual pathway for circadian entrainment in the hamster (Mesocricetus auratus).J. Physiol. 1991; 439: 115-145Crossref PubMed Google Scholar), raising the possibility that ipRGCs exhibit specializations for spatial and temporal integration. Several properties of ipRGCs may be inferred from another non-image visual function, the pupillary light reflex (PLR), where contraction of the iris muscle limits the amount of light entering the eye. Photoreceptor contributions to the PLR have been studied extensively because it is relatively quick and readily quantified (Keenan et al., 2
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