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      Rod photoreceptors drive circadian photoentrainment across a wide range of light intensities

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          Abstract

          In mammals, synchronization of the circadian pacemaker in the hypothalamus is achieved through direct input from the eyes conveyed by intrinsically photosensitive retinal ganglion cells (ipRGCs). Circadian photoentrainment can be maintained by rod and cone photoreceptors, but their functional contributions and their retinal circuits that impinge on ipRGCs are not well understood. We demonstrate in genetic mouse models lacking functional rods, or where rods are the only functional photoreceptors, that rods are solely responsible for photoentrainment at scotopic light intensities. Surprisingly, rods were also capable of driving circadian photoentrainment at photopic intensities where they were incapable of supporting a visually–guided behavior. Using animals in which cone photoreceptors were ablated, we demonstrate that rods signal through cones at high light intensities, but not low light intensities. Thus two distinct retinal circuits drive ipRGC function to support circadian photoentrainment across a wide range of light intensities.

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          Most cited references46

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          Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN.

          Human vision starts with the activation of rod photoreceptors in dim light and short (S)-, medium (M)-, and long (L)- wavelength-sensitive cone photoreceptors in daylight. Recently a parallel, non-rod, non-cone photoreceptive pathway, arising from a population of retinal ganglion cells, was discovered in nocturnal rodents. These ganglion cells express the putative photopigment melanopsin and by signalling gross changes in light intensity serve the subconscious, 'non-image-forming' functions of circadian photoentrainment and pupil constriction. Here we show an anatomically distinct population of 'giant', melanopsin-expressing ganglion cells in the primate retina that, in addition to being intrinsically photosensitive, are strongly activated by rods and cones, and display a rare, S-Off, (L + M)-On type of colour-opponent receptive field. The intrinsic, rod and (L + M) cone-derived light responses combine in these giant cells to signal irradiance over the full dynamic range of human vision. In accordance with cone-based colour opponency, the giant cells project to the lateral geniculate nucleus, the thalamic relay to primary visual cortex. Thus, in the diurnal trichromatic primate, 'non-image-forming' and conventional 'image-forming' retinal pathways are merged, and the melanopsin-based signal might contribute to conscious visual perception.
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            Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice.

            In the mammalian retina, besides the conventional rod-cone system, a melanopsin-associated photoreceptive system exists that conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment. On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive. Furthermore, pupil reflex, light-induced phase delays of the circadian clock and period lengthening of the circadian rhythm in constant light are all partially impaired. Here, we investigated whether additional photoreceptive systems participate in these responses. Using mice lacking rods and cones, we measured the action spectrum for phase-shifting the circadian rhythm of locomotor behaviour. This spectrum matches that for the pupillary light reflex in mice of the same genotype, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells. We have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.
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              Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice.

              In the mammalian retina, a small subset of retinal ganglion cells (RGCs) are intrinsically photosensitive, express the opsin-like protein melanopsin, and project to brain nuclei involved in non-image-forming visual functions such as pupillary light reflex and circadian photoentrainment. We report that in mice with the melanopsin gene ablated, RGCs retrograde-labeled from the suprachiasmatic nuclei were no longer intrinsically photosensitive, although their number, morphology, and projections were unchanged. These animals showed a pupillary light reflex indistinguishable from that of the wild type at low irradiances, but at high irradiances the reflex was incomplete, a pattern that suggests that the melanopsin-associated system and the classical rod/cone system are complementary in function.
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                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nature neuroscience
                1097-6256
                1546-1726
                27 July 2010
                15 August 2010
                September 2010
                1 March 2011
                : 13
                : 9
                : 1107-1112
                Affiliations
                [1 ]Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA
                [2 ]Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10065
                [3 ]Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California Keck School of Medicine, Los Angeles, CA 90089
                [4 ]Department of Neuroscience, Johns Hopkins University–School of Medicine, Baltimore MD
                Author notes
                [* ]Correspondence to Samer Hattar ( shattar@ 123456jhu.edu ) and Alapakkam Sampath ( asampath@ 123456usc.edu )
                Editorial correspondence: Dr. Samer Hattar, Assistant Professor, Johns Hopkins University, Department of Biology, 3400 N. Charles Street/Mudd 227, Baltimore, MD 21218, Tel: 410–516–4231, fax: 410–516–5213, shattar@ 123456jhu.edu
                Article
                nihpa223351
                10.1038/nn.2617
                2928860
                20711184
                bfdef2d6-6228-4c52-aff0-51e7ec58ec38

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Eye Institute : NEI
                Award ID: R01 GM076430-06 ||GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Eye Institute : NEI
                Award ID: R01 GM076430-05 ||GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Eye Institute : NEI
                Award ID: R01 GM076430-04 ||GM
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: National Eye Institute : NEI
                Award ID: R01 EY017606 ||EY
                Categories
                Article

                Neurosciences
                iprgcs,melanopsin,cones,non–image forming vision,outer retinal photoreceptors,retinal ganglion cells

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