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1.
J Comp Neurol ; 524(14): 2845-72, 2016 10 01.
Article in English | MEDLINE | ID: mdl-26972791

ABSTRACT

The long-term goal of this research is to understand how retinal ganglion cells that express the photopigment melanopsin, also known as OPN4, contribute to vision in humans and other primates. Here we report the results of anatomical studies using our polyclonal antibody specifically against human melanopsin that confirm and extend previous descriptions of melanopsin cells in primates. In macaque and human retina, two distinct populations of melanopsin cells were identified based on dendritic stratification in either the inner or the outer portion of the inner plexiform layer (IPL). Variation in dendritic field size and cell density with eccentricity was confirmed, and dendritic spines, a new feature of melanopsin cells, were described. The spines were the sites of input from DB6 diffuse bipolar cell axon terminals to the inner stratifying type of melanopsin cells. The outer stratifying melanopsin type received inputs from DB6 bipolar cells via a sparse outer axonal arbor. Outer stratifying melanopsin cells also received inputs from axon terminals of dopaminergic amacrine cells. On the outer stratifying melanopsin cells, ribbon synapses from bipolar cells and conventional synapses from amacrine cells were identified in electron microscopic immunolabeling experiments. Both inner and outer stratifying melanopsin cell types were retrogradely labeled following tracer injection in the lateral geniculate nucleus (LGN). In addition, a method for targeting melanopsin cells for intracellular injection using their intrinsic fluorescence was developed. This technique was used to demonstrate that melanopsin cells were tracer coupled to amacrine cells and would be applicable to electrophysiological experiments in the future. J. Comp. Neurol. 524:2845-2872, 2016. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.


Subject(s)
Retina/cytology , Retina/metabolism , Retinal Ganglion Cells/metabolism , Rod Opsins/biosynthesis , Rod Opsins/genetics , Amino Acid Sequence , Animals , Cell Count/methods , Humans , Macaca , Macaca fascicularis , Macaca nemestrina , Middle Aged , Species Specificity
2.
Proc Natl Acad Sci U S A ; 112(42): 13093-8, 2015 Oct 20.
Article in English | MEDLINE | ID: mdl-26392540

ABSTRACT

The molecular circadian clocks in the mammalian retina are locally synchronized by environmental light cycles independent of the suprachiasmatic nuclei (SCN) in the brain. Unexpectedly, this entrainment does not require rods, cones, or melanopsin (OPN4), possibly suggesting the involvement of another retinal photopigment. Here, we show that the ex vivo mouse retinal rhythm is most sensitive to short-wavelength light but that this photoentrainment requires neither the short-wavelength-sensitive cone pigment [S-pigment or cone opsin (OPN1SW)] nor encephalopsin (OPN3). However, retinas lacking neuropsin (OPN5) fail to photoentrain, even though other visual functions appear largely normal. Initial evidence suggests that OPN5 is expressed in select retinal ganglion cells. Remarkably, the mouse corneal circadian rhythm is also photoentrainable ex vivo, and this photoentrainment likewise requires OPN5. Our findings reveal a light-sensing function for mammalian OPN5, until now an orphan opsin.


Subject(s)
Cornea/physiology , Membrane Proteins/physiology , Opsins/physiology , Retina/physiology , Suprachiasmatic Nucleus/physiology , Animals , Membrane Proteins/genetics , Mice , Mice, Knockout , Opsins/genetics , Ultraviolet Rays
3.
Nature ; 457(7227): 281-7, 2009 Jan 15.
Article in English | MEDLINE | ID: mdl-19118382

ABSTRACT

A subset of retinal ganglion cells has recently been discovered to be intrinsically photosensitive, with melanopsin as the pigment. These cells project primarily to brain centres for non-image-forming visual functions such as the pupillary light reflex and circadian photoentrainment. How well they signal intrinsic light absorption to drive behaviour remains unclear. Here we report fundamental parameters governing their intrinsic light responses and associated spike generation. The membrane density of melanopsin is 10(4)-fold lower than that of rod and cone pigments, resulting in a very low photon catch and a phototransducing role only in relatively bright light. Nonetheless, each captured photon elicits a large and extraordinarily prolonged response, with a unique shape among known photoreceptors. Notably, like rods, these cells are capable of signalling single-photon absorption. A flash causing a few hundred isomerized melanopsin molecules in a retina is sufficient for reaching threshold for the pupillary light reflex.


Subject(s)
Photons , Retinal Ganglion Cells/metabolism , Retinal Ganglion Cells/radiation effects , Rod Opsins/metabolism , Action Potentials/radiation effects , Animals , Brain/metabolism , Kinetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Pupil/physiology , Pupil/radiation effects , Reflex, Pupillary/radiation effects
4.
Nature ; 453(7191): 102-5, 2008 May 01.
Article in English | MEDLINE | ID: mdl-18432195

ABSTRACT

Rod and cone photoreceptors detect light and relay this information through a multisynaptic pathway to the brain by means of retinal ganglion cells (RGCs). These retinal outputs support not only pattern vision but also non-image-forming (NIF) functions, which include circadian photoentrainment and pupillary light reflex (PLR). In mammals, NIF functions are mediated by rods, cones and the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs). Rod-cone photoreceptors and ipRGCs are complementary in signalling light intensity for NIF functions. The ipRGCs, in addition to being directly photosensitive, also receive synaptic input from rod-cone networks. To determine how the ipRGCs relay rod-cone light information for both image-forming and non-image-forming functions, we genetically ablated ipRGCs in mice. Here we show that animals lacking ipRGCs retain pattern vision but have deficits in both PLR and circadian photoentrainment that are more extensive than those observed in melanopsin knockouts. The defects in PLR and photoentrainment resemble those observed in animals that lack phototransduction in all three photoreceptor classes. These results indicate that light signals for irradiance detection are dissociated from pattern vision at the retinal ganglion cell level, and animals that cannot detect light for NIF functions are still capable of image formation.


Subject(s)
Retinal Cone Photoreceptor Cells/metabolism , Retinal Ganglion Cells/cytology , Retinal Ganglion Cells/metabolism , Retinal Rod Photoreceptor Cells/metabolism , Rod Opsins/metabolism , Vision, Ocular/physiology , Animals , Brain/cytology , Brain/metabolism , Circadian Rhythm/physiology , Circadian Rhythm/radiation effects , Cues , Electroretinography , Light , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/physiology , Pupil/physiology , Pupil/radiation effects , Reflex/physiology , Reflex/radiation effects , Rod Opsins/deficiency , Rod Opsins/genetics , Vision, Ocular/radiation effects , Visual Acuity/physiology
6.
Science ; 311(5767): 1617-21, 2006 Mar 17.
Article in English | MEDLINE | ID: mdl-16543463

ABSTRACT

The parietal-eye photoreceptor is unique because it has two antagonistic light signaling pathways in the same cell-a hyperpolarizing pathway maximally sensitive to blue light and a depolarizing pathway maximally sensitive to green light. Here, we report the molecular components of these two pathways. We found two opsins in the same cell: the blue-sensitive pinopsin and a previously unidentified green-sensitive opsin, which we name parietopsin. Signaling components included gustducin-alpha and Galphao, but not rod or cone transducin-alpha. Single-cell recordings demonstrated that Go mediates the depolarizing response. Gustducin-alpha resembles transducin-alpha functionally and likely mediates the hyperpolarizing response. The parietopsin-Go signaling pair provides clues about how rod and cone phototransduction might have evolved.


Subject(s)
Biological Evolution , Lizards/physiology , Ocular Physiological Phenomena , Photoreceptor Cells, Vertebrate/physiology , Rod Opsins/physiology , Vision, Ocular , 3',5'-Cyclic-GMP Phosphodiesterases/metabolism , Amino Acid Sequence , Animals , Cell Line , Cyclic GMP/metabolism , GTP-Binding Protein alpha Subunits/genetics , GTP-Binding Protein alpha Subunits/physiology , Humans , Lizards/genetics , Molecular Sequence Data , Patch-Clamp Techniques , Photoreceptor Cells, Vertebrate/chemistry , Rod Opsins/analysis , Rod Opsins/genetics , Transducin/genetics , Transducin/physiology
7.
Curr Opin Neurobiol ; 15(4): 415-22, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16023851

ABSTRACT

It has been accepted for a hundred years or more that rods and cones are the only photoreceptive cells in the retina. The light signals generated in rods and cones, after processing by downstream retinal neurons (bipolar, horizontal, amacrine and ganglion cells), are transmitted to the brain via the axons of the ganglion cells for further analysis. In the past few years, however, convincing evidence has rapidly emerged indicating that a small subset of retinal ganglion cells in mammals is also intrinsically photosensitive. Melanopsin is the signaling photopigment in these cells. The main function of the inner-retina photoreceptors is to generate and transmit non-image-forming visual information, although some role in conventional vision (image detection) is also possible.


Subject(s)
Retinal Ganglion Cells/physiology , Rod Opsins/physiology , Animals , Humans , Retinal Cone Photoreceptor Cells/physiology , Retinal Ganglion Cells/cytology , Retinal Rod Photoreceptor Cells/physiology
8.
Proc Natl Acad Sci U S A ; 102(29): 10339-44, 2005 Jul 19.
Article in English | MEDLINE | ID: mdl-16014418

ABSTRACT

In mammals, intrinsically photosensitive retinal ganglion cells (ipRGCs) mediate non-image-forming visual functions such as pupillary light reflex (PLR) and circadian photoentrainment. This photosensitivity requires melanopsin, an invertebrate opsin-like protein expressed by the ipRGCs. The precise role of melanopsin remains uncertain. One suggestion has been that melanopsin may be a photoisomerase, serving to regenerate an unidentified pigment in ipRGCs. This possibility was echoed by a recent report that melanopsin is expressed also in the mouse retinal pigment epithelium (RPE), a key center for regeneration of rod and cone pigments. To address this question, we studied mice lacking RPE65, a protein essential for the regeneration of rod and cone pigments. Rpe65-/- ipRGCs were approximately 20- to 40-fold less photosensitive than normal at both single-cell and behavioral (PLR) levels but were rescued by exogenous 9-cis-retinal (an 11-cis-retinal analog), indicating the requirement of a vitamin A-based chromophore for ipRGC photosensitivity. In contrast, 9-cis-retinal was unable to restore intrinsic photosensitivity to melanopsin-ablated ipRGCs, arguing against melanopsin functioning merely in photopigment regeneration. Interestingly, exogenous all-trans-retinal was also able to rescue the low sensitivity of rpe65-/- ipRGCs, suggesting that melanopsin could be a bistable pigment. Finally, we detected no melanopsin in the RPE and no changes in rod and cone sensitivities due to melanopsin ablation. Together, these results strongly suggest that melanopsin is the photopigment in the ipRGCs.


Subject(s)
Light Signal Transduction/physiology , Retinal Ganglion Cells/metabolism , Rod Opsins/metabolism , Animals , Carrier Proteins , Diterpenes , Eye Proteins/genetics , Galactosides , Immunohistochemistry , Indoles , Light Signal Transduction/genetics , Mice , Mice, Knockout , Photic Stimulation , Retinal Ganglion Cells/drug effects , Retinaldehyde/pharmacology , Vitamin A/pharmacology , cis-trans-Isomerases
9.
Nature ; 433(7027): 749-54, 2005 Feb 17.
Article in English | MEDLINE | ID: mdl-15716953

ABSTRACT

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.


Subject(s)
Color Perception/physiology , Macaca/physiology , Retinal Ganglion Cells/physiology , Rod Opsins/metabolism , Thalamic Nuclei/physiology , Animals , Cells, Cultured , Darkness , Humans , In Vitro Techniques , Light , Light Signal Transduction/radiation effects , Retina/cytology , Retina/physiology , Retina/radiation effects , Retinal Cone Photoreceptor Cells/physiology , Retinal Cone Photoreceptor Cells/radiation effects , Retinal Ganglion Cells/cytology , Retinal Ganglion Cells/radiation effects , Retinal Rod Photoreceptor Cells/physiology , Retinal Rod Photoreceptor Cells/radiation effects , Rod Opsins/genetics , Thalamic Nuclei/radiation effects , Visual Pathways/physiology , Visual Pathways/radiation effects
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