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Midget retinal ganglion cells (RGCs) make up the majority of foveal RGCs in the primate retina. The receptive fields of midget RGCs exhibit both spectral and spatial opponency and are implicated in both color and achromatic form vision, yet the exact mechanisms linking their responses to visual perception remain unclear. Efforts to develop color vision models that accurately predict all the features of human color and form vision based on midget RGCs provide a case study connecting experimental and theoretical neuroscience, drawing on diverse research areas such as anatomy, physiology, psychophysics, and computer vision. Recent technological advances have allowed researchers to test some predictions of color vision models in new and precise ways, producing results that challenge traditional views. Here, we review the progress in developing models of color-coding receptive fields that are consistent with human psychophysics, the biology of the primate visual system and the response properties of midget RGCs.

According to classical opponent color theory, hue sensations are mediated by spectrally opponent neurons that are excited by some wavelengths of light and inhibited by others, while black-and-white sensations are mediated by spectrally non-opponent neurons that respond with the same sign to all wavelengths. However, careful consideration of the morphology and physiology of spectrally opponent L vs M midget retinal ganglion cells (RGCs) in the primate retina indicates that they are ideally suited to mediate black-and-white sensations and poorly suited to mediate color. Here we present a computational model that demonstrates how the cortex could use unsupervised learning to efficiently separate the signals from L vs M midget RGCs into distinct signals for black and white based only correlation of activity over time, and why it is unlikely that these same ganglion cells could simultaneously mediate our perception of red and green. Our model also shows how, in theory, a separate small population of midget RGCs with input from S, M and L cones would be ideally suited to mediating hue perception.

Microglial cells are the primary resident immune cells in the retina. In healthy adults, they are ramified; that is, they have extensive processes that move continually. In adult retinas, microglia maintain the normal structure and function of neurons and other glial cells, but the mechanism underlying this process is not well-understood. In the mouse hippocampus, microglia engulf small pieces of axons and presynaptic terminals via a process called trogocytosis. Here we report that microglia in the adult macaque retina also engulf pieces of neurons and glial cells, but not at sites of synapses. We analyzed microglia in a volume of serial, ultrathin sections of central macaque retina in which many neurons that ramify in the inner plexiform layer (IPL) had been reconstructed previously. We surveyed the IPL and identified the somas of microglia by their small size and scant cytoplasm. We then reconstructed the microglia and studied their interactions with other cells. We found that ramified microglia frequently ingested small pieces of each major type of inner retinal neuron and Müller glial cells via trogocytosis. There were a few instances where the interactions took place near synapses, but the synapses, themselves, were never engulfed. If trogocytosis by retinal microglia plays a role in synaptic remodeling, it was not apparent from the ultrastructure. Instead, we propose that trogocytosis enables these microglia to present antigens derived from normal inner retinal cells and, when activated, they would promote antigen-specific tolerance.

The functional roles and synaptic features of horizontal cells in the mammalian retina are still controversial. Evidence exists for feedback signaling from horizontal cells to cones and feed-forward signaling from horizontal cells to bipolar cells, but the details of the latter remain elusive. Here, immunohistochemistry and confocal microscopy were used to analyze the expression patterns of the SNARE protein syntaxin-4, the GABA receptor subunits α1 and ρ, and the cation-chloride cotransporters NKCC and KCC2 in the outer plexiform layer of primate retina. In macaque retina, as observed previously in other species, syntaxin-4 was expressed on dendrites and axon terminals of horizontal cells at cone pedicles and rod spherules. At cones, syntaxin-4 appeared densely clustered in two bands, at horizontal cell dendritic tips and at the level of desmosome-like junctions. Interestingly, in the lower band where horizontal cells may synapse directly onto bipolar cells, syntaxin-4 was highly enriched beneath short-wavelength sensitive (S) cones and colocalized with calbindin, a marker for HII horizontal cells. The enrichment at S-cones was not observed in either mouse or ground squirrel. Furthermore, high amounts of both GABA receptor and cation-chloride cotransporter subunits were found beneath primate S-cones. Finally, while syntaxin-4 was expressed by both HI and HII horizontal cell types, the intense clustering and colocalization with calbindin at S-cones indicated an enhanced expression in HII cells. Taken together, GABA receptors beneath cone pedicles, chloride transporters, and syntaxin-4 are putative constituents of a synaptic set of proteins which would be required for a GABA-mediated feed-forward pathway via horizontal cells carrying signals directly from cones to bipolar cells.

Trichromacy is unique to primates among placental mammals, enabled by blue (short/S), green (medium/M), and red (long/L) cones. In humans, great apes, and Old World monkeys, cones make a poorly understood choice between M and L cone subtype fates. To determine mechanisms specifying M and L cones, we developed an approach to visualize expression of the highly similar M- and L-opsin mRNAs. M-opsin was observed before L-opsin expression during early human eye development, suggesting that M cones are generated before L cones. In adult human tissue, the early-developing central retina contained a mix of M and L cones compared to the late-developing peripheral region, which contained a high proportion of L cones. Retinoic acid (RA)-synthesizing enzymes are highly expressed early in retinal development. High RA signaling early was sufficient to promote M cone fate and suppress L cone fate in retinal organoids. Across a human population sample, natural variation in the ratios of M and L cone subtypes was associated with a noncoding polymorphism in the NR2F2 gene, a mediator of RA signaling. Our data suggest that RA promotes M cone fate early in development to generate the pattern of M and L cones across the human retina.

AimsTo evaluate the myopia control efficacy of Diffusion Optics Technology (DOT) spectacle lenses in children over a 4-year treatment period.MethodsCYPRESS Part 1 (NCT03623074) was a 3-year multicentre, randomised, controlled, double-masked trial comparing two investigational spectacle lens DOT designs (Test 1, Test 2) and standard single vision Control lenses in 256 North American children aged 6–10 years. Children completing Part 1 (n=200) were invited to enrol in CYPRESS Part 2 (NCT04947735) for an additional 1-year period. In Part 2, Test 1 (n=35) and Control groups (n=42) continued with their original lens assignment and the Test 2 group (n=21) were crossed over to Test 1 (DOT 0.2) lenses. The co-primary endpoints were change from baseline in axial length (AL) and cycloplegic spherical equivalent refraction (cSER).ResultsTest 1 spectacle lenses demonstrated superiority to the Control in both co-primary endpoints: with a difference between means (Test 1−Control) of −0.13 mm for AL (p=0.018) and 0.33 D for cSER (p=0.008) in Part 1 and −0.05 mm for AL (p=0.038) and 0.13 D for cSER (p=0.043) in Part 2. Comparing treatment effects in Part 1 and 2 suggests that COVID-19 public health restrictions negatively impacted treatment efficacy in study years 2 and 3.ConclusionDOT 0.2 spectacle lenses are safe and effective at reducing myopia progression, with additional benefit evident in year 4 of wear. These results support the hypothesis that a mild reduction in retinal contrast can slow myopia progression in young children. The unprecedented disruption in participant schooling and lifestyle during the COVID-19 pandemic may have depressed treatment efficacy in Part 1.

There is enormous variation in the X-linked L/M (long/middle wavelength sensitive) gene array underlying \"normal\" color vision in humans. This variability has been shown to underlie individual variation in color matching behavior. Recently, red-green color blindness has also been shown to be associated with distinctly different genotypes. This has opened the possibility that there may be important phenotypic differences within classically defined groups of color blind individuals. Here, adaptive optics retinal imaging has revealed a mechanism for producing dichromatic color vision in which the expression of a mutant cone photopigment gene leads to the loss of the entire corresponding class of cone photoreceptor cells. Previously, the theory that common forms of inherited color blindness could be caused by the loss of photoreceptor cells has been discounted. We confirm that remarkably, this loss of one-third of the cones does not impair any aspect of vision other than color.

Ganglion cells are the projection neurons of the retina. Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin and also receive input from rods and cones via bipolar cells and amacrine cells. In primates, multiple types of ipRGCs have been identified. The ipRGCs with somas in the ganglion cell layer have been studied extensively, but less is known about those with somas in the inner nuclear layer, the “displaced” cells. To investigate their synaptic inputs, three sets of horizontal, ultrathin sections through central macaque retina were collected using serial block-face scanning electron microscopy. One displaced ipRGC received nearly all of its excitatory inputs from ON bipolar cells and would therefore be expected to have ON responses to light. In each of the three volumes, there was also at least one cell that had a large soma in the inner nuclear layer, varicose axons and dendrites with a large diameter that formed large, extremely sparse arbor in the outermost stratum of the inner plexiform layer. They were identified as the displaced M1 type of ipRGCs based on this morphology and on the high density of granules in their somas. They received extensive input from amacrine cells, including the dopaminergic type. The vast majority of their excitatory inputs were from OFF bipolar cells, including two subtypes with extensive input from the primary rod pathway. They would be expected to have OFF responses to light stimuli below the threshold for melanopsin or soon after the offset of a light stimulus.

Light absorption by photopigment molecules expressed in the photoreceptors in the retina is the first step in seeing. Two types of photoreceptors in the human retina are responsible for image formation: rods, and cones. Except at very low light levels when rods are active, all vision is based on cones. Cones mediate high acuity vision and color vision. Furthermore, they are critically important in the visual feedback mechanism that regulates refractive development of the eye during childhood. The human retina contains a mosaic of three cone types, short-wavelength (S), long-wavelength (L), and middle-wavelength (M) sensitive; however, the vast majority (~94%) are L and M cones. The OPN1LW and OPN1MW genes, located on the X-chromosome at Xq28, encode the protein component of the light-sensitive photopigments expressed in the L and M cones. Diverse haplotypes of exon 3 of the OPN1LW and OPN1MW genes arose thru unequal recombination mechanisms that have intermixed the genes. A subset of the haplotypes causes exon 3- skipping during pre-messenger RNA splicing and are associated with vision disorders. Here, we review the mechanism by which splicing defects in these genes cause vision disorders.

AbstractBackgroundMutations in the L/M cone opsin gene array cause abnormally high perceived retinal contrast and the development of myopia. Environmental factors may also lead to high visual contrast and cause myopia. Diffusion optics technology (DOT) lenses are designed to reduce contrast signalling in the retina and slow myopia progression.MethodsThe Control of Myopia Using Peripheral Diffusion Lenses Efficacy and Safety Study (CYPRESS, NCT03623074) is a 36-month, multicentre, randomised, controlled, double-masked trial evaluating two investigational spectacle lenses versus control lenses in myopic children aged 6–10, with a planned interim analysis at 12 months. The primary endpoints are change from baseline in axial length (AL) and spherical equivalent refraction (SER).Results256 children (58% female; mean age at screening, 8.1 years) were dispensed spectacles. Across all groups, baseline averages were AL 24.02 mm (SD±0.77 mm), SER −2.01 D (SD±0.9 D) using manifest refraction, and SER −1.94 D (SD±1.0 D) using cycloplegic autorefraction. At 12 months, mean difference in SER progression for test 1 versus control was −0.40 D (p<0.0001), representing a 74% reduction and −0.32 D for Test 2 (p<0.0001), representing a 59% reduction. The difference in AL progression for test 1 versus control was 0.15 mm (p<0.0001) and test 2 versus control was 0.10 mm (p=0.0018).Conclusion12-month results from this ongoing trial demonstrate the safety and effectiveness of DOT spectacles for reducing myopic progression.