Circuit Reorganization Shapes the Developing Human Foveal Midget Connectome toward Single-Cone Resolution.
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ABSTRACT:
SUBMITTER: Zhang C
PROVIDER: S-EPMC8428693 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeBlue cone monochromacy (BCM) is a rare inherited cone disorder in which both long- (L-) and middle- (M-) wavelength sensitive cone classes are either impaired or nonfunctional. Assessing genotype-phenotype relationships in BCM can improve our understanding of retinal development in the absence of functional L- and M-cones. Here we examined foveal cone structure in patients with genetically-confirmed BCM, using adaptive optics scanning light ophthalmoscopy (AOSLO).MethodsTwenty-three male patients (aged 6-75 years) with genetically-confirmed BCM were recruited for high-resolution imaging. Eight patients had a deletion of the locus control region (LCR), and 15 had a missense mutation-Cys203Arg-affecting the first two genes in the opsin gene array. Foveal cone structure was assessed using confocal and non-confocal split-detection AOSLO across a 300 × 300 µm area, centered on the location of peak cell density.ResultsOnly one of eight patients with LCR deletions and 10 of 15 patients with Cys203Arg mutations had analyzable images. Mean total cone density for Cys203Arg patients was 16,664 ± 11,513 cones/mm2 (n = 10), which is, on average, around 40% of normal. Waveguiding cone density was 2073 ± 963 cones/mm2 (n = 9), which was consistent with published histological estimates of S-cone density in the normal eye. The one patient with an LCR deletion had a total cone density of 10,246 cones/mm2 and waveguiding density of 1535 cones/mm2.ConclusionsOur results show that BCM patients with LCR deletions and Cys203Arg mutations have a population of non-waveguiding photoreceptors, although the spectral identity and level of function remain unknown.
| S-EPMC9624264 | biostudies-literature
Project description:PurposeAdaptive optics scanning light ophthalmoscopy (AOSLO) imaging in patients with achromatopsia (ACHM) and albinism is not always successful. Here, we tested whether optical coherence tomography (OCT) measures of foveal structure differed between patients for whom AOSLO images were either quantifiable or unquantifiable.MethodsThe study included 166 subjects (84 with ACHM; 82 with albinism) with previously acquired OCT scans, AOSLO images, and best-corrected visual acuity (BCVA, if available). Foveal OCT scans were assessed for outer retinal structure, outer nuclear layer thickness, and hypoplasia. AOSLO images were graded as quantifiable if a peak cone density could be measured and/or usable if the location of peak density could be identified and the parafoveal mosaic was quantifiable.ResultsForty-nine percent of subjects with ACHM and 57% of subjects with albinism had quantifiable AOSLO images. Older age and better BCVA were found in subjects with quantifiable AOSLO images for both ACHM (P = 0.0214 and P = 0.0276, respectively) and albinism (P = 0.0073 and P < 0.0004, respectively). There was a significant trend between ellipsoid zone appearance and ability to quantify AOSLO (P = 0.0028). In albinism, OCT metrics of cone structure did not differ between groups.ConclusionsPreviously reported AOSLO-based cone density measures in ACHM may not necessarily reflect the degree of remnant cone structure in these patients.Translational relevanceUntil AOSLO is successful in all patients with ACHM and albinism, the possibility of the reported data from a particular cohort not being representative of the entire population remains an important issue to consider when interpreting results from AOSLO studies.
| S-EPMC8132001 | biostudies-literature
Project description:PurposeTo characterize the association between foveal shape and cone and retinal pigment epithelium (RPE) cell topographies in healthy humans.MethodsMultimodal adaptive scanning light ophthalmoscopy and optical coherence tomography (OCT) were used to acquire images of foveal cones, RPE cells, and retinal layers in eyes of 23 healthy participants with normal foveas. Distributions of cone and RPE cell densities were fitted with nonlinear mixed-effects models. A linear mixed-effects model was used to examine the relationship between cone and RPE inter-cell distances and foveal shape as obtained from the OCT scans of retinal thickness.ResultsThe best-fit model to the cone densities was a power function with a nasal-temporal asymmetry. There was a significant linear relationship among cone and RPE cell spacing, foveal shape, and foveal cell topography. The model predictions of the central 10° show that the contributions of both the cones and RPE cells are necessary to account for foveal shape.ConclusionsThe results indicate that there is a strong relationship between cone and RPE cell spacing and the shape of the human adolescent and adult fovea. This finding adds to the existing evidence of the critical role that the RPE serves in fetal foveal development and through adolescence, possibly via the imposition of constraints on the number and distribution of foveal cones.
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Project description:Gene therapy trials for inherited photoreceptor disorders are planned. Anatomical metrics to select the best candidates and outcomes are needed. Adaptive optics (AO) imaging enables visualization of photoreceptor structure, although analytical tools are lacking. Here we present criteria to assess residual photoreceptor integrity in achromatopsia (ACHM).Two AOSLOs, at the Medical College of Wisconsin and Moorfields Eye Hospital, were used to image the photoreceptor mosaic of 11 subjects with ACHM and 7 age-matched controls. Images were obtained, processed, and montaged using previously described methods. Cone density and reflectivity were quantified to assess residual cone photoreceptor structure.All subjects with ACHM had reduced numbers of cone photoreceptors, albeit to a variable degree. In addition, the relative cone reflectivity varied greatly. Interestingly, subjects with GNAT2-associated ACHM had the greatest number of residual cones and the reflectivity of those cones was significantly greater than that of the cones in the subjects with CNGA3/CNGB3-associated ACHM.We present cone reflectivity as a metric that can be used to characterize cone structure in ACHM. This method may be applicable to subjects with other cone disorders. In ACHM, we hypothesize that cone numerosity (and/or density) combined with cone reflectivity could be used to gauge the therapeutic potential. As gene replacement would not be expected to add cones, reflectivity could be a more powerful AO-metric for monitoring the cellular response to treatment and could provide a more immediate indicator of efficacy than behavioral measures, which may take longer to change.
| S-EPMC4235328 | biostudies-literature
Project description:PurposeTo test the hypothesis that foveal cone topography is symmetrical between contralateral eyes.MethodsWe used adaptive optics scanning light ophthalmoscopy to acquire images of the foveal cone mosaic in each eye of 58 subjects with normal vision (35 female, 23 male). Cones were semiautomatically identified over a 300 × 300-µm foveal area. From these cone coordinates, maps of cone density were derived, and we extracted estimates of peak cone density from each map. Mosaic regularity was assessed using Voronoi cell area regularity (VCAR). Average roundness and average area of the 70%, 75%, 80%, 85%, and 90% of peak density isodensity contours were evaluated.ResultsThe average peak cone density for right eyes was 180,286 cones/mm2 (n = 49) and for left eyes was 182,397 cones/mm2 (n = 45), with a mean absolute difference of 6363 cones/mm2 (n = 43). Peak density, cone spacing, VCAR, and average area within the isodensity contours of fellow eyes were not significantly different (P = 0.60, P = 0.83, P = 0.30, and P = 0.39, respectively). However, the average roundness of the isodensity contours was 2% more circular in the right eyes than in the left eyes (P = 0.02).ConclusionsThere is interocular symmetry of peak foveal cone density, mosaic regularity, and area encompassing the most densely packed cells in subjects with normal vision. The origin and significance of the observed interocular difference in average roundness of the isodensity contours are unclear.
| S-EPMC7746960 | biostudies-literature
Project description:PurposeCongenital achromatopsia (ACHM) is an autosomal recessive disorder in which cone function is absent or severely reduced. Gene therapy in animal models of ACHM have shown restoration of cone function, though translation of these results to humans relies, in part, on the presence of viable cone photoreceptors at the time of treatment. Here, we characterized residual cone structure in subjects with CNGB3-associated ACHM.MethodsHigh-resolution imaging (optical coherence tomography [OCT] and adaptive optics scanning light ophthalmoscopy [AOSLO]) was performed in 51 subjects with CNGB3-associated ACHM. Peak cone density and inter-cone spacing at the fovea was measured using split-detection AOSLO. Foveal outer nuclear layer thickness was measured in OCT images, and the integrity of the photoreceptor layer was assessed using a previously published OCT grading scheme.ResultsAnalyzable images of the foveal cones were obtained in 26 of 51 subjects, with nystagmus representing the major obstacle to obtaining high-quality images. Peak foveal cone density ranged from 7,273 to 53,554 cones/mm2, significantly lower than normal (range, 84,733-234,391 cones/mm2), with the remnant cones being either contiguously or sparsely arranged. Peak cone density was correlated with OCT integrity grade; however, there was overlap of the density ranges between OCT grades.ConclusionsThe degree of residual foveal cone structure varies greatly among subjects with CNGB3-associated ACHM. Such measurements may be useful in estimating the therapeutic potential of a given retina, providing affected individuals and physicians with valuable information to more accurately assess the risk-benefit ratio as they consider enrolling in experimental gene therapy trials. (www.clinicaltrials.gov, NCT01846052.).
| S-EPMC4978151 | biostudies-literature
Project description:We have generated a high-resolution Hi-C map of developing human retinal organoids to elucidate spatiotemporal dynamics of genomic architecture and its relationship with gene expression patterns. We demonstrate progressive stage-specific alterations in DNA topology and correlate these changes with transcription of cell-type-restricted gene markers during retinal differentiation. Temporal Hi-C reveals a shift toward A compartment for protein-coding genes and B compartment for non-coding RNAs, displaying high and low expression, respectively. Notably, retina-enriched genes are clustered near lost boundaries of topologically associated domains (TADs), and higher-order assemblages (i.e., TAD cliques) localize in active chromatin regions with binding sites for eye-field transcription factors. These genes gain chromatin contacts at their transcription start site as organoid differentiation proceeds. Our study provides a global view of chromatin architecture dynamics associated with diversification of cell types during retinal development and serves as a foundational resource for in-depth functional investigations of retinal developmental traits.
| S-EPMC10790351 | biostudies-literature
Project description:Albinism is associated with disrupted foveal development, though intersubject variability is becoming appreciated. We sought to quantify this variability, and examine the relationship between foveal cone specialization and pit morphology in patients with a clinical diagnosis of albinism.We recruited 32 subjects with a clinical diagnosis of albinism. DNA was obtained from 25 subjects, and known albinism genes were analyzed for mutations. Relative inner and outer segment (IS and OS) lengthening (fovea-to-perifovea ratio) was determined from manually segmented spectral domain-optical coherence tomography (SD-OCT) B-scans. Foveal pit morphology was quantified for eight subjects from macular SD-OCT volumes. Ten subjects underwent imaging with adaptive optics scanning light ophthalmoscopy (AOSLO), and cone density was measured.We found mutations in 22 of 25 subjects, including five novel mutations. All subjects lacked complete excavation of inner retinal layers at the fovea, though four subjects had foveal pits with normal diameter and/or volume. Peak cone density and OS lengthening were variable and overlapped with that observed in normal controls. A fifth hyper-reflective band was observed in the outer retina on SD-OCT in the majority of the subjects with albinism.Foveal cone specialization and pit morphology vary greatly in albinism. Normal cone packing was observed in the absence of a foveal pit, suggesting a pit is not required for packing to occur. The degree to which retinal anatomy correlates with genotype or visual function remains unclear, and future examination of larger patient groups will provide important insight on this issue.
| S-EPMC4098060 | biostudies-literature
Project description:PurposeTo assess the relationship between cone spacing and visual acuity in eyes with rod-cone degeneration (RCD) followed longitudinally.MethodsHigh-resolution images of the retina were obtained using adaptive optics scanning laser ophthalmoscopy from 13 eyes of nine RCD patients and 13 eyes of eight healthy subjects at two sessions separated by 10 or more months (mean 765 days, range 311-1935 days). Cone spacing Z-score measured as close as possible (average <0.25°) to the preferred retinal locus was compared with visual acuity (letters read on the Early Treatment of Diabetic Retinopathy Study [ETDRS] chart and logMAR) and foveal sensitivity.ResultsCone spacing was significantly correlated with ETDRS letters read (ρ = -0.47, 95%CI -0.67 to -0.24), logMAR (ρ = 0.46, 95%CI 0.24 to 0.66), and foveal sensitivity (ρ = -0.30, 95%CI -0.52 to -0.018). There was a small but significant increase in mean cone spacing Z-score during follow-up of +0.97 (95%CI 0.57 to 1.4) in RCD patients, but not in healthy eyes, and there was no significant change in any measure of visual acuity.ConclusionsCone spacing was correlated with visual acuity and foveal sensitivity. In RCD patients, cone spacing increased during follow-up, while visual acuity did not change significantly. Cone spacing Z-score may be a more sensitive measure of cone loss at the fovea than visual acuity in patients with RCD.
| S-EPMC6657704 | biostudies-literature
Project description:The basis of cross-suppression between rod and cone channels has long been an enigma. Using rabbit retinal connectome RC1, we show that all cone bipolar cell (BC) classes inhibit rod BCs via amacrine cell (AC) motifs (C1-6); that all cone BC classes are themselves inhibited by AC motifs (R1-5, R25) driven by rod BCs. A sparse symmetric AC motif (CR) is presynaptic and postsynaptic to both rod and cone BCs. ON cone BCs of all classes drive inhibition of rod BCs via motif C1 wide-field GABAergic ACs (γACs) and motif C2 narrow field glycinergic ON ACs (GACs). Each rod BC receives ≈10 crossover AC synapses and each ON cone BC can target ≈10 or more rod BCs via separate AC processes. OFF cone BCs mediate monosynaptic inhibition of rod BCs via motif C3 driven by OFF γACs and GACs and disynaptic inhibition via motifs C4 and C5 driven by OFF wide-field γACs and narrow-field GACs, respectively. Motifs C4 and C5 form halos of 60-100 inhibitory synapses on proximal dendrites of AI γACs. Rod BCs inhibit surrounding arrays of cone BCs through AII GAC networks that access ON and OFF cone BC patches via motifs R1, R2, R4, R5 and a unique ON AC motif R3 that collects rod BC inputs and targets ON cone BCs. Crossover synapses for motifs C1, C4, C5, and R3 are 3-4× larger than typical feedback synapses, which may be a signature for synaptic winner-take-all switches. J. Comp. Neurol. 527:87-116, 2019. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.
| S-EPMC5823792 | biostudies-literature