Vision Research最新文献

Glaucoma is a leading cause of blindness worldwide and glaucoma patients exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs. Combining some previous published results and some new data, this paper provides our current view on how high IOP (H-IOP) affects the light response sensitivity of a subset of RGCs, the alpha-ganglion cells (αGCs), as well as their presynaptic bipolar cells (DBCs and HBCs) and A2 amacrine cells (AIIACs) in dark-adapted mouse retinas. Our data demonstrate that H-IOP in experimental glaucoma mice significantly decreases light-evoked spike response sensitivity of sONαGCs and sOFFαGCs (i.e., raises thresholds by 1.5–2.5 log units), but not that of the tONαGCs and tOFFαGCs. The sensitivity loss in sONαGCs and sOFFαGCs is mediated by a H-IOP induced suppression of AIIAC response which is caused by a decrease of transmission efficacy of the DBC_R→AIIAC synapse. We also provide evidence supporting the hypothesis that BK channels in the A17AC→DBC_R feedback synapse are the H-IOP sensor that regulates the DBC_R→AIIAC synaptic efficacy, as BK channel blocker IBTX mimics the action of H-IOP. Our results provide useful information for designing strategies for early detection and possible treatments of glaucoma as physiological changes occur before irreversible structural damage.

This focused review highlights the importance of yes-associated protein (YAP)/transcriptional coactivator with PDZ binding motif (TAZ) mechanosignaling in human trabecular meshwork and Schlemm’s canal cells in response to glaucoma-associated extracellular matrix stiffening and cyclic mechanical stretch, as well as biochemical pathway modulators (with signaling crosstalk) including transforming growth factor beta 2, glucocorticoids, Wnt, lysophosphatidic acid, vascular endothelial growth factor, and oxidative stress. We provide a comprehensive overview of relevant literature from the last decade, highlight intriguing research avenues with translational potential, and close with an outlook on future directions.

Optineurin (OPTN) is a gene associated with familial normal tension glaucoma (NTG). While NTG involves intraocular pressure (IOP)-independent neurodegeneration of the visual pathway that progresses with age, how OPTN dysfunction leads to NTG remains unclear. Here, we generated an OPTN knockout mouse (Optn^−/−) model to test the hypothesis that a loss-of-function mechanism induces structural and functional eye deterioration with aging. Eye anatomy, visual function, IOP, retinal histology, and retinal ganglion cell survival were compared to littermate wild-type (WT) control mice. Consistent with OPTN’s role in NTG, loss of OPTN did not increase IOP or alter gross eye anatomy in young (2–3 months) or aged (12 months) mice. When retinal layers were quantitated, young Optn^−/− mice had thinner retina in the peripheral regions than young WT mice, primarily due to thinner ganglion cell-inner plexiform layers. Despite this, visual function in Optn^−/− mice was not severely impaired, even with aging. We also assessed relative abundance of retinal cell subtypes, including amacrine cells, bipolar cells, cone photoreceptors, microglia, and astrocytes. While many of these cellular subtypes were unaffected by Optn deletion, more dopaminergic amacrine cells were observed in aged Optn^−/− mice. Taken together, our findings showed that complete loss of Optn resulted in mild retinal changes and less visual function impairment, supporting the possibility that OPTN-associated glaucoma does not result from a loss-of-function disease mechanism. Further research using these Optn mice will elucidate detailed molecular pathways involved in NTG and identify clinical or environmental risk factors that can be targeted for glaucoma treatment.

Force sensing is a fundamental ability that allows cells and organisms to interact with their physical environment. The eye is constantly subjected to mechanical forces such as blinking and eye movements. Furthermore, elevated intraocular pressure (IOP) can cause mechanical strain at the optic nerve head, resulting in retinal ganglion cell death (RGC) in glaucoma. How mechanical stimuli are sensed and affect cellular physiology in the eye is unclear. Recent studies have shown that mechanosensitive ion channels are expressed in many ocular tissues relevant to glaucoma and may influence IOP regulation and RGC survival. Furthermore, variants in mechanosensitive ion channel genes may be associated with risk for primary open angle glaucoma. These findings suggest that mechanosensitive channels may be important mechanosensors mediating cellular responses to pressure signals in the eye. In this review, we focus on mechanosensitive ion channels from three major channel families—PIEZO, two-pore potassium and transient receptor potential channels. We review the key properties of these channels, their effects on cell function and physiology, and discuss their possible roles in glaucoma pathophysiology.

The aim of this study was to assess the perceptibility and acceptability thresholds of maxillofacial silicones for light and dark skin colors and to evaluate the effect of gender and professional experience on these thresholds. Two different sets of specimens (as light and dark) each, consisting of 14 (25 × 25 × 6-mm³) silicone skin replications, were produced. Four specimens of each set were produced from the same silicon mixture of the relevant set and polymerized simultaneously to provide standardized fabrication conditions. These 4 light/dark specimens were assigned as “baseline color specimens (BCs)” in each set, while the other 10 specimens were produced with a color difference level that increased gradually from BC. These stepped levels were obtained by controlled increasing of the pigment concentration in the relevant baseline silicon mixture. Color difference levels of specimens were calculated by using the CIELAB and CIEDE2000 formulas. Observers comprised of 3 different professional experiences as first-year dental students, interns, and dentists (n = 30/group, gender-balanced) were included. Combinations consisting of 5 specimens with 4 BCs and 1 different color were shown to the observers to assess whether the color difference was perceptible or acceptable. Perceptibility and acceptability percentages were regressed with color difference levels to estimate the best fit curve and confidence intervals were calculated (α = 0.05). The highest estimation of the coefficient of determination (R²) was found in the cubic curve for all parameters. A significant difference was found between the light and dark colors. The perceptibility thresholds (ΔE*_ab/ΔE₀₀) were 0.8/0.59 and 2.63/1.75 for light and dark colors, respectively. The acceptability thresholds (ΔE*_ab/ΔE₀₀) were 3.35/2.25, 10.07/7.04 for light and dark colors, respectively. No significant differences were found between gender and among experience groups concerning visual thresholds. Regardless of gender and experience, observers could perceive color differences more easily in light skin colors.

This initial methods study presents the initial immunohistochemical and transcriptomic changes in the optic nerve head and retina from three research-consented brain-dead organ donors following prolonged and transient intraocular pressure (IOP) elevation. In this initial study, research-consented brain-dead organ donors were exposed to unilateral elevation of IOP for 7.5 h (Donor 1), 30 h (Donor 2), and 1 h (Donor 3) prior to organ procurement. Optic nerve tissue and retinal tissue was obtained following organ procurement for immunohistological and transcriptomic analysis.

Optic nerve sections in Donor 1 exposed to 7.5-hours of unilateral sub-ischemic IOP elevation demonstrated higher levels of protein expression of the astrocytic marker, glial fibrillary acidic protein (GFAP), within the lamina cribrosa with greatest expression inferior temporally in the treated eye compared to control. Spatial transcriptomic analysis performed on optic nerve head tissues from Donor 2 exposed to 30 h of unilateral IOP elevation demonstrated differential transcription of mRNA across laminar and scleral regions. Immunohistochemistry of retinal sections from Donor 2 exhibited higher GFAP and IBA1 expression in the treated eye compared with control, but this was not observed in Donor 3, which was exposed to only 1-hour of IOP elevation. While there were no differences in GFAP protein expression in the retina following the 1-hour IOP elevation in Donor 3, there were higher levels of transcription of GFAP in the inner nuclear layer, and CD44 in the retinal ganglion cell layer, indicative of astrocytic and Müller glial reactivity as well as an early inflammatory response, respectively.

We found that transcriptomic differences can be observed across treated and control eyes following unilateral elevation of IOP in brain dead organ donors. The continued development of this model affords the unique opportunity to define the acute mechanotranscriptomic response of the optic nerve head, evaluate the injury and repair mechanisms in the retina in response to IOP elevation, and enable correlation of in vivo imaging and functional testing with ex vivo cellular responses for the first time in the living human eye.

Exfoliation syndrome is a leading cause of secondary glaucoma worldwide. Among the risk-factors for exfoliation syndrome and exfoliation glaucoma that have been investigated, a genetic association with 15q24.1 is among the most striking. The leading candidates for the causal gene at this locus are LOXL1 and/or LOXL1-AS1, but studies have not yet coalesced in establishing, or ruling out, either candidate. Here, we contribute to studies of the 15q24.1 locus by making a partially humanized mouse model in which 166 kb of human genomic DNA from the 15q24.1 locus was introduced into the mouse genome via BAC transgenesis (B6-Tg(RP11-71M11)Andm). Transgenic expression of human genes in the BAC was only detectable for LOXL1-AS1. One cohort of 34 mice (21 experimental hemizygotes and 13 non-carrier control littermates) was assessed by slit-lamp exams and SD-OCT imaging at early (1–2 months) and mid (4–5 months) time points; fundus exams were performed at 5 months of age. A second smaller cohort (3 hemizygotes) were aged extensively (>12 months) to screen for overt abnormalities. Across all genotypes and ages, 136 slit-lamp exams, 128 SD-OCT exams, and 42 fundus exams detected no overt indices of exfoliation syndrome. Quantitatively, small, but statistically significant, age-related declines in ganglion cell complex thickness and total retinal thickness were detected in the hemizygotes at 4 months of age. Overall, this study demonstrates complexity in gene regulation from the 15q24.1 locus and suggests that LOXL1-AS1 is unlikely to be a monogenic cause of exfoliation syndrome but may contribute to glaucomatous retinal damage.

When observers perceive 3D relations, they represent depth and spatial locations with the ground as a reference. This frame of reference could be egocentric, that is, moving with the observer, or allocentric, that is, remaining stationary and independent of the moving observer. We tested whether the representation of relative depth and of spatial location took an egocentric or allocentric frame of reference in three experiments, using a blind walking task. In Experiments 1 and 2, participants either observed a target in depth, and then straightaway blind walked for the previously seen distance between the target and the self; or walked to the side or along an oblique path for 3 m and then started blind walking for the previously seen distance. The difference between the conditions was whether blind walking started from the observation point. Results showed that blind walking distance varied with the starting locations. Thus, the represented distance did not seem to go through spatial updating with the moving observer and the frame of reference was likely allocentric. In Experiment 3, participants observed a target in space, then immediately blind walked to the target, or blind walked to another starting point and then blind walked to the target. Results showed that the end location of blind walking was different for different starting points, which suggested the representation of spatial location is likely to take an allocentric frame of reference. Taken together, these experiments convergingly suggested that observers used an allocentric frame of reference to construct their mental space representation.

Neon color spreading (NCS) is an illusory color phenomenon that provides a dramatic example of surface completion and filling-in. Numerous studies have varied both spatial and temporal aspects of the neon-generating stimulus to explore variations in the strength of the effect. Here, we take a novel, parametric, low-level psychophysical approach to studying NCS in two experiments. In Experiment 1, we test the ability of both cone-isolating and equiluminant stimuli to generate neon color spreading for both increments and decrements in cone modulations. As expected, sensitivity was low to S(hort-wavelength) cone stimuli due to their poor spatial resolution, but sensitivity was similar for the other color directions. We show that when these differences in detection sensitivity are accounted for, the particular cone type, and the polarity (increment or decrement), make little difference in generating neon color spreading, with NCS visible at about twice detection threshold level in all cases. In Experiment 2, we use L-cone flicker modulations (reddish and greenish excursions around grey) to study sensitivity to NCS as a function of temporal frequency from 0.5 to 8 Hz. After accounting for detectability, the temporal contrast sensitivity functions for NCS are approximately constant or even increase over the studied frequency range. Therefore there is no evidence in this study that the processes underlying NCS are slower than the low-level processes of simple flicker detection. These results point to relatively fast mechanisms, not slow diffusion processes, as the substrate for NCS.