Cone Vision Research Articles

Parallel Spectral Tuning of a Cone Visual Pigment Provides Evidence for Ancient Deep-Sea Adaptations in Cetaceans.

Dichromatic color vision is mediated by two cone visual pigments in many eutherian mammals. After reentry into the sea, early cetaceans lost their violet-sensitive visual pigment (short wavelength-sensitive 1) independently in the baleen and toothed whale ancestors and thus obtained only monochromatic cone vision. Subsequently, losses of the middle/long wavelength-sensitive (M/LWS) pigment have also been reported in multiple whale lineages, leading to rhodopsin (RH1)-mediated rod monochromatic vision. To further elucidate the phenotypic evolution of whale visual pigments, we assessed the spectral tuning of both M/LWS and RH1 from representative cetacean taxa. Interestingly, although the coding sequences for M/LWS are intact in both the pygmy right whale and the Baird's beaked whale, no spectral sensitivity was detected in vitro. Pseudogenization of other cone vision-related genes is observed in the pygmy right whale, suggesting a loss of cone-mediated vision. After ancestral sequence reconstructions, ancient M/LWS pigments from cetacean ancestors were resurrected and functionally measured. Spectral tuning of M/LWS from the baleen whale ancestor shows that it is green sensitive, with a 40-nm shift in sensitivity to a shorter wavelength. For the ancestor of sperm whales, although no spectral sensitivity could be recorded for its M/LWS pigment, a substantial sensitivity shift (20 to 30 nm) to a shorter wavelength may have also occurred before its functional inactivation. The parallel phenotypic evolution of M/LWS to shorter wavelength sensitivity might be visual adaptations in whales allowing more frequent deep-sea activities, although additional ecological differentiations may have led to their subsequent losses.

Ablation of Fatty Acid Transport Protein-4 Enhances Cone Survival, M-cone Vision, and Synthesis of Cone-Tropic 9-cis-Retinal in rd12 Mouse Model of Leber Congenital Amaurosis.

The canonical visual cycle employing RPE65 as the retinoid isomerase regenerates 11-cis-retinal to support both rod- and cone-mediated vision. Mutations of RPE65 are associated with Leber congenital amaurosis that results in rod and cone photoreceptor degeneration and vision loss of affected patients at an early age. Dark-reared Rpe65-/- mouse has been known to form isorhodopsin that employs 9-cis-retinal as the photosensitive chromophore. The mechanism regulating 9-cis-retinal synthesis and the role of the endogenous 9-cis-retinal in cone survival and function remain largely unknown. In this study, we found that ablation of fatty acid transport protein-4 (FATP4), a negative regulator of 11-cis-retinol synthesis catalyzed by RPE65, increased the formation of 9-cis-retinal, but not 11-cis-retinal, in a light-independent mechanism in both sexes of RPE65-null rd12 mice. Both rd12 and rd12;Fatp4-/- mice contained a massive amount of all-trans-retinyl esters in the eyes, exhibiting comparable scotopic vision and rod degeneration. However, expression levels of M- and S-opsins as well as numbers of M- and S-cones surviving in the superior retinas of rd12;Fatp4-/ - mice were at least twofold greater than those in age-matched rd12 mice. Moreover, FATP4 deficiency significantly shortened photopic b-wave implicit time, improved M-cone visual function, and substantially deaccelerated the progression of cone degeneration in rd12 mice, whereas FATP4 deficiency in mice with wild-type Rpe65 alleles neither induced 9-cis-retinal formation nor influenced cone survival and function. These results identify FATP4 as a new regulator of synthesis of 9-cis-retinal, which is a "cone-tropic" chromophore supporting cone survival and function in the retinas with defective RPE65.

Txnip deletions and missense alleles prolong the survival of cones in a retinitis pigmentosa mouse model.

Retinitis pigmentosa (RP) is an inherited retinal disease in which there is a loss of cone-mediated daylight vision. As there are >100 disease genes, our goal is to preserve cone vision in a disease gene-agnostic manner. Previously we showed that overexpressing TXNIP, an α-arrestin protein, prolonged cone vision in RP mouse models, using an AAV to express it only in cones. Here, we expressed different alleles of Txnip in the retinal pigmented epithelium (RPE), a support layer for cones. Our goal was to learn more of TXNIP's structure-function relationships for cone survival, as well as determine the optimal cell type expression pattern for cone survival. The C-terminal half of TXNIP was found to be sufficient to remove GLUT1 from the cell surface, and improved RP cone survival, when expressed in the RPE, but not in cones. Knock-down of HSP90AB1, a TXNIP-interactor which regulates metabolism, improved the survival of cones alone and was additive for cone survival when combined with TXNIP. From these and other results, it is likely that TXNIP interacts with several proteins in the RPE to indirectly support cone survival, with some of these interactions different from those that lead to cone survival when expressed only in cones.

Txnip deletions and missense alleles prolong the survival of cones in a retinitis pigmentosa mouse model

Retinitis pigmentosa (RP) is an inherited retinal disease in which there is a loss of cone-mediated daylight vision. As there are >100 disease genes, our goal is to preserve cone vision in a disease gene-agnostic manner. Previously we showed that overexpressing TXNIP, an α-arrestin protein, prolonged cone vision in RP mouse models, using an AAV to express it only in cones. Here, we expressed different alleles of Txnip in the retinal pigmented epithelium (RPE), a support layer for cones. Our goal was to learn more of TXNIP’s structure-function relationships for cone survival, as well as determine the optimal cell type expression pattern for cone survival. The C-terminal half of TXNIP was found to be sufficient to remove GLUT1 from the cell surface, and improved RP cone survival, when expressed in the RPE, but not in cones. Knock-down of HSP90AB1, a TXNIP-interactor which regulates metabolism, improved the survival of cones alone and was additive for cone survival when combined with TXNIP. From these and other results, it is likely that TXNIP interacts with several proteins in the RPE to indirectly support cone survival, with some of these interactions different from those that lead to cone survival when expressed only in cones.

Melanopsin-mediated amplification of cone signals in the human visual cortex.

The ambient daylight variation is coded by melanopsin photoreceptors and their luxotonic activity increases towards midday when colour temperatures are cooler, and irradiances are higher. Although melanopsin and cone photoresponses can be mediated via separate pathways, the connectivity of melanopsin cells across all levels of the retina enables them to modify cone signals. The downstream effects of melanopsin-cone interactions on human vision are however, incompletely understood. Here, we determined how the change in daytime melanopsin activation affects the human cone pathway signals in the visual cortex. A 5-primary silent-substitution method was developed to evaluate the dependence of cone-mediated signals on melanopsin activation by spectrally tuning the lights and stabilizing the rhodopsin activation under a constant cone photometric luminance. The retinal (white noise electroretinogram) and cortical responses (visual evoked potential) were simultaneously recorded with the photoreceptor-directed lights in 10 observers. By increasing the melanopsin activation, a reverse response pattern was observed with cone signals being supressed in the retina by 27% (p = 0.03) and subsequently amplified by 16% (p = 0.01) as they reach the cortex. We infer that melanopsin activity can amplify cone signals at sites distal to retinal bipolar cells to cause a decrease in the psychophysical Weber fraction for cone vision.

Path Planning for Fixed-Wing Unmanned Aerial Vehicles: An Integrated Approach with Theta* and Clothoids

Unmanned Aerial Vehicles (UAVs) have emerged as a compelling alternative to manned operations, offering the capability to navigate hazardous environments without risks for human operators. Despite their potential, optimizing UAV missions in complex and unstructured environments remains a pivotal challenge. Path planning becomes a crucial aspect to increase mission efficiency, although it is inherently complex due to various factors such as obstacles, no-fly zones, non-cooperative aircraft, and flight mechanics limitations. This paper presents a path-planning technique for fixed-wing unmanned aerial vehicles (UAVs) based on the Theta* algorithm. The approach introduces innovative features, such as the use of Euler spiral, or clothoids, to serve as connection arcs between nodes, mitigating trajectory discontinuities. The design of clothoids can be linked to the aircraft performance model, establishing a connection between curvature constraints and the specific characteristics of the vehicle. Furthermore, to lower the computational burden, the implementation of an adaptive exploration distance and a vision cone was considered, reducing the number of explored solutions. This methodology ensures a seamless and optimized flight path for fixed-wing UAVs operating in static environments, showcasing a noteworthy improvement in trajectory smoothness. The proposed methodology has been numerically evaluated in several complex test cases as well as in a real urban scenario to prove its effectiveness.

Comparison of visual and semi-automated kilovoltage cone beam CT image QA analysis.

Established kilovoltage cone-beam computed tomography (kV-CBCT) image quality assurance (QA) guidelines often rely on recommendations provided by the American Association of Physicists in Medicine (AAPM) task group (TG) reports with metrics that use visual analysis. This can result in measurement variations by different users, especially in visually subjective analyzes such as low contrast resolution. Consequently, there is a growing interest in more automated means of image QA analysis that can offer increased consistency, accuracy, and convenience. This work compares visual QA to semi-automated software QA analysis to establish the performance and viability of a semi-automated method. In this study, a commercial product (RIT Radia. Radiological Imaging Technology, Colorado Springs, CO) was used to evaluate 68 months of kV-CBCT images of a Catphan® 504 phantom obtained from a Varian TrueBeam® linear accelerator. Six key metrics were examined: high contrast resolution, low contrast resolution, Hounsfield unit constancy, uniformity and noise, and spatial linearity. The results of this method were then compared to those recorded visually using Bland-Altman, and/or paired sample t-test. Comparison of all modules showed a non-random, statistically significant difference between visual and semi-automated methods except for LDPE and Teflon in the Hounsfield unit constancy analysis, which falls outside the paired sample t-test's 5% significance level. A small high contrast resolution bias indicates the two analysis methods are largely equivalent, while a large low contrast resolution bias indicates greater semi-automated target detection. Wide limits of agreement in the uniformity module suggests variability due to multiple visual observers. Spatial linearity results measured differences of less than 0.17%. Semi-automated QA analysis offered greater stability over visual analysis. Additionally, semi-automated QA results satisfied or exceeded visual QA passing criteria and allowed for fast and consistent image quality analysis.

Vision screening and vocational aptitude: A factor analysis approach.

For a good vision screening battery to quickly and accurately reflect the status of the human visual system it should be relevant, reliable, and streamlined. Because the early visual system has limited functional architecture, many simple measurements of the visual system may in fact be measuring the shared computations and parallel processes of other visual functions, making much of the measurement process redundant. This can make a screening battery repetitious and therefore inefficient. The purpose of this research is to investigate these redundancies in a large occupational screening dataset using factor analysis. 192 subjects participated in the Operational Based Vision Assessment (OBVA) Laboratory Automated Vision Testing (AVT) procedure. The AVT includes digital tests for visual acuity, luminance and cone contrast sensitivity, motion coherence, stereopsis, and binocular motor function. Psychometric thresholds and fusional ranges were collected from each subject and a factor analysis was utilized to investigate independent latent variables in the dataset. A promax rotation revealed 5 factors that explained 74% of the total variance: (1) medium and high spatial frequency vision, (2) stereoacuity and horizontal fusional range, (3) cone contrast sensitivity, (4) motion perception, and (5) low spatial frequency vision. Practically, these results suggest that the screening battery can be reduced to 5 independent measurements that capture much of the variance in the dataset. Furthermore, the factors predicted operational and vocational aptitude better than any single variable. More interestingly, these relationships also reiterate known computational processes within the human visual system, such as the parallel processing of low and high spatial frequency content.

Long-Range Order and Directional Defect Propagation in the Nonreciprocal XY Model with Vision Cone Interactions.

We study a two-dimensional, nonreciprocal XY model, where each spin interacts only with its nearest neighbors in a certain angle around its current orientation, i.e., its "vision cone." Using energetic arguments and MonteCarlo simulations, we show that a true long-range ordered phase emerges. A necessary ingredient is a configuration-dependent bond dilution entailed by the vision cones. Strikingly, defects propagate in a directional manner, thereby breaking the parity and time-reversal symmetry of the spin dynamics. This is detectable by a nonzero entropy production rate.

Cones and cone pathways remain functional in advanced retinal degeneration

Most defects causing retinal degeneration in retinitis pigmentosa (RP) are rod-specific mutations, but the subsequent degeneration of cones, which produces loss of daylight vision and high-acuity perception, is the most debilitating feature of the disease. To understand better why cones degenerate and how cone vision might be restored, we have made the first single-cell recordings of light responses from degenerating conesand retinal interneurons after most rods have died and cones have lost their outer-segment disk membranes and synaptic pedicles. We show that degenerating cones have functional cyclic-nucleotide-gated channels and can continue to give light responses, apparently produced by opsin localized either to small areas of organized membrane near the ciliary axoneme or distributed throughout the inner segment. Light responses of second-order horizontal and bipolar cells are less sensitive but otherwise resemble those of normal retina. Furthermore, retinal output as reflected in responses of ganglion cells is less sensitive but maintains spatiotemporal receptive fields at cone-mediated light levels. Together, these findings show that cones and their retinal pathways can remain functional even as degeneration is progressing, an encouraging result for future research aimed at enhancing the light sensitivity of residual cones to restore vision in patients with genetically inherited retinal degeneration.

Volume-accumulated reflectivity of the outer retina (integral) on spectral domain optical coherence tomography as a predictor of cone cell density: a pilot study

BackgroundThe study aims to investigate the relationship between the volume-accumulated reflectivity (termed “integral”) on spectral domain optical coherence tomography (SD-OCT) and cone density on adaptive optics (AO) imaging.MethodsIn this cross-sectional study, both eyes of 32 healthy subjects and 5 patients with inherited retinal diseases (IRD) were studied. The parameter, integral, was defined as the volume-accumulated reflectivity values in a selected region on OCT images; integrals of the ellipsoid zone (EZ) and interdigitation zone (IZ) were measured at 2°, 3°, 4°, 5°and 6° eccentricity along the four meridians on fovea-centered OCT B-scans. Cone density in the same region was measured using a flood illumination adaptive optics camera RTX1.ResultsIntegrals of EZ, IZ and cone density shared similar distribution patterns. Integral of the IZ was better correlated with cone density in both healthy people (r = 0.968, p < 0.001) and those with IRD (r = 0.823, p < 0.001) than direct measurements of reflectivity on OCT images. A strong correlation was found between best corrected visual acuity (BCVA) and cone density at 2° eccentricity (r = -0.857, p = 0.002). BCVA was also correlated with the integral of the IZ at the foveola (r = -0.746, p = 0.013) and fovea (r = -0.822, p = 0.004).ConclusionsThe new parameter “integral” of the photoreceptor outer segment measured from SD-OCT was noted to correlate with cone density and visual function in this pilot study.

The evolution of the green-light-sensitive visual opsin genes (RH2) in teleost fishes

Vertebrates have four visual cone opsin classes that mediate sensitivity from ultraviolet to red wavelengths of light. The rhodopsin-like 2 (RH2) opsin is sensitive to the central mostly green part of the spectrum. While lost in some terrestrial vertebrates (mammals), the RH2 opsin gene has proliferated during the evolution of teleost fishes. Here, we investigated the genomes of 132 extant teleosts and found between zero and eight RH2 gene copies per species. The RH2 gene shows a dynamic evolutionary history with repeated gene duplications, gene losses, and gene conversions affecting entire orders, families, and species. At least four ancestral duplications provided the substrate for today’s RH2 diversity, with duplications occurring in the common ancestors of Clupeocephala (twice), Neoteleostei, and likely Acanthopterygii as well. Despite these evolutionary dynamics, we identified conserved RH2 synteny in two main gene clusters; the slc6A13/synpr cluster is highly conserved within Percomorpha and also present across most teleosts, including Otomorpha, Euteleostei and in parts in tarpons (Elopomorpha), and the mutSH5 cluster, which is specific for Otomorpha. When comparing the number of visual opsin genes (SWS1, SWS2, RH2, LWS, and total cone opsins) with habitat depth, we found that deeper-dwelling species had less (or none) long-wavelength-sensitive opsins. Using retinal/eye transcriptomes in a phylogenetic representative dataset of 32 species, we show that if present in the genome, RH2 is expressed in most fishes except for some species within the tarpons, characins, and gobies (and Osteoglossomorpha and some other characin species have lost the gene). Those species instead express a green-shifted long-wavelength-sensitive LWS opsin. Our study applies modern genomic and transcriptomic tools within a comparative framework to elucidate the evolutionary history of the visual sensory system in teleost fishes.

Müller glial cell photosensitivity: A novel function bringing higher complexity to vertebrate retinal physiology

The retina of vertebrates is responsible for detecting and capturing ambient light for image and non-image forming (NIF) functions through diverse projections to the brain which regulate visual processing, pupillary light responses, photic synchronization of circadian rhythms and suppression of pineal melatonin, among others. For this, vertebrates have retained through evolution at least two sets of photoreceptors specialized primarily in such visual and NIF tasks: visual photoreceptors cones and rods responsible for day/night vision, and intrinsically photosensitive retinal ganglion cells (ipRGC) together with horizontal cells in some vertebrates, expressing melanopsin (Opn4). Interestingly, Opn4 as well as encephalopsin (Opn3) and neuropsin (Opn5), responding to blue and UV light, respectively, are expressed in the inner retina and command light detection in the blue range of the visible spectra; they are responsible for a number of NIF functions still lacking characterization. Though most retinal photoreceptors are derived from ciliary or neuronal progenitor cells, in recent years Müller glial cells (MCs), the most abundant retinal glial cell type, have been shown to express different blue opsins (Opn3 and Opn5) and the photoisomerase retinal G protein-coupled receptor (RGR), and to respond directly to light. MCs display different essential functions to maintain the homeostasis and cell survival of the whole retina, contributing to glutamate metabolism and chromophore recycling. The novel photoreceptive capacity of MCs, mainly in the blue region, offers several highly intriguing possibilities that increase the complexity levels for light detection in the retina and its light-activated circuits, calling for further investigation. The goal of the present review is to discuss the state of the art of research on the principal macroglial cells in the retina, focusing mainly on the novel photic responses driven by MCs, the biochemical mechanisms triggered after light stimulation and their putative functions and implications.

Txnip Gene Therapy of Retinitis Pigmentosa Improves Cone Health.

Retinitis pigmentosa (RP) is a hereditary retinal degenerative disease that can lead to blindness. In RP, rod photoreceptors die first, followed by cone photoreceptors death due to unknown mechanisms. However, one clue for cone death concerns their metabolism. Early changes suggest that they do not have enough glucose, which normally fuels their metabolism. We sought to design adeno-associated virus (AAV)-based gene therapy to address their metabolic challenges and found that overexpressing Txnip is an effective gene therapy that extends cone survival and vision in three strains of RP mice. The Txnip-mediated rescue was found to be dependent upon lactate dehydrogenase b (Ldhb), which is required for lactate catabolism. Txnip also was found to improve mitochondrial health. Herein, we propose a model in which Txnip shifts cones from their normal reliance on glucose to enhanced utilization of lactate to benefit cones in a condition where the glucose supply is limiting.

Photoreceptor Function and Structure in Autosomal Dominant Vitelliform Macular Dystrophy Caused by BEST1 Mutations.

The purpose of this study was to evaluate rod and cone function and outer retinal structure within macular lesions, and surrounding extralesional areas of patients with autosomal dominant Best vitelliform macular dystrophy caused by BEST1 mutations. Seventeen patients from seven families were examined with dark- and light-adapted chromatic perimetry and optical coherence tomography. Subsets of patients had long-term follow-up (14-22 years, n = 6) and dark-adaptation kinetics measured (n = 5). Within central lesions with large serous retinal detachments, rod sensitivity was severely reduced but visual acuity and cone sensitivity were relatively retained. In surrounding extralesional areas, there was a mild but detectable widening of the subretinal space in some patients and some retinal areas. Available evidence was consistent with subretinal widening causing slower dark-adaptation kinetics. Over long-term follow-up, some eyes showed formation of de novo satellite lesions at retinal locations that years previously demonstrated subretinal widening. A subclinical abnormality consisting of a retina-wide mild thickening of the outer nuclear layer was evident in many patients and thickening increased in the subset of patients with long-term follow-up. Outcome measures for future clinical trials should include evaluations of rod sensitivity within central lesions and quantitative measures of outer retinal structure in normal-appearing regions surrounding the lesions.

The circadian clock mediates the response to oxidative stress in a cone photoreceptor‒like (661W) cell line via regulation of glutathione peroxidase activity.

Background: The mammalian retina contains an autonomous circadian clock that controls many physiological functions within this tissue. Our previous studies have indicated that disruption of this circadian clock by removing Bmal1 from the retina affects the visual function, retinal circuitry, and cone photoreceptor viability during aging. In the present study, we employed a mouse-derived cone photoreceptor‒like cell, 661W, to investigate which molecular mechanisms of the circadian clock may modulate cone photoreceptor viability during aging. Methods: Bmal1 knockout (BKO) cells were generated from 661W cells using the CRISPR/Cas9 gene editing tool. Deletion of Bmal1 from 661W was verified by western blot and monitoring Per2-luc bioluminescence circadian rhythms. To investigate the effect of Bmal1 removal on an oxidative stress challenge, cells were treated with hydrogen peroxide (H 2O 2,1 mM) for two hours and then cell viability was assessed. Cells were also cultured and harvested for gene expression analysis and antioxidant assay. Results: Our data indicated that 661W cells contain a functional circadian clock that mediates the response to an oxidative stress challenge in vitro and that such a response is no longer present in the BKO cell. We also hypothesized that the effect was due to the circadian regulation of the intracellular antioxidant defense mechanism.Our results revealed that in 661W cells, the antioxidant defense mechanism showed time dependent variation , whereas in BKO cells, there was an overall reduction in this antioxidant defense mechanism, and it no longer showed time dependent variation. Conclusions: Our work supported the notion that the presence of a functional circadian clock and its ability to modulate the response to an oxidative stress is the underlying mechanism that may protect cones during aging.

Cone of Vision as a Behavioural Cue for VR Collaboration

Mutual awareness of visual attention is essential for collaborative work. In the field of collaborative virtual environments (CVE), it has been proposed to use Field-of-View (FoV) frustum visualisations as a cue to support mutual awareness during collaboration. Recent studies on FoV frustum visualisations focus on asymmetric collaboration with AR/VR hardware setups and 3D reconstructed environments. In contrast, we focus on the general-purpose CVEs (i.e., VR shared offices), whose popularity is increasing due to the availability of low-cost headsets, and the restrictions imposed by the pandemic. In these CVEs collaboration roles are symmetrical, and the same 2D content available on desktop computers is displayed on 2D surfaces in a 3D space (VR screens). We prototyped one such CVE to evaluate FoV frustrum visualisation within this collaboration scenario. We also implement a FoV visualisation generated from an average fixation map (AFM), therefore directly generated by users' gaze behaviour which we call Cone of Vision (CoV). Our approach to displaying the frustum visualisations is tailored for 2D surfaces in 3D space and allows for self-awareness of this visual cue. We evaluate CoV in the context of a general exploratory data analysis (EDA) with 10 pairs of participants. Our findings indicate that CoV is beneficial during shifts between independent and collaborative work and supports collaborative progression across the visualisation. Self-perception of the CoV improves visual attention coupling, reduces the number of times users watch the collaborator's avatars and offers a consistent representation of the shared reality.

Zebrafish and inherited photoreceptor disease: Models and insights.

Photoreceptor dysfunctions and degenerative diseases are significant causes of vision loss in patients, with few effective treatments available. Targeted interventions to prevent or reverse photoreceptor-related vision loss are not possible without a thorough understanding of the underlying mechanism leading to disease, which is exceedingly difficult to accomplish in the human system. Cone diseases are particularly challenging to model, as some popular genetically modifiable model animals are nocturnal with a rod-dominant visual system and cones that have dissimilarities to human cones. As a result, cone diseases, which affect visual acuity, colour perception, and central vision in patients, are generally poorly understood in terms of pathology and mechanism. Zebrafish (Danio rerio) provide the opportunity to model photoreceptor diseases in a diurnal vertebrate with a cone-rich retina which develops many macular degeneration-like pathologies. Zebrafish undergo external development, allowing early-onset retinal diseases to be detected and studied, and many ophthalmic tools are available for zebrafish visual assessment during development and adulthood. There are numerous zebrafish models of photoreceptor disease, spanning the various types of photoreceptor disease (developmental, rod, cone, and mixed photoreceptor diseases) and genetic/molecular cause. In this review, we explore the features of zebrafish that make them uniquely poised to model cone diseases, summarize the established zebrafish models of inherited photoreceptor disease, and discuss how disease in these models compares to the human presentation, where applicable. Further, we highlight the contributions of these zebrafish models to our understanding of photoreceptor biology and disease, and discuss future directions for utilising and investigating these diverse models.

Circadian Regulation of the Rod Contribution to Mesopic Vision in Mice.

At intermediate (mesopic) light levels, rods and cones are both active and can contribute to vision. This presents a challenge to the retina because the visual responses originating with rods and cones are distinct, yet their visual responses must be seamlessly combined. The current study aimed to establish how the circadian clock regulates rod and/or cone vision in these conditions, given the strong time-of-day change in the reliance on each photoreceptor. Visual responses were recorded in the retina and visual thalamus of anaesthetized male mice at distinct circadian time points, and the method of receptor silent substitution was used to selectively stimulate different photoreceptor types. With stimuli designed to only activate rods, responses in the mesopic range were highly rhythmic and peaked in amplitude in the subjective night. This rhythm was abolished following intravitreal injection of the gap junction blocker meclofenamic acid, consistent with a circadian variation in the strength of electrical coupling of photoreceptors. In contrast, responses to stimuli designed to only activate cones were arrhythmic within the mesopic to photopic range when adapted to the background irradiance. The outcome was that combined rod-plus-cone responses showed a stable contrast-response relationship across mesopic-photopic backgrounds in the circadian day, whereas at night, responses were significantly amplified at lower light levels. These data support the idea that the circadian clock is a key regulator of vision, in this case defining the relative amplitude of rod/cone vision across the mesopic transition according to time of day.SIGNIFICANCE STATEMENT Although the importance of circadian clocks in regulating vision has been long recognized, less is known about how the clock shapes vision in conditions where both rods and cones are active (mesopic conditions). Here, the novel approach of receptor silent substitution has been applied to trace rod and cone visual responses in mice across the circadian cycle and has identified pronounced rhythms in rod, but not cone, vision. This has the effect of boosting responses in dimmer backgrounds at night at the cost of impaired contrast-response stability across the mesopic to photopic range. Thus, the circadian clock drives anticipatory changes in the relative contribution of rods versus cones to vision, which match the prevailing visual environment.

Intravitreal Fluocinolone Acetonide for Diabetic Macular Edema: Long-Term Effect and Structure/Function Correlation.

The long-term effect of intravitreal Fluocinolone acetonide (FAc) on retinal morphology and function in diabetic macular edema (DME) was investigated. Seventeen eyes of twelve consecutive DME patients, treated by intravitreal FAc, were retrospectively evaluated. Retinal morphology was assessed with central macular thickness (CMT). Retinal function was assessed by best-corrected visual acuity (BCVA) and cone b-wave and photopic negative response (PhNR). The main outcome was a mean change in CMT at month 24. The secondary outcomes were changes in cone b-wave and PhNR at month 24. The incidence of adverse events was also recorded. Mean CMT decreased from 406.52 µm (±138.74) at baseline to 310 µm (±130.39) at 24 months (p = 0.008). No significant changes in the other parameters were found. At baseline, BCVA and PhNR amplitude were negatively correlated (r = −0.55) with CMT. At the end of follow-up, the change in CMT was negatively correlated with baseline CMT (r = −0.53, p = 0.03) and positively correlated with baseline PhNR amplitude (r = 0.58, p < 0.01). A significant, long-term reduction in CMT was observed in DME patients after FAc implant. The anti-edema effect tended to be stronger in patients with the poorest baseline retinal morphology (CMT) and function (PhNR). Structure/function correlations might help to characterize the patients who may benefit from this treatment.