Responses Of Retinal Ganglion Cells Research Articles

Multifactorial Pathogenic Processes of Retinal Ganglion Cell Degeneration in Glaucoma towards Multi-Target Strategies for Broader Treatment Effects.

Glaucoma is a chronic neurodegenerative disease characterized by apoptosis of retinal ganglion cell (RGC) somas, degeneration of axons, and loss of synapses at dendrites and axon terminals. Glaucomatous neurodegeneration encompasses multiple triggers, multiple cell types, and multiple molecular pathways through the etiological paths with biomechanical, vascular, metabolic, oxidative, and inflammatory components. As much as intrinsic responses of RGCs themselves, divergent responses and intricate interactions of the surrounding glia also play decisive roles for the cell fate. Seen from a broad perspective, multitarget treatment strategies have a compelling pathophysiological basis to more efficiently manipulate multiple pathogenic processes at multiple injury sites in such a multifactorial neurodegenerative disease. Despite distinct molecular programs for somatic and axonal degeneration, mitochondrial dysfunction and glia-driven neuroinflammation present interdependent processes with widespread impacts in the glaucomatous retina and optic nerve. Since dysfunctional mitochondria stimulate inflammatory responses and proinflammatory mediators impair mitochondria, mitochondrial restoration may be immunomodulatory, while anti-inflammatory treatments protect mitochondria. Manipulation of these converging routes may thus allow a unified treatment strategy to protect RGC axons, somas, and synapses. This review presents an overview of recent research advancements with emphasis on potential treatment targets to achieve the best treatment efficacy to preserve visual function in glaucoma.

Melanopsin-driven pupil response in summer and winter in unipolar seasonal affective disorder

A retinal subsensitivity to environmental light may trigger Seasonal Affective Disorder (SAD) under low wintertime light conditions. The main aim of this study was to assess the responses of melanopsin-containing retinal ganglion cells in participants (N= 65) diagnosed with unipolar SAD compared to controls with no history of depression. Participants attended a summer visit, a winter visit, or both. Retinal responses to light were measured using the post-illumination pupil response (PIPR) to assess melanopsin-driven responses in the non-visual light input pathway. Linear mixed-effects modeling was used to test a group*season interaction on the Net PIPR (red minus blue light response, percent baseline). We observed a significant group*season interaction such that the PIPR decreased from summer to winter significantly in the SAD group while not in the control group. The SAD group PIPR was significantly lower in winter compared to controls but did not differ between groups in summer. Only 60% of the participants underwent an eye health exam, although all participants reported no history of retinal pathology, and eye exam status was neither associated with outcome nor different between groups. This seasonal variation in melanopsin driven non-visual responses to light may be a risk factor for SAD, and further highlights individual differences in responses to light for direct or indirect effects of light on mood.

Oxidative Stress and Hypoxia Modify Mitochondrial Homeostasis During Glaucoma.

Aims: Cellular response to hypoxia can include transition from respiration to glycolysis via upregulation of glycolytic enzymes and transporters, as well as mitophagy induction to eliminate surplus mitochondria. Our purpose was to evaluate the impact of hypoxia-inducible factor-1α (HIF-1α) stabilization on mitochondrial homeostasis and oxidative stress in a chronic model of glaucoma. Results: Retina and optic nerve (ON) were evaluated from young and aged DBA/2J (D2) glaucoma model mice and the control strain, the DBA/2-Gpnmb+. Hypoxic retinal ganglion cells (RGCs) were observed in young and aged D2 retina, with a significant increase in HIF-1α protein in the aged D2 retina. Reactive oxygen species observed in young D2 retina and ON were followed by significant decreases in antioxidant capacity in aged D2 retina and ON. HIF-1α targets such as neuron-specific glucose transporter-3 and lactate dehydrogenase were decreased or unchanged, respectively, in aged D2 retina despite an increased hypoxia response in RGCs. Mitochondrial mass was decreased in aged D2 retina concomitant with decreased mitochondrially encoded electron transport chain transcripts despite a stable nuclear-encoded TFAM (mitochondrial transcription factor), suggesting a breakdown in the nuclear-mitochondrial communication. Decreased mitophagy-associated proteins p62 and Rheb were observed in aged D2 retina, although p62 was significantly increased in the aged D2 ON. Innovation and Conclusion: The increased reactive oxygen species concomitant with HIF-1α upregulation despite reduced glucose transporters, mis-match of nuclear- and mitochondrial-encoded transcripts, and signs of reduced mitophagy suggest that retinas from D2 mice with chronic intraocular pressure elevation transition to pseudohypoxia without consistent metabolic reprogramming before significant RGC loss. Antioxid. Redox Signal. 35, 1341-1357.

The photopic negative response in autism spectrum disorder

ABSTRACT Clinical relevance To ascertain if the photopic negative response of the electroretinogram is different in autism spectrum disorder as a potential clinical marker. Background Visual function can be atypical in autism spectrum disorder and structural imaging of the ganglion cell layers has been reported to differ in these individuals. Therefore, we sought to investigate if the photopic negative response of the full field electroretinograms, a measure of ganglion cell function, could help explain the visual perceptual differences in autism spectrum disorder and support the structural changes observed. Methods Participants (n = 55 autism spectrum disorder, aged 5.4–26.7 years) and control (n = 87, aged 5.4–27.3 years) were recruited for the study. Full-field light-adapted electroretinograms using a Troland protocol with 10 flash strengths from −0.367 to 1.204 log photopic cd.s.m−2 were recorded in each eye. The photopic negative response amplitudes at Tmin and at t = 72 ms were compared between groups along with the a- and b-wave values. Results There were no significant interactions between groups for the Photopic Negative Response measures of amplitude or time (p > 0.30). There was a group interaction between groups and flash strengths for the b-wave amplitude as previously reported (p < 0.001). Conclusion The photopic negative response results suggest that there are no significant differences in the summed retinal ganglion cell responses produced by a full-field stimulus.

Restoration of visual function in advanced disease after transplantation of purified human pluripotent stem cell-derived cone photoreceptors.

SummaryAge-related macular degeneration and other macular diseases result in the loss of light-sensing cone photoreceptors, causing irreversible sight impairment. Photoreceptor replacement may restore vision by transplanting healthy cells, which must form new synaptic connections with the recipient retina. Despite recent advances, convincing evidence of functional connectivity arising from transplanted human cone photoreceptors in advanced retinal degeneration is lacking. Here, we show restoration of visual function after transplantation of purified human pluripotent stem cell-derived cones into a mouse model of advanced degeneration. Transplanted human cones elaborate nascent outer segments and make putative synapses with recipient murine bipolar cells (BCs), which themselves undergo significant remodeling. Electrophysiological and behavioral assessments demonstrate restoration of surprisingly complex light-evoked retinal ganglion cell responses and improved light-evoked behaviors in treated animals. Stringent controls exclude alternative explanations, including material transfer and neuroprotection. These data provide crucial validation for photoreceptor replacement therapy and for the potential to rescue cone-mediated vision.

Retinal Ganglion Cells Functional Changes in a Mouse Model of Alzheimer's Disease Are Linked with Neurotransmitter Alterations.

Alzheimer's disease (AD) is the most prevalent form of dementia worldwide. This neurodegenerative syndrome affects cognition, memory, behavior, and the visual system, particularly the retina. This work aims to determine whether the 5xFAD mouse, a transgenic model of AD, displays changes in the function of retinal ganglion cells (RGCs) and if those alterations are correlated with changes in the expression of glutamate and gamma-aminobutyric acid (GABA) neurotransmitters. In young (2-3-month-old) and adult (6-7-month-old) 5xFAD and WT mice, we have studied the physiological response, firing rate, and burst of RGCs to various types of visual stimuli using a multielectrode array system. The firing rate and burst response in 5xFAD RGCs showed hyperactivity at the early stage of AD in young mice, whereas hypoactivity was seen at the later stage of AD in adults. The physiological alterations observed in 5xFAD correlate well with an increase in the expression of glutamate in the ganglion cell layer in young and adults. GABA staining increased in the inner nuclear and plexiform layer, which was more pronounced in the adult than the young 5xFAD retina, altering the excitation/inhibition balance, which could explain the observed early hyperactivity and later hypoactivity in RGC physiology. These findings indicate functional changes may be caused by neurochemical alterations of the retina starting at an early stage of the AD disease.

Nonlinear Spatial Integration Underlies the Diversity of Retinal Ganglion Cell Responses to Natural Images.

How neurons encode natural stimuli is a fundamental question for sensory neuroscience. In the early visual system, standard encoding models assume that neurons linearly filter incoming stimuli through their receptive fields, but artificial stimuli, such as contrast-reversing gratings, often reveal nonlinear spatial processing. We investigated to what extent such nonlinear processing is relevant for the encoding of natural images in retinal ganglion cells in mice of either sex. We found that standard linear receptive field models yielded good predictions of responses to flashed natural images for a subset of cells but failed to capture the spiking activity for many others. Cells with poor model performance displayed pronounced sensitivity to fine spatial contrast and local signal rectification as the dominant nonlinearity. By contrast, sensitivity to high-frequency contrast-reversing gratings, a classical test for nonlinear spatial integration, was not a good predictor of model performance and thus did not capture the variability of nonlinear spatial integration under natural images. In addition, we also observed a class of nonlinear ganglion cells with inverse tuning for spatial contrast, responding more strongly to spatially homogeneous than to spatially structured stimuli. These findings highlight the diversity of receptive field nonlinearities as a crucial component for understanding early sensory encoding in the context of natural stimuli.SIGNIFICANCE STATEMENT Experiments with artificial visual stimuli have revealed that many types of retinal ganglion cells pool spatial input signals nonlinearly. However, it is still unclear how relevant this nonlinear spatial integration is when the input signals are natural images. Here we analyze retinal responses to natural scenes in large populations of mouse ganglion cells. We show that nonlinear spatial integration strongly influences responses to natural images for some ganglion cells, but not for others. Cells with nonlinear spatial integration were sensitive to spatial structure inside their receptive fields, and a small group of cells displayed a surprising sensitivity to spatially homogeneous stimuli. Traditional analyses with contrast-reversing gratings did not predict this variability of nonlinear spatial integration under natural images.

Influence of Retinal Degeneration Stages on RGC Threshold under epiretinal electrical stimulation: A Modeling Study

Retinal prosthesis is an effective treatment to restore partial functional vision for degeneration diseases such as retinitis pigmentosa (RP). The persistent degeneration of the retina can influence the effect of retina prosthesis. However, how the different stages of retinal degeneration influence the retinal ganglion cell (RGC) responses to external electric stimulation remains unclear. In our present study, we established the multilayer retinal model of normal mouse and retinal degeneration (rd1) mouse in different degeneration stages (early, middle and late stage). Meanwhile, the morphology-realistic RGC models with membrane dynamics in different degeneration stages were also established. The effects of retinal structure, ganglion cell morphology and Na+ conductance on RGC threshold in response to electrical stimulation were explored. The simulation results showed that the RGC threshold of early degeneration stage was basically the same as that of the normal retina. While the thresholds of middle and late degeneration stages were both higher than that of the early stage, and the late stage showed a higher RGC threshold than the middle stage. This study would provide theoretical support for personalizing design of visual prostheses to treat different degeneration stages of RP patients.

Distributed chromatic processing at the interface between retina and brain in the larval zebrafish

Larval zebrafish (Danio rerio) are an ideal organism for studying color vision, as their retina possesses four types of cone photoreceptors, covering most of the visible range and into the UV.1,2 Additionally, their eye and nervous systems are accessible to imaging, given that they are naturally transparent.3-5 Recent studies have found that, through a set of wavelength-range-specific horizontal, bipolar, and retinal ganglion cells (RGCs),6-9 the eye relays tetrachromatic information to several retinorecipient areas (RAs).10-13 The main RA is the optic tectum, receiving 97% of the RGC axons via the neuropil mass termed arborization field 10 (AF10).14,15 Here, we aim to understand the processing of chromatic signals at the interface between RGCs and their major brain targets. We used 2-photon calcium imaging to separately measure the responses of RGCs and neurons in the brain to four different chromatic stimuli in awake animals. We find that chromatic information is widespread throughout the brain, with a large variety of responses among RGCs, and an even greater diversity in their targets. Specific combinations of response types are enriched in specific nuclei, but there is no single color processing structure. In the main interface in this pathway, the connection between AF10 and tectum, we observe key elements of neural processing, such as enhanced signal decorrelation and improved chromatic decoding.16,17 A richer stimulus set revealed that these enhancements occur in the context of a more distributed code in tectum, facilitating chromatic signal association in this small vertebrate brain.

Retinal ganglion cell dysfunction in mice following acute intraocular pressure is exacerbated by P2X7 receptor knockout

There is increasing evidence for the vulnerability of specific retinal ganglion cell (RGC) types in those with glaucoma and in animal models. In addition, the P2X7-receptor (P2X7-R) has been suggested to contribute to RGC death following stimulation and elevated IOP, though its role in RGC dysfunction prior to death has not been examined. Therefore, we examined the effect of an acute, non-ischemic intraocular pressure (IOP) insult (50 mmHg for 30 min) on RGC function in wildtype mice and P2X7-R knockout (P2X7-KO) mice. We examined retinal function using electroretinogram recordings and individual RGC responses using multielectrode arrays, 3 days following acute IOP elevation. Immunohistochemistry was used to examine RGC cell death and P2X7-R expression in several RGC types. Acute intraocular pressure elevation produced pronounced dysfunction in RGCs; whilst other retinal neuronal responses showed lesser changes. Dysfunction at 3 days post-injury was not associated with RGC loss or changes in receptive field size. However, in wildtype animals, OFF-RGCs showed reduced spontaneous and light-elicited activity. In the P2X7-KO, both ON- and OFF-RGC light-elicited responses were reduced. Expression of P2X7-R in wildtype ON-RGC dendrites was higher than in other RGC types. In conclusion, OFF-RGCs were vulnerable to acute IOP elevation and their dysfunction was not rescued by genetic ablation of P2X7-R. Indeed, knockout of P2X7-R also caused ON-RGC dysfunction. These findings aid our understanding of how pressure affects RGC function and suggest treatments targeting the P2X7-R need to be carefully considered.

Naturalistic spatiotemporal modulation of epiretinal stimulation increases the response persistence of retinal ganglion cell

Objective. Retinal stimulation in blind patients evokes the sensation of discrete points of light called phosphenes, which allows them to perform visually guided tasks, such as orientation, navigation, object recognition, object manipulation and reading. However, the clinical benefit of artificial vision in profoundly blind patients is still tenuous, as several engineering and biophysical obstacles keep it far away from natural perception. The relative preservation of the inner retinal neurons in hereditary degenerative retinal diseases, such as retinitis pigmentosa, supports artificial vision through the network-mediated stimulation of retinal ganglion cells (RGCs). However, the response of RGCs to repeated electrical stimulation rapidly declines, primarily because of the intrinsic desensitisation of their excitatory network. In patients, upon repetitive stimulation, phosphenes fade out in less than half of a second, which drastically limits the understanding of the percept. Approach. A more naturalistic stimulation strategy, based on spatiotemporal modulation of electric pulses, could overcome the desensitisation of RGCs. To investigate this hypothesis, we performed network-mediated epiretinal stimulations paired to electrophysiological recordings in retinas explanted from both male and female retinal degeneration 10 mice. Main results. The results showed that the spatial and temporal modulation of the network-mediated epiretinal stimulation prolonged the persistence of the RGC’s response from 400 ms up to 4.2 s. Significance. A time-varied, non-stationary and interrupted stimulation of the retinal network, mimicking involuntary microsaccades, might reduce the fading of the visual percept and improve the clinical efficacy of retinal implants.

Optogenetic therapy: high spatiotemporal resolution and pattern discrimination compatible with vision restoration in non-human primates

Vision restoration is an ideal medical application for optogenetics, because the eye provides direct optical access to the retina for stimulation. Optogenetic therapy could be used for diseases involving photoreceptor degeneration, such as retinitis pigmentosa or age-related macular degeneration. We describe here the selection, in non-human primates, of a specific optogenetic construct currently tested in a clinical trial. We used the microbial opsin ChrimsonR, and showed that the AAV2.7m8 vector had a higher transfection efficiency than AAV2 in retinal ganglion cells (RGCs) and that ChrimsonR fused to tdTomato (ChR-tdT) was expressed more efficiently than ChrimsonR. Light at 600 nm activated RGCs transfected with AAV2.7m8 ChR-tdT, from an irradiance of 1015 photons.cm−2.s−1. Vector doses of 5 × 1010 and 5 × 1011 vg/eye transfected up to 7000 RGCs/mm2 in the perifovea, with no significant immune reaction. We recorded RGC responses from a stimulus duration of 1 ms upwards. When using the recorded activity to decode stimulus information, we obtained an estimated visual acuity of 20/249, above the level of legal blindness (20/400). These results lay the groundwork for the ongoing clinical trial with the AAV2.7m8 - ChR-tdT vector for vision restoration in patients with retinitis pigmentosa.

TRPV1 Supports Axogenic Enhanced Excitability in Response to Neurodegenerative Stress.

Early progression in neurodegenerative disease involves challenges to homeostatic processes, including those controlling axonal excitability and dendritic organization. In glaucoma, the leading cause of irreversible blindness, stress from intraocular pressure (IOP) causes degeneration of retinal ganglion cells (RGC) and their axons which comprise the optic nerve. Previously, we discovered that early progression induces axogenic, voltage-gated enhanced excitability of RGCs, even as dendritic complexity in the retina reduces. Here, we investigate a possible contribution of the transient receptor potential vanilloid type 1 (TRPV1) channel to enhanced excitability, given its role in modulating excitation in other neural systems. We find that genetic deletion of Trpv1 (Trpv1−/−) influences excitability differently for RGCs firing continuously to light onset (αON-Sustained) vs. light offset (αOFF-Sustained). Deletion drives excitability in opposing directions so that Trpv1−/− RGC responses with elevated IOP equalize to that of wild-type (WT) RGCs without elevated IOP. Depolarizing current injections in the absence of light-driven presynaptic excitation to directly modulate voltage-gated channels mirrored these changes, while inhibiting voltage-gated sodium channels and isolating retinal excitatory postsynaptic currents abolished both the differences in light-driven activity between WT and Trpv1−/− RGCs and changes in response due to IOP elevation. Together, these results support a voltage-dependent, axogenic influence of Trpv1−/− with elevated IOP. Finally, Trpv1−/− slowed the loss of dendritic complexity with elevated IOP, opposite its effect on axon degeneration, supporting the idea that axonal and dendritic degeneration follows distinctive programs even at the level of membrane excitability.

Regulation of distinct caspase-8 functions in retinal ganglion cells and astroglia in experimental glaucoma

Retinal ganglion cells (RGCs) expanding from the retina to the brain are primary victims of neurodegeneration in glaucoma, a leading cause of blindness; however, the neighboring astroglia survive the glaucoma-related stress and promote neuroinflammation. In light of diverse functions of caspase-8 in apoptosis, cell survival, and inflammation, this study investigated the importance of caspase-8 in different fates of glaucomatous RGCs and astroglia using two experimental approaches in parallel. In the first approach, cell type-specific responses of RGCs and astroglia to a caspase-8 cleavage-inhibiting pharmacological treatment were studied in rat eyes with or without experimentally induced glaucoma. The second approach utilized an experimental model of glaucoma in mice in which astroglial caspase-8 was conditionally deleted by cre/lox. Findings of these experiments revealed cell type-specific distinct processes that regulate caspase-8 functions in experimental glaucoma, which are involved in inducing the apoptosis of RGCs and promoting the survival and inflammatory responses of astroglia. Deletion of caspase-8 in astroglia protected RGCs against glia-driven inflammatory injury, while the inhibition of caspase-8 cleavage inhibited apoptosis in RGCs themselves. Various caspase-8 functions impacting both RGC apoptosis and astroglia-driven neuroinflammation may suggest the multi-target potential of caspase-8 regulation to provide neuroprotection and immunomodulation in glaucoma.

Quercetin Regulates Inflammatory Response of Retinal Ganglion Cells by Affecting the Tumor Necrosis Factor Receptor Associated Factor 6/Transforming Growth Factor-β-Activated Kinase-1 Signaling Pathway

To investigate the protective effect of quercetin on the lipopolysaccharide-induced inflammatory response of retinal ganglion cell line 5 cells and to explore its possible molecular mechanism. Retinal ganglion cell line 5 cells were cultured in vitro and assigned into blank control group, lipopolysaccharide (1.0 μg/ml) induction group, lipopolysaccharide+low dose (0.25 μg/ml) quercetin group, lipopolysaccharide+medium dose (0.5 μg/ml) quercetin group and lipopolysaccharide+high dose (1.0 μg/ml) quercetin group. The relative survival rate of retinal ganglion cell line 5 cells was determined by cell counting kit-8 assay and the levels of inflammatory factors interleukin-6 and tumor necrosis factor-alpha were detected using enzymelinked immunosorbent assay kits. In addition, the levels of tumor necrosis factor receptor-associated factor 6, phosphorylation-transforming growth factor-beta-activated kinase 1 and transforming growth factorbeta- activated kinase 1 were measured by western blotting. The results of cell counting kit-8 assay revealed that quercetin could dramatically elevate the relative survival rate of retinal ganglion cell line 5 cells. The levels of inflammatory factors interleukin-6 and tumor necrosis factor-alpha in different quercetin groups were significantly lower than those in lipopolysaccharide induction group and the levels of interleukin-6 and tumor necrosis factor-alpha in cell supernatant declined with the increase of quercetin concentration in a concentration-dependent manner. In addition, the expression levels of tumor necrosis factor receptorassociated factor 6 and phosphorylation-transforming growth factor-beta-activated kinase 1 in different quercetin groups were remarkably lower than those in lipopolysaccharide induction group and they also declined with the increase of quercetin concentration in a concentration-dependent manner. Quercetin displays a protective effect against the lipopolysaccharide-induced inflammatory response of retinal ganglion cell line 5 cells and its mechanism is related to suppression of the activation of the tumor necrosis factor receptor-associated factor 6/transforming growth factor-beta-activated kinase 1 signaling pathway.

A Data‐Driven and Biologically Inspired Preprocessing Scheme to Improve Visual Object Recognition

Autonomous object recognition in images is one of the most critical topics in security and commercial applications. Due to recent advances in visual neuroscience, the researchers tend to extend biologically plausible schemes to improve the accuracy of object recognition. Preprocessing is one part of the visual recognition system that has received much less attention. In this paper, we propose a new, simple, and biologically inspired pre processing technique by using the data‐driven mechanism of visual attention. In this part, the responses of Retinal Ganglion Cells (RGCs) are simulated. After obtaining these responses, an efficient threshold is selected. Then, the points of the raw image with the most information are extracted according to it. Then, the new images with these points are created, and finally, by combining these images with entropy coefficients, the most salient object is located. After extracting appropriate features, the classifier categorizes the initial image into one of the predefined object categories. Our system was evaluated on the Caltech‐101 dataset. Experimental results demonstrate the efficacy and effectiveness of this novel method of preprocessing.

Decoding network-mediated retinal response to electrical stimulation: implications for fidelity of prosthetic vision

Objective. Patients with photovoltaic subretinal implant PRIMA demonstrated letter acuity ∼0.1 logMAR worse than sampling limit for 100 μm pixels (1.3 logMAR) and performed slower than healthy subjects tested with equivalently pixelated images. To explore the underlying differences between natural and prosthetic vision, we compare the fidelity of retinal response to visual and subretinal electrical stimulation through single-cell modeling and ensemble decoding. Approach. Responses of retinal ganglion cells (RGCs) to optical or electrical white noise stimulation in healthy and degenerate rat retinas were recorded via multi-electrode array. Each RGC was fit with linear–nonlinear and convolutional neural network models. To characterize RGC noise, we compared statistics of spike-triggered averages (STAs) in RGCs responding to electrical or visual stimulation of healthy and degenerate retinas. At the population level, we constructed a linear decoder to determine the accuracy of the ensemble of RGCs on N-way discrimination tasks. Main results. Although computational models can match natural visual responses well (correlation ∼0.6), they fit significantly worse to spike timings elicited by electrical stimulation of the healthy retina (correlation ∼0.15). In the degenerate retina, response to electrical stimulation is equally bad. The signal-to-noise ratio of electrical STAs in degenerate retinas matched that of the natural responses when 78 ± 6.5% of the spikes were replaced with random timing. However, the noise in RGC responses contributed minimally to errors in ensemble decoding. The determining factor in accuracy of decoding was the number of responding cells. To compensate for fewer responding cells under electrical stimulation than in natural vision, more presentations of the same stimulus are required to deliver sufficient information for image decoding. Significance. Slower-than-natural pattern identification by patients with the PRIMA implant may be explained by the lower number of electrically activated cells than in natural vision, which is compensated by a larger number of the stimulus presentations.

Reconstruction of natural images from responses of primate retinal ganglion cells.

The visual message conveyed by a retinal ganglion cell (RGC) is often summarized by its spatial receptive field, but in principle also depends on the responses of other RGCs and natural image statistics. This possibility was explored by linear reconstruction of natural images from responses of the four numerically-dominant macaque RGC types. Reconstructions were highly consistent across retinas. The optimal reconstruction filter for each RGC - its visual message - reflected natural image statistics, and resembled the receptive field only when nearby, same-type cells were included. ON and OFF cells conveyed largely independent, complementary representations, and parasol and midget cells conveyed distinct features. Correlated activity and nonlinearities had statistically significant but minor effects on reconstruction. Simulated reconstructions, using linear-nonlinear cascade models of RGC light responses that incorporated measured spatial properties and nonlinearities, produced similar results. Spatiotemporal reconstructions exhibited similar spatial properties, suggesting that the results are relevant for natural vision.

Targeted Stimulation of Retinal Ganglion Cells in Epiretinal Prostheses: A Multiscale Computational Study.

Retinal prostheses aim at restoring partial sight to patients that are blind due to retinal degenerative diseases by electrically stimulating the surviving healthy retinal neurons. Ideally, the electrical stimulation of the retina is intended to induce localized, focused, percepts only; however, some epiretinal implant subjects have reported seeing elongated phosphenes in a single electrode stimulation due to the axonal activation of retinal ganglion cells (RGCs). This issue can be addressed by properly devising stimulation waveforms so that the possibility of inducing axonal activation of RGCs is minimized. While strategies to devise electrical stimulation waveforms to achieve a focal RGCs response have been reported in literature, the underlying mechanisms are not well understood. This article intends to address this gap; we developed morphologically and biophysically realistic computational models of two classified RGCs: D1-bistratified and A2-monostratified. Computational results suggest that the sodium channel band (SOCB) is less sensitive to modulations in stimulation parameters than the distal axon (DA), and DA stimulus threshold is less sensitive to physiological differences among RGCs. Therefore, over a range of RGCs distal axon diameters, short-pulse symmetric biphasic waveforms can enhance the stimulation threshold difference between the SOCB and the DA. Appropriately designed waveforms can avoid axonal activation of RGCs, implying a consequential reduction of undesired strikes in the visual field.

Intraocular Pressure Elevation Compromises Retinal Ganglion Cell Light Adaptation.

PurposeFunctional adaptation to ambient light is a key characteristic of retinal ganglion cells (RGCs), but little is known about how adaptation is affected by factors that are harmful to RGC health. We explored adaptation-induced changes to RGC physiology when exposed to increased intraocular pressure (IOP), a major risk factor for glaucoma.MethodsWild-type mice of both sexes were subjected to 2 weeks of IOP elevation using the bead model. Retinas were assessed using a multielectrode array to record RGC responses to checkerboard white noise stimulation under both scotopic and photopic light levels. This information was used to calculate a spike-triggered average (STA) for each RGC with which to compare between lighting levels.ResultsLow but not high IOP elevation resulted in several distinct RGC functional changes: (1) diminished adaptation-dependent receptive field (RF) center-surround interactions; (2) increased likelihood of a scotopic STA; and (3) increased spontaneous firing rate. Center RF size change with lighting level varied among RGCs, and both the center and surround STA peak times were consistently increased under scotopic illumination, although none of these properties were impacted by IOP level.ConclusionsThese findings provide novel evidence that RGCs exhibit reduced light-dependent adaptation and increased excitability when IOP is elevated to low but not high levels. These results may reveal functional changes that occur early in glaucoma, which can potentially be used to identify patients with glaucoma at earlier stages when intervention is most beneficial.