Browsing by Subject "Retinal Ganglion Cells"
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Item Open Access A polyaxonal amacrine cell population in the primate retina.(The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014-03) Greschner, Martin; Field, Greg D; Li, Peter H; Schiff, Max L; Gauthier, Jeffrey L; Ahn, Daniel; Sher, Alexander; Litke, Alan M; Chichilnisky, EJAmacrine cells are the most diverse and least understood cell class in the retina. Polyaxonal amacrine cells (PACs) are a unique subset identified by multiple long axonal processes. To explore their functional properties, populations of PACs were identified by their distinctive radially propagating spikes in large-scale high-density multielectrode recordings of isolated macaque retina. One group of PACs exhibited stereotyped functional properties and receptive field mosaic organization similar to that of parasol ganglion cells. These PACs had receptive fields coincident with their dendritic fields, but much larger axonal fields, and slow radial spike propagation. They also exhibited ON-OFF light responses, transient response kinetics, sparse and coordinated firing during image transitions, receptive fields with antagonistic surrounds and fine spatial structure, nonlinear spatial summation, and strong homotypic neighbor electrical coupling. These findings reveal the functional organization and collective visual signaling by a distinctive, high-density amacrine cell population.Item Open Access Anatomical identification of extracellularly recorded cells in large-scale multielectrode recordings.(J Neurosci, 2015-03-18) Li, Peter H; Gauthier, Jeffrey L; Schiff, Max; Sher, Alexander; Ahn, Daniel; Field, Greg D; Greschner, Martin; Callaway, Edward M; Litke, Alan M; Chichilnisky, EJThis study combines for the first time two major approaches to understanding the function and structure of neural circuits: large-scale multielectrode recordings, and confocal imaging of labeled neurons. To achieve this end, we develop a novel approach to the central problem of anatomically identifying recorded cells, based on the electrical image: the spatiotemporal pattern of voltage deflections induced by spikes on a large-scale, high-density multielectrode array. Recordings were performed from identified ganglion cell types in the macaque retina. Anatomical images of cells in the same preparation were obtained using virally transfected fluorescent labeling or by immunolabeling after fixation. The electrical image was then used to locate recorded cell somas, axon initial segments, and axon trajectories, and these signatures were used to identify recorded cells. Comparison of anatomical and physiological measurements permitted visualization and physiological characterization of numerically dominant ganglion cell types with high efficiency in a single preparation.Item Open Access Calcineurin activation causes retinal ganglion cell degeneration.(Mol Vis, 2012) Qu, Juan; Matsouaka, Roland; Betensky, Rebecca A; Hyman, Bradley T; Grosskreutz, Cynthia LPURPOSE: We previously reported that calcineurin, a Ca(2+)/calmodulin-dependent serine/threonine phosphatase, is activated and proposed that it participates in retinal ganglion cell (RGC) apoptosis in two rodent ocular hypertension models. In this study, we tested whether calcineurin activation by itself, even in the absence of ocular hypertension, is sufficient to cause RGC degeneration. METHODS: We compared RGC and optic nerve morphology after adeno-associated virus serotype 2 (AAV2)-mediated transduction of RGCs with constitutively active calcineurin (CaNCA) or unactivated, wild-type calcineurin (CaNwt). Retinas and optic nerves were harvested 7-16 weeks after injection of the AAV into mouse vitreous. In flatmounted retinas, the transduced RGCs were identified with immunohistochemistry. The morphology of the RGCs was revealed by immunostaining for neurofilament SMI32 or by using GFP-M transgenic mice. A modified Sholl analysis was applied to analyze the RGC dendritic morphology. Optic nerve damage was assessed with optic nerve grading according to the Morrison standard. RESULTS: CaNwt and CaNCA were highly expressed in the injected eyes. Compared to the CaNwt-expressing RGCs, the CaNCA-expressing RGCs had smaller somas, smaller dendritic field areas, shorter total dendrite lengths, and simpler dendritic branching patterns. At 16 weeks, the CaNCA-expressing eyes had greater optic nerve damage than the CaNwt-expressing eyes. CONCLUSIONS: Calcineurin activation is sufficient to cause RGC dendritic degeneration and optic nerve damage. These data support the hypothesis that calcineurin activation is an important mediator of RGC degeneration, and are consistent with the hypothesis that calcineurin activation may contribute to RGC neurodegeneration in glaucoma.Item Open Access Cell type-specific changes in retinal ganglion cell function induced by rod death and cone reorganization in rats.(Journal of neurophysiology, 2017-07) Yu, Wan-Qing; Grzywacz, Norberto M; Lee, Eun-Jin; Field, Greg DWe have determined the impact of rod death and cone reorganization on the spatiotemporal receptive fields (RFs) and spontaneous activity of distinct retinal ganglion cell (RGC) types. We compared RGC function between healthy and retinitis pigmentosa (RP) model rats (S334ter-3) at a time when nearly all rods were lost but cones remained. This allowed us to determine the impact of rod death on cone-mediated visual signaling, a relevant time point because the diagnosis of RP frequently occurs when patients are nightblind but daytime vision persists. Following rod death, functionally distinct RGC types persisted; this indicates that parallel processing of visual input remained largely intact. However, some properties of cone-mediated responses were altered ubiquitously across RGC types, such as prolonged temporal integration and reduced spatial RF area. Other properties changed in a cell type-specific manner, such as temporal RF shape (dynamics), spontaneous activity, and direction selectivity. These observations identify the extent of functional remodeling in the retina following rod death but before cone loss. They also indicate new potential challenges to restoring normal vision by replacing lost rod photoreceptors.NEW & NOTEWORTHY This study provides novel and therapeutically relevant insights to retinal function following rod death but before cone death. To determine changes in retinal output, we used a large-scale multielectrode array to simultaneously record from hundreds of retinal ganglion cells (RGCs). These recordings of large-scale neural activity revealed that following the death of all rods, functionally distinct RGCs remain. However, the receptive field properties and spontaneous activity of these RGCs are altered in a cell type-specific manner.Item Open Access Correlated firing among major ganglion cell types in primate retina.(The Journal of physiology, 2011-01) Greschner, Martin; Shlens, Jonathon; Bakolitsa, Constantina; Field, Greg D; Gauthier, Jeffrey L; Jepson, Lauren H; Sher, Alexander; Litke, Alan M; Chichilnisky, EJRetinal ganglion cells exhibit substantial correlated firing: a tendency to fire nearly synchronously at rates different from those expected by chance. These correlations suggest that network interactions significantly shape the visual signal transmitted from the eye to the brain. This study describes the degree and structure of correlated firing among the major ganglion cell types in primate retina. Correlated firing among ON and OFF parasol, ON and OFF midget, and small bistratified cells, which together constitute roughly 75% of the input to higher visual areas, was studied using large-scale multi-electrode recordings. Correlated firing in the presence of constant, spatially uniform illumination exhibited characteristic strength, time course and polarity within and across cell types. Pairs of nearby cells with the same light response polarity were positively correlated; cells with the opposite polarity were negatively correlated. The strength of correlated firing declined systematically with distance for each cell type, in proportion to the degree of receptive field overlap. The pattern of correlated firing across cell types was similar at photopic and scotopic light levels, although additional slow correlations were present at scotopic light levels. Similar results were also observed in two other retinal ganglion cell types. Most of these observations are consistent with the hypothesis that shared noise from photoreceptors is the dominant cause of correlated firing. Surprisingly, small bistratified cells, which receive ON input from S cones, fired synchronously with ON parasol and midget cells, which receive ON input primarily from L and M cones. Collectively, these results provide an overview of correlated firing across cell types in the primate retina, and constraints on the underlying mechanisms.Item Open Access Efficient coding of spatial information in the primate retina.(The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012-11) Doi, Eizaburo; Gauthier, Jeffrey L; Field, Greg D; Shlens, Jonathon; Sher, Alexander; Greschner, Martin; Machado, Timothy A; Jepson, Lauren H; Mathieson, Keith; Gunning, Deborah E; Litke, Alan M; Paninski, Liam; Chichilnisky, EJ; Simoncelli, Eero PSensory neurons have been hypothesized to efficiently encode signals from the natural environment subject to resource constraints. The predictions of this efficient coding hypothesis regarding the spatial filtering properties of the visual system have been found consistent with human perception, but they have not been compared directly with neural responses. Here, we analyze the information that retinal ganglion cells transmit to the brain about the spatial information in natural images subject to three resource constraints: the number of retinal ganglion cells, their total response variances, and their total synaptic strengths. We derive a model that optimizes the transmitted information and compare it directly with measurements of complete functional connectivity between cone photoreceptors and the four major types of ganglion cells in the primate retina, obtained at single-cell resolution. We find that the ganglion cell population exhibited 80% efficiency in transmitting spatial information relative to the model. Both the retina and the model exhibited high redundancy (~30%) among ganglion cells of the same cell type. A novel and unique prediction of efficient coding, the relationships between projection patterns of individual cones to all ganglion cells, was consistent with the observed projection patterns in the retina. These results indicate a high level of efficiency with near-optimal redundancy in visual signaling by the retina.Item Open Access Functional connectivity in the retina at the resolution of photoreceptors.(Nature, 2010-10) Field, Greg D; Gauthier, Jeffrey L; Sher, Alexander; Greschner, Martin; Machado, Timothy A; Jepson, Lauren H; Shlens, Jonathon; Gunning, Deborah E; Mathieson, Keith; Dabrowski, Wladyslaw; Paninski, Liam; Litke, Alan M; Chichilnisky, EJTo understand a neural circuit requires knowledge of its connectivity. Here we report measurements of functional connectivity between the input and ouput layers of the macaque retina at single-cell resolution and the implications of these for colour vision. Multi-electrode technology was used to record simultaneously from complete populations of the retinal ganglion cell types (midget, parasol and small bistratified) that transmit high-resolution visual signals to the brain. Fine-grained visual stimulation was used to identify the location, type and strength of the functional input of each cone photoreceptor to each ganglion cell. The populations of ON and OFF midget and parasol cells each sampled the complete population of long- and middle-wavelength-sensitive cones. However, only OFF midget cells frequently received strong input from short-wavelength-sensitive cones. ON and OFF midget cells showed a small non-random tendency to selectively sample from either long- or middle-wavelength-sensitive cones to a degree not explained by clumping in the cone mosaic. These measurements reveal computations in a neural circuit at the elementary resolution of individual neurons.Item Open Access Global Motion Processing by Populations of Direction-Selective Retinal Ganglion Cells.(The Journal of neuroscience : the official journal of the Society for Neuroscience, 2020-07) Cafaro, Jon; Zylberberg, Joel; Field, Greg DSimple stimuli have been critical to understanding neural population codes in sensory systems. Yet it remains necessary to determine the extent to which this understanding generalizes to more complex conditions. To examine this problem, we measured how populations of direction-selective ganglion cells (DSGCs) from the retinas of male and female mice respond to a global motion stimulus with its direction and speed changing dynamically. We then examined the encoding and decoding of motion direction in both individual and populations of DSGCs. Individual cells integrated global motion over ∼200 ms, and responses were tuned to direction. However, responses were sparse and broadly tuned, which severely limited decoding performance from small DSGC populations. In contrast, larger populations compensated for response sparsity, enabling decoding with high temporal precision (<100 ms). At these timescales, correlated spiking was minimal and had little impact on decoding performance, unlike results obtained using simpler local motion stimuli decoded over longer timescales. We use these data to define different DSGC population decoding regimes that use or mitigate correlated spiking to achieve high-spatial versus high-temporal resolution.SIGNIFICANCE STATEMENT ON-OFF direction-selective ganglion cells (ooDSGCs) in the mammalian retina are typically thought to signal local motion to the brain. However, several recent studies suggest they may signal global motion. Here we analyze the fidelity of encoding and decoding global motion in a natural scene across large populations of ooDSGCs. We show that large populations of DSGCs are capable of signaling rapid changes in global motion.Item Open Access High-sensitivity rod photoreceptor input to the blue-yellow color opponent pathway in macaque retina.(Nat Neurosci, 2009-09) Field, Greg D; Greschner, Martin; Gauthier, Jeffrey L; Rangel, Carolina; Shlens, Jonathon; Sher, Alexander; Marshak, David W; Litke, Alan M; Chichilnisky, EJSmall bistratified cells (SBCs) in the primate retina carry a major blue-yellow opponent signal to the brain. We found that SBCs also carry signals from rod photoreceptors, with the same sign as S cone input. SBCs exhibited robust responses under low scotopic conditions. Physiological and anatomical experiments indicated that this rod input arose from the AII amacrine cell-mediated rod pathway. Rod and cone signals were both present in SBCs at mesopic light levels. These findings have three implications. First, more retinal circuits may multiplex rod and cone signals than were previously thought to, efficiently exploiting the limited number of optic nerve fibers. Second, signals from AII amacrine cells may diverge to most or all of the approximately 20 retinal ganglion cell types in the peripheral primate retina. Third, rod input to SBCs may be the substrate for behavioral biases toward perception of blue at mesopic light levels.Item Open Access Ignoring correlated activity causes a failure of retinal population codes.(Nature communications, 2020-09-14) Ruda, Kiersten; Zylberberg, Joel; Field, Greg DFrom starlight to sunlight, adaptation alters retinal output, changing both the signal and noise among populations of retinal ganglion cells (RGCs). Here we determine how these light level-dependent changes impact decoding of retinal output, testing the importance of accounting for RGC noise correlations to optimally read out retinal activity. We find that at moonlight conditions, correlated noise is greater and assuming independent noise severely diminishes decoding performance. In fact, assuming independence among a local population of RGCs produces worse decoding than using a single RGC, demonstrating a failure of population codes when correlated noise is substantial and ignored. We generalize these results with a simple model to determine what conditions dictate this failure of population processing. This work elucidates the circumstances in which accounting for noise correlations is necessary to take advantage of population-level codes and shows that sensory adaptation can strongly impact decoding requirements on downstream brain areas.Item Open Access Macular Vascular Microcirculation in Eyes With Open-angle Glaucoma Using Different Visual Field Severity Classification Systems.(Journal of glaucoma, 2019-09) Bojikian, Karine D; Nobrega, Priscilla; Wen, Joanne C; Zhang, Qinqin; Mudumbai, Raghu C; Johnstone, Murray A; Wang, Ruikang K; Chen, Philip PPrecis
We found significant differences in macular vascular microcirculation between normal and glaucomatous eyes using optical coherence tomography angiography (OCTA). Macular vascular microcirculation changes also showed significant correlations with visual field (VF) severity classification systems.Purpose
To correlate VF severity defined by different classification systems and macular vascular microcirculation in eyes with glaucoma using OCTA.Patients and methods
Twenty normal and 58 open-angle glaucoma (OAG) eyes were scanned using a swept-source OCTA (Plex Elite 9000) and macular vascular microcirculation was measured by calculating the overall blood flux index (BFI) and vessel area density (VAD) over the entire 6×6 mm area excluding the big retinal vessels. Glaucomatous eyes were staged into severity groups based on 4 VF severity classifications: Hodapp-Parrish-Anderson scale, Glaucoma Severity Staging system, ICD-10 glaucoma staging definitions, and VF mean deviation. Central 10-degree VF mean sensitivity (CMS) was calculated based on 24-2 VF. One-way analysis of variance was used to analyze the differences and correlation between macular vascular microcirculation and other clinical parameters.Results
Glaucomatous eyes had significantly lower ganglion cell and inner plexiform layer BFI and VAD (P<0.0001) compared with normal eyes. In OAG patients, BFI and VAD were significantly higher in mild OAG compared with severe OAG with all VF disease severity classification systems (P<0.001). Glaucoma Severity Staging had the highest correlation with changes in macular vascular microcirculation metrics (r=0.734 for BFI; r=0.647 for VAD) and VF CMS had highest correlation with macular vascular microcirculation metrics (r=0.887 for BFI; r=0.903 for VAD).Conclusion
Macular vascular microcirculation metrics detected by OCTA correlate with disease severity in glaucomatous eyes. VF CMS, calculated from only 12 tested central 10-degree points, correlated best with macular OCTA.Item Open Access Monte Carlo methods for localization of cones given multielectrode retinal ganglion cell recordings.(Network (Bristol, England), 2013-01) Sadeghi, K; Gauthier, JL; Field, GD; Greschner, M; Agne, M; Chichilnisky, EJ; Paninski, LIt has recently become possible to identify cone photoreceptors in primate retina from multi-electrode recordings of ganglion cell spiking driven by visual stimuli of sufficiently high spatial resolution. In this paper we present a statistical approach to the problem of identifying the number, locations, and color types of the cones observed in this type of experiment. We develop an adaptive Markov Chain Monte Carlo (MCMC) method that explores the space of cone configurations, using a Linear-Nonlinear-Poisson (LNP) encoding model of ganglion cell spiking output, while analytically integrating out the functional weights between cones and ganglion cells. This method provides information about our posterior certainty about the inferred cone properties, and additionally leads to improvements in both the speed and quality of the inferred cone maps, compared to earlier "greedy" computational approaches.Item Open Access Nogo receptor 1 is expressed by nearly all retinal ganglion cells.(PloS one, 2018-01) Solomon, Alexander M; Westbrook, Teleza; Field, Greg D; McGee, Aaron WA variety of conditions ranging from glaucoma to blunt force trauma lead to optic nerve atrophy. Identifying signaling pathways for stimulating axon growth in the optic nerve may lead to treatments for these pathologies. Inhibiting signaling by the nogo-66 receptor 1 (NgR1) promotes the re-extension of axons following a crush injury to the optic nerve, and while NgR1 mRNA and protein expression are observed in the retinal ganglion cell (RGC) layer and inner nuclear layer, which retinal cell types express NgR1 remains unknown. Here we determine the expression pattern of NgR1 in the mouse retina by co-labeling neurons with characterized markers of specific retinal neurons together with antibodies specific for NgR1 or Green Fluorescent Protein expressed under control of the ngr1 promoter. We demonstrate that more than 99% of RGCs express NgR1. Thus, inhibiting NgR1 function may ubiquitously promote the regeneration of axons by RGCs. These results provide additional support for the therapeutic potential of NgR1 signaling in reversing optic nerve atrophy.Item Open Access Pathway-Specific Asymmetries between ON and OFF Visual Signals.(The Journal of neuroscience : the official journal of the Society for Neuroscience, 2018-11) Ravi, Sneha; Ahn, Daniel; Greschner, Martin; Chichilnisky, EJ; Field, Greg DVisual processing is largely organized into ON and OFF pathways that signal stimulus increments and decrements, respectively. These pathways exhibit natural pairings based on morphological and physiological similarities, such as ON and OFF α-ganglion cells in the mammalian retina. Several studies have noted asymmetries in the properties of ON and OFF pathways. For example, the spatial receptive fields (RFs) of OFF α-cells are systematically smaller than ON α-cells. Analysis of natural scenes suggests that these asymmetries are optimal for visual encoding. To test the generality of ON/OFF asymmetries, we measured the spatiotemporal RF properties of multiple RGC types in rat retina. Through a quantitative and serial classification, we identified three functional pairs of ON and OFF RGCs. We analyzed the structure of their RFs and compared spatial integration, temporal integration, and gain across ON and OFF pairs. Similar to previous results from the cat and primate, RGC types with larger spatial RFs exhibited briefer temporal integration and higher gain. However, each pair of ON and OFF RGC types exhibited distinct asymmetric relationships between RF properties, some of which were opposite to the findings of previous reports. These results reveal the functional organization of six RGC types in the rodent retina and indicate that ON/OFF asymmetries are pathway specific.SIGNIFICANCE STATEMENT Circuits that process sensory input frequently process increments separately from decrements, so-called ON and OFF responses. Theoretical studies indicate that this separation, and associated asymmetries in ON and OFF pathways, may be beneficial for encoding natural stimuli. However, the generality of ON and OFF pathway asymmetries has not been tested. Here we compare the functional properties of three distinct pairs of ON and OFF pathways in the rodent retina and show that their asymmetries are pathway specific. These results provide a new view on the partitioning of vision across diverse ON and OFF signaling pathways.Item Open Access Retinal Ganglion Cells With a Glaucoma OPTN(E50K) Mutation Exhibit Neurodegenerative Phenotypes when Derived from Three-Dimensional Retinal Organoids.(Stem cell reports, 2020-07) VanderWall, Kirstin B; Huang, Kang-Chieh; Pan, Yanling; Lavekar, Sailee S; Fligor, Clarisse M; Allsop, Anna R; Lentsch, Kelly A; Dang, Pengtao; Zhang, Chi; Tseng, Henry C; Cummins, Theodore R; Meyer, Jason SRetinal ganglion cells (RGCs) serve as the connection between the eye and the brain, with this connection disrupted in glaucoma. Numerous cellular mechanisms have been associated with glaucomatous neurodegeneration, and useful cellular models of glaucoma allow for the precise analysis of degenerative phenotypes. Human pluripotent stem cells (hPSCs) serve as powerful tools for studying human disease, particularly cellular mechanisms underlying neurodegeneration. Thus, efforts focused upon hPSCs with an E50K mutation in the Optineurin (OPTN) gene, a leading cause of inherited forms of glaucoma. CRISPR/Cas9 gene editing introduced the OPTN(E50K) mutation into existing lines of hPSCs, as well as generating isogenic controls from patient-derived lines. RGCs differentiated from OPTN(E50K) hPSCs exhibited numerous neurodegenerative deficits, including neurite retraction, autophagy dysfunction, apoptosis, and increased excitability. These results demonstrate the utility of OPTN(E50K) RGCs as an in vitro model of neurodegeneration, with the opportunity to develop novel therapeutic approaches for glaucoma.Item Open Access Retinal representation of the elementary visual signal.(Neuron, 2014-01) Li, Peter H; Field, Greg D; Greschner, Martin; Ahn, Daniel; Gunning, Deborah E; Mathieson, Keith; Sher, Alexander; Litke, Alan M; Chichilnisky, EJThe propagation of visual signals from individual cone photoreceptors through parallel neural circuits was examined in the primate retina. Targeted stimulation of individual cones was combined with simultaneous recording from multiple retinal ganglion cells of identified types. The visual signal initiated by an individual cone produced strong responses with different kinetics in three of the four numerically dominant ganglion cell types. The magnitude and kinetics of light responses in each ganglion cell varied nonlinearly with stimulus strength but in a manner that was independent of the cone of origin after accounting for the overall input strength of each cone. Based on this property of independence, the receptive field profile of an individual ganglion cell could be well estimated from responses to stimulation of each cone individually. Together, these findings provide a quantitative account of how elementary visual inputs form the ganglion cell receptive field.Item Open Access "Silent" NMDA Synapses Enhance Motion Sensitivity in a Mature Retinal Circuit.(Neuron, 2017-12) Sethuramanujam, Santhosh; Yao, Xiaoyang; deRosenroll, Geoff; Briggman, Kevin L; Field, Greg D; Awatramani, Gautam BRetinal direction-selective ganglion cells (DSGCs) have the remarkable ability to encode motion over a wide range of contrasts, relying on well-coordinated excitation and inhibition (E/I). E/I is orchestrated by a diverse set of glutamatergic bipolar cells that drive DSGCs directly, as well as indirectly through feedforward GABAergic/cholinergic signals mediated by starburst amacrine cells. Determining how direction-selective responses are generated across varied stimulus conditions requires understanding how glutamate, acetylcholine, and GABA signals are precisely coordinated. Here, we use a combination of paired patch-clamp recordings, serial EM, and large-scale multi-electrode array recordings to show that a single high-sensitivity source of glutamate is processed differentially by starbursts via AMPA receptors and DSGCs via NMDA receptors. We further demonstrate how this novel synaptic arrangement enables DSGCs to encode direction robustly near threshold contrasts. Together, these results reveal a space-efficient synaptic circuit model for direction computations, in which "silent" NMDA receptors play critical roles.