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.2022 Nov 7:16:1040090.
doi: 10.3389/fncel.2022.1040090. eCollection 2022.

Differences in the spatial fidelity of evoked and spontaneous signals in the degenerating retina

Affiliations

Differences in the spatial fidelity of evoked and spontaneous signals in the degenerating retina

Maya Carleton et al. Front Cell Neurosci..

Abstract

Vision restoration strategies aim to reestablish vision by replacing the function of lost photoreceptors with optoelectronic hardware or through gene therapy. One complication to these approaches is that retinal circuitry undergoes remodeling after photoreceptor loss. Circuit remodeling following perturbation is ubiquitous in the nervous system and understanding these changes is crucial for treating neurodegeneration. Spontaneous oscillations that arise during retinal degeneration have been well-studied, however, other changes in the spatiotemporal processing of evoked and spontaneous activity have received less attention. Here we use subretinal electrical stimulation to measure the spatial and temporal spread of both spontaneous and evoked activity during retinal degeneration. We found that electrical stimulation synchronizes spontaneous oscillatory activity, over space and through time, thus leading to increased correlations in ganglion cell activity. Intriguingly, we found that spatial selectivity was maintained inrd10 retina for evoked responses, with spatial receptive fields comparable towt retina. These findings indicate that different biophysical mechanisms are involved in mediating feed forward excitation, and the lateral spread of spontaneous activity in therd10 retina, lending support toward the possibility of high-resolution vision restoration.

Keywords: blindness; electrical stimulation; retina; retinal ganglion cell; retinal prosthetics; retinitis pigmentosa; vision restoration.

Copyright © 2022 Carleton and Oesch.

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Conflict of interest statement

Author NO had an equity interest in Nanovision Biosciences, Inc. and serves on the Scientific Advisory Board. Nanovision Biosciences, Inc. was not involved in the study design, collection, analysis, interpretation of data, the writing of this manuscript, or the decision to submit for publication. These studies were supported by a grant from NIH (EY029259 to NO). Although this grant has been identified for conflict-of-interest management based on the overall scope of the project and its potential benefit to Nanovision Biosciences, Inc., the research findings included in this work may not necessarily relate to the interests of Nanovision Biosciences, Inc. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Example recording set up.(A) 4 × 8 30 μm iridium oxide electrode grid with schematic representation of RGC’s overlaid. The white circle with red outline indicates the cell of interested closest to the blue stimulating electrode, with a red loose patch recording electrode. The green circle is the secondary cell of interest recordedvia the green loose patch electrode.(B) Example rates from cell A (red circle) and cell B (green circle) in rd10 retina.
FIGURE 2
FIGURE 2
Cross correlations of evoked and spontaneous activity between RGC pairs.(A) Heatmaps of spike rate cross-correlations between pairs of RGCs where each line is a pairwise cross-correlation forwt (n = 27), and(B)rd10 RGCs (n = 23) in control conditions and(C,D) during application of inhibitory antagonists (5 μM SR-95531, 50 μM TPMPA, and 5 μM strychnine),wt (n = 18) andrd10 (n = 41). A 20 nC, 1 ms biphasic stimulus was used. Traces below each heatmap are the average cross-correlation for all RGC pairs in each condition.
FIGURE 3
FIGURE 3
Comparison of cross-correlation between RGC pairs for stimulation and no stimulation conditions.(A) Heatmaps of cross-correlations between RGC pairs forwt control conditions (n = 11) and(B)rd10 (n = 10) during no stimulation.(C) Box plots for comparison of times of cross-correlation peaks forwt andrd10 RGC pairs at 20 nC and 0 nC.(D) Box plots for cross-correlation peak magnitude.(E,F) Heatmaps of cross-correlations between RGC pairs forwt (n = 10) andrd10 (n = 15) during inhibition block (5-μM SR 95531, 50 μM TPMPA, and 5 μM strychnine).(G,H) Same as panels(C,D), but during inhibition block. For box plots, filled black circles represent data points, open circles represent outliers, whiskers show 1 standard deviation, gray diamonds represent the mean. *Denotesp < 0.05. Traces below each heatmap are the average cross-correlation for all RGC pairs in each condition.
FIGURE 4
FIGURE 4
Patterns of MI between RGC pairs(A) Heatmaps of MI between RGC pairs forwt (n = 22) and(B)rd10 (n = 21).(C,D) Histograms showing the averaged binned MI for all RHC pairs shown in the heatmap above.(E–H) Same as(A–D), but during inhibition block (5 μM SR-95531, 50 μM TPMPA, and 5 μM strychnine).wt (n = 28),rd10 (n = 38). A 20 nC, 1 ms per phase, biphasic stimulation was delivered at time 2 s. Shaded regions show time periods used to integrate evoked and spontaneous MI.
FIGURE 5
FIGURE 5
Comparison of evoked and spontaneous MI betweenwt andrd10 RGC pairs.(A) Box plots showing integrated MI between RGC pairs inwt andrd10 retina for evoked and spontaneous time periods.(B) Same as panel(A), but in inhibition block (5 μM SR-95531, 50 μM TPMPA, and 5 μM strychnine). Filled black circles represent data points, open circles represent outliers, whiskers show 1 standard deviation, gray diamonds represent the mean. *Denotesp < 0.05.
FIGURE 6
FIGURE 6
Comparison of spontaneous MI between RGC pairs at different stimulation levels.(A) Box plots showing integrated MI between RGC pairs inwt andrd10 retina for spontaneous activity following 10 or 10 nC stimulation.(B) Same as panel(A), but in inhibition block (5 μM SR-95531, 50 μM TPMPA, and 5 μM strychnine). Filled black circles represent data points, open circles represent outliers, whiskers show 1 standard deviation, gray diamonds represent the mean. *Denotesp < 0.05.
FIGURE 7
FIGURE 7
Spontaneous MI between RGC pairs is blocked by gap junctions and excitatory synapses.(A) Average spontaneous firing rates forrd10 RGCs pairs in control conditions, 100 μM MFA, and 50 μm AP5 and 10 μm NBQX.(B) Average spontaneous MI betweenrd10 RGC pairs in control conditions, 100 μM MFA, and 50 μM AP5 and 100 μM NBQX. Filled black circles represent data points, open circles represent outliers, whiskers show 1 standard deviation, gray diamonds represent the mean. *Denotesp < 0.05.
FIGURE 8
FIGURE 8
Relationship between MI and inter-pair distance.(A) Scatter plots forwt (black diamonds) andrd10 (grey circles) RGC pair spontaneous MI time plotted against inter-pair distance. Solid black line and broken grey line shows the linear fit forwt andrd10, respectively.(B) Binned spontaneous MI under 100 μm and over 100 μm in control conditions for bothwt andrd10. Filled black circles represent data points, open circles represent outliers, whiskers show 1 standard deviation, gray diamonds represent the mean.(C,D) Same as(A,B) but for in inhibition block (5 μM SR-95531, 50 μM TPMPA, and 5 μM strychnine). *Denotesp < 0.05.
FIGURE 9
FIGURE 9
Comparison of receptive field sizes betweenwt andrd10 at 20 nC(A), 10 nC(B), and 5 nC(C). Black and gray markers show average evoked spike rates for stimulation plotted against distance from stimulating electrode forwt andrd10 RGCs, respectively. Solid lines show the Gaussian fit to the average spike rates forwt (black) andrd10 (gray). Widths were measured as the 1 standard deviation width of the Gaussian fit. Comparison of receptive field size between a single pulse and a 50 Hz pulse train.(D) Average evoked spike rates for wt RGCs plotted against distance from stimulating electrode for a single 20 nC pulse (black symbols) and for a 200 ms pulse train at 50 Hz, 20 nC per phase (gray symbols).(E) Same as panel(D), but forrd10 RGCs. Solid lines are the best Gaussian fit to the average data for single pulse (black) and pulse train (gray).
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