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Abstract
Retinal prostheses are being developed to restore vision for the blind with retinal diseases such as retinitis pigmentosa (RP) or age-related macular degeneration (AMD). Among the many issues for prosthesis development, stimulation encoding strategy is one of the most essential electrophysiological issues. The more we understand the retinal circuitry how it encodes and processes visual information, the greater it could help decide stimulation encoding strategy for retinal prosthesis. Therefore, we examined how retinal ganglion cells (RGCs) in in-vitro retinal preparation act together to encode a visual scene with multielectrode array (MEA). Simultaneous recording of many RGCs with MEA showed that nearby neurons often fired synchronously, with spike delays mostly within 1 ms range. This synchronized firing – narrow correlation – was blocked by gap junction blocker, heptanol, but not by glutamatergic synapse blocker, kynurenic acid. By tracking down all the RGC pairs which showed narrow correlation, we could harvest 40 functional connectivity maps of RGCs which showed the cell cluster firing together. We suggest that finding functional connectivity map would be useful in stimulation encoding strategy for the retinal prosthesis since stimulating the cluster of RGCs would be more efficient than separately stimulating each individual RGC.
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Fig. 2.
Spike-triggered averaging of the random checkerboard stimulus. Each stack of stimulus frames represents 300 ms, 200 ms, 100 ms, and 0 ms preceding an action potential. These sequences were then aligned and ensemble averaged.
Fig. 3.
Synchronous firing between nearby ganglion cells (46a, 63a). (A) Synchronized firing between two cells both in dark and full-field illumination are shown in raster plot. Sync raster was plotted when 63a cell fire spike within −5~+5 ms from the 46a cell. With PSTH, 46a and 63a cells were identified as OFF cells. (B) Cross-correlation analysis between two RGC spike trains. Cross-correlogram of 46a and 63a showed narrow central peak both in dark and full-field illumination with white light (intensity 1.45 μW/cm2), while the inset figure shows the cross-correlogram of the uncorrelated cells (46a and 62a). Dashed line indicates 99% confidence limits (bin: 1 msec).
Fig. 4.
Spatio-temporal receptive field of ON cell (A) and OFF cell (B). (A) a. Four frames of the spatio-temporal receptive field of ON cell are shown in succession to illustrate how the receptive field was evolved over time. Each frame shows spike-triggered average (STA) of stimulus, which preceded the action potential by the delay in milliseconds noted below each frame. The recording channel for RGC spike (channel 46) is marked by black cross. The boundary of STA of stimulus for this cell is marked by black line. Receptive field was determined by reverse correlation to flickering random checkerboard stimulation (pixel size: 200 μm, flicker interval: 100 ms, and mean intensity: 0.77 μW/cm2). × and Y axis represent column and row of 8×8 MEA (0~8), respectively. b. This RGC was confirmed as ON cell by PSTH with light stimulus. (B) a. Four frames of the spatio- temporal receptive field of OFF cell are shown. The recording channel for RGC spike (channel 72) is marked by black cross. The boundary of STA of stimulus for this cell is marked by black line. b. This RGC was confirmed as OFF cell by PSTH with light stimulus.
Fig. 5.
Effects of kynurenic acid and heptanol on narrow correlation. (A) Narrow correlation persisted still when glutamate receptor was blocked with kynurenic acid (100 uM). Left: Control, Right: After treatment with kynurenic acid. (B) Narrow correlation was blocked with gap junction channel blocker, heptanol. The ordinate scale in left (Control) and right (Heptanol, 1 mM) is different. Dashed line indicates 99% confidence limits both in A and B (bin: 0.8 msec).
Fig. 6.
Two representative functional connectivity maps of the cluster of RGCs firing together. (A) Functional connectivity map A. (B) Functional connectivity map B. The neuron 45a depicts the first cell recorded and sorted on the 4th column and the 5th row of 8×8 MEA. The correlated cells are drawn with closedcircles and connected with reciprocal arrows. These two functional connectivity maps were harvested from the same retinal preparation.
Table 1.
Retinal ganglion cell pairs which show correlated firing whit different reference cell
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