Spiking Characteristics of Network-Mediated Responses Arising in Direction-Selective Ganglion Cells of Rabbit and Mouse Retinas to Electric Stimulation for Retinal Prostheses

Abstract

To restore the sight of individuals blinded by outer retinal degeneration, numerous retinal prostheses have been developed. However, the performance of those implants is still hampered by some factors including the lack of comprehensive understanding of the electrically-evoked responses arising in various retinal ganglion cell (RGC) types. In this study, we characterized the electrically-evoked network-mediated responses (hereafter referred to as electric responses) of ON-OFF direction-selective (DS) RGCs in rabbit and mouse retinas for the first time. Interestingly, both species in common demonstrated strong negative correlations between spike counts of electric responses and direction selective indices (DSIs), suggesting electric stimulation activates inhibitory presynaptic neurons that suppress null direction responses for high direction tuning in their light responses. The DS cells of the two species showed several differences including different numbers of bursts. Also, spiking patterns were more heterogeneous across DS RGCs of rabbits than those of mice. The electric response magnitudes of rabbit DS cells showed positive and negative correlations with ON and OFF light response magnitudes to preferred direction motion, respectively. But the mouse DS cells showed positive correlations in both comparisons. Our Fano Factor (FF) and spike time tiling coefficient (STTC) analyses revealed that spiking consistencies across repeats were reduced in late electric responses in both species. Moreover, the response consistencies of DS RGCs were lower than those of non-DS RGCs. Our results indicate the species-dependent retinal circuits may result in different electric response features and therefore suggest a proper animal model may be crucial in prosthetic researches.

Electrically-evoked responses for retinal prostheses are differentially altered depending on ganglion cell types in outer retinal neurodegeneration caused by Crb1 gene mutation

“…Among all RGCs classified by their light responses, the electrically-evoked responses of representative 6 cells of each RGC type were shown (Figures 4A-C), which showed the highest peak firing rate (PFR) in ON and OFF types (Figures 4A, B). The spiking patterns of those RGCs seemed largely similar to those reported earlier by our group from the healthy retinas (Tsai et al, 2009;Fried, 2015, 2016b;Im et al, 2018;Lee and Im, 2019;Otgondemberel et al, 2021), but minor deviations were observed in responses of ON and DS RGCs. For example, most ON RGCs showed two bursts of spikes which were separated by silent periods (n = 12/14; Figure 4Ai), while some ON RGCs showed three bursts (n = 2/14; Figure 4Aii).…”

“…Another distinct populational features of the rd8 RGCs was also observed in DS RGCs: since the responses of wt DS RGC were already investigated by creating scatter plots of spike counts in our earlier work (Otgondemberel et al, 2021), we similarly plotted spike counts as a function of average DSI (DSI AVG ) (Figure 6A). Spike counts of the early responses in the rd8 DS RGCs yielded a weak negative correlation with the DSI AVG , which was somewhat analogous to wt ones (r = −0.15 vs. −0.57 for rd8 vs. wt; see Otgondemberel et al, 2021 for wt data).…”

“…Another distinct populational features of the rd8 RGCs was also observed in DS RGCs: since the responses of wt DS RGC were already investigated by creating scatter plots of spike counts in our earlier work (Otgondemberel et al, 2021), we similarly plotted spike counts as a function of average DSI (DSI AVG ) (Figure 6A). Spike counts of the early responses in the rd8 DS RGCs yielded a weak negative correlation with the DSI AVG , which was somewhat analogous to wt ones (r = −0.15 vs. −0.57 for rd8 vs. wt; see Otgondemberel et al, 2021 for wt data). However, spike counts of the late and the total responses showed sharp contrasts between the rd8 and wt retinas, having positive correlations in the rd8 DS RGCs (r = 0.67 and 0.40 for the late and the total responses, respectively; Figures 6Aii, Aiii) but negative correlations in the wt DS RGCs (r = −0.98 and −0.90 for the late and the total responses, respectively; see Otgondemberel et al, 2021 for wt data).…”

“…Accordingly, we questioned how similar spiking activities arise in each RGC type between the rd8 and wt retinas. To compare with our previous results recorded from wt and rd10 mice (Yoon et al, 2020;Otgondemberel et al, 2021), the rd8 retinas were electrically stimulated with a 4-ms-long monophasic cathodal current (−100 µA). We recorded spiking responses from 14 ON, 15 OFF, and 6 DS RGCs of rd8 animals at PW8-18, and analyzed the RGCs as a whole regardless of the ages because the retinal foldings did not show dependence on age (Figure 2) and the histological changes (i.e., thickness of ONL) of the rd8 retinas were minimal during that time period (Figure 3).…”

“…In the case of electrically-evoked spikes, additional code was used before the spike detection to remove electric artifacts from raw recordings. Also, the spiking activities of electric responses were divided into early, late, and total responses in the same way of previous studies ( Tsai et al, 2009 ; Im and Fried, 2015 , Im et al, 2018 ; Lee and Im, 2018 , 2019 ; Yoon et al, 2020 ; Otgondemberel et al, 2021 ). In other words, to divide direct and indirect responses, we separate the spiking activities of each type RGC into early and late responses based on the end of first burst ( Figures 4A–C ).…”