Towards optogenetic vision restoration with high resolution

Abstract

In many cases of inherited retinal degenerations, ganglion cells are spared despite photoreceptor cell death, making it possible to stimulate them to restore visual function. Several studies have shown that it is possible to express an optogenetic protein in ganglion cells and make them light sensitive, a promising strategy to restore vision. However the spatial resolution of optogenetically-reactivated retinas has rarely been measured, especially in the primate. Since the optogenetic protein is also expressed in axons, it is unclear if these neurons will only be sensitive to the stimulation of a small region covering their somas and dendrites, or if they will also respond to any stimulation overlapping with their axon, dramatically impairing spatial resolution. Here we recorded responses of mouse and macaque retinas to random checkerboard patterns following an in vivo optogenetic therapy. We show that optogenetically activated ganglion cells are each sensitive to a small region of visual space. A simple model based on this small receptive field predicted accurately their responses to complex stimuli. From this model, we simulated how the entire population of light sensitive ganglion cells would respond to letters of different sizes. We then estimated the maximal acuity expected by a patient, assuming it could make an optimal use of the information delivered by this reactivated retina. The obtained acuity is above the limit of legal blindness. Our model also makes interesting predictions on how acuity might vary upon changing the therapeutic strategy, assuming an optimal use of the information present in the retinal activity. Optogenetic therapy could thus potentially lead to high resolution vision, under conditions that our model helps to determinine.

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

“…In our case, the size of the gap correctly discriminated (edge of the symbol: 44 µm) represents a visual acuity of 20/249, which is above the legal threshold for blindness (20/400 62,63 ). This value is consistent with the predictions of simulations 64 and better than any acuity reported to date with visual prosthetics (20/ 546 5 ). The impossibility of recording all cells from the ChR-tdT-expressing population would clearly have underestimated visual acuity, which could probably be enhanced even further.…”

Receptoral Mechanisms for Fast Cholinergic Transmission in Direction-Selective Retinal Circuitry

“…EPSCs and IPSCs exhibited similar rectification (p = 0.126, t = 1.63; Figures 3A-D). Similar to LN models of spike responses of ChR2 + GCs to optogenetic WN stimuli (Ferrari et al, 2020), our LN models exhibited high predictive accuracy that was limited primarily by the reliability of PSCs across trials ( Figure 3E). Notably, PSC reliability decreased gradually during continuous stimulation, despite the stability of presynaptic V m ( Figure 3F).…”

Sonogenetic stimulation of the brain at a spatiotemporal resolution suitable for vision restoration

“…Optogenetic therapy provides an alternative for the non-invasive stimulation of neurons at higher resolution, as demonstrated on the retina [18][19][20][21] . However, despite encouraging preliminary results in studies aiming to elicit visual perception at the cortical level [22][23][24] , approaches for optical stimulation of the cortex are hindered by the dura mater and by the scattering and absorption of light by tissues.…”