Retinal prostheses hold the potential for artificial vision in blind people affected by incurable diseases of the outer retinal layer. Available technologies provide only a small field of view: a significant limitation for totally blind people. To overcome this problem, we recently proposed a large and high-density photovoltaic epiretinal device, known as POLYRETINA. Here, we report the in vivo assessment of POLYRETINA. First, we characterise a model of chemically-induced blindness in Göttingen minipigs. Then, we develop and test a minimally invasive injection procedure to insert the large epiretinal implant into the eye. Last, we show that POLYRETINA restores light-evoked cortical responses in blind animals at safe irradiance levels. These results indicate that POLYRETINA holds the potential for artificial vision in totally blind patients affected by retinitis pigmentosa.

Objective. Optogenetics provides a means to probe functional connections between brain areas. By activating a set of presynaptic neurons and recording the activity from a downstream brain area, one can establish the sign and strength of a feedforward connection. One challenge is that there are virtually limitless patterns that can be used to stimulate a presynaptic brain area. Functional influences on downstream brain areas can depend not just on whether presynaptic neurons were activated, but how they were activated. Corticofugal axons from the auditory cortex (ACtx) heavily innervate the auditory tectum, the inferior colliculus (IC). Here, we sought to determine whether different modes of corticocollicular activation could titrate the strength of feedforward modulation of sound processing in IC neurons. Approach. We used multi-channel electrophysiology and optogenetics to record from multiple regions of the IC in awake head-fixed mice while optogenetically stimulating ACtx neurons expressing Chronos, an ultra-fast channelrhodopsin. To identify cortical activation patterns associated with the strongest effects on IC firing rates, we employed a closed-loop evolutionary optimization procedure that tailored the voltage command signal sent to the laser based on spike feedback from single IC neurons. Main results. Within minutes, our evolutionary search procedure converged on ACtx stimulation configurations that produced more effective and widespread enhancement of IC unit activity than generic activation parameters. Cortical modulation of midbrain spiking was bi-directional, as the evolutionary search procedure could be programmed to converge on activation patterns that either suppressed or enhanced soundevoked IC firing rate. Significance. This study introduces a closed-loop optimization procedure to probe functional connections between brain areas. Our findings demonstrate that the influence of descending feedback projections on subcortical sensory processing can vary both in sign and degree depending on how cortical neurons are activated in time.

2Optogenetics provides a means to probe functional connections between brain areas. By activating a set of presynaptic neurons and recording the activity from a downstream brain area, one 4 can establish the sign and strength of a feedforward connection. One challenge is that there are virtually limitless patterns that can be used to stimulate a presynaptic brain area. Functional influences on 6 downstream brain areas can depend not just on whether presynaptic neurons were activated, but how they were activated. Corticofugal axons from the auditory cortex (ACtx) heavily innervate the auditory 8 tectum, the inferior colliculus (IC). Despite the anatomical weight of this connection, optogenetic activation of ACtx neurons produced only modest changes in the IC neuron firing rates. To determine 30 activation patterns associated with the strongest effects on IC firing rates, we applied a machine learning algorithm that utilized the firing rate of single IC neurons to iteratively tailor the voltage 32 command signal sent to the laser. We show that the temporal patterning of ACtx spiking strongly impacts the cortical influence on midbrain sound processing. 34 145:209-223. Bleeck S, Patterson RD, Winter IM (2003) Using genetic algorithms to find the most effective stimulus for 458 sensory neurons. J Neurosci Methods 125:73-82. Chambers AR, Hancock KE, Maison SF, Liberman MC, Polley DB (2012) Sound-evoked olivocochlear 460 activation in unanesthetized mice. J Assoc Res Otolaryngol 13:209-217. Chambers AR, Hancock KE, Sen K, Polley DB (2014) Online stimulus optimization rapidly reveals 462 multidimensional selectivity in auditory cortical neurons. J Neurosci 34:8963-8975. Chen C, Cheng M, Ito T, Song S (2018) Neuronal Organization in the Inferior Colliculus Revisited with 464 Cell-Type-Dependent Monosynaptic Tracing. J Neurosci 38:3318-3332. Coomes DL, Schofield RM, Schofield BR (2005) Unilateral and bilateral projections from cortical cells to 466 the inferior colliculus in guinea pigs. Brain Res 1042:62-72. Cunningham JP, Nuyujukian P, Gilja V, Chestek CA, Ryu SI, Shenoy K V. (2011) A closed-loop human 468 simulator for investigating the role of feedback control in brain-machine interfaces. J Neurophysiol 105:1932-1949. 470 Diamond IT, Jones EG, Powell TPS (1969) The projection of the auditory cortex upon the diencephalon and brain stem in the cat. Brain Res 15:305-340.472 DiMattina C, Zhang K (2013) Adaptive stimulus optimization for sensory systems neuroscience. Front Neural Circuits 7:1-16. 474 Feliciano M, Potashner SJ (1995) Evidence for a Glutamatergic Pathway from the Guinea Pig Auditory Cortex to the Inferior Colliculus. J Neurochem 65:1348-1357. 476 Feng X-J, Shea-Brown E, Greenwald B, Kosut R, Rabitz H (2007a) Optimal deep brain stimulation of the subthalamic nucleus-a computational study. J Comput Neurosci. 478 Feng XJ, Greenwald B, Rabitz H, Shea-Brown E, Kosut R (2007b) Toward closed-loop optimization of deep brain stimulation for Parkinson's disease: Concepts and lessons from a computational model. J 480 Ne...