PROJECT SUMMARY Blindness caused by photoreceptor death, such as in Retinitis Pigmentosa and Macular Degeneration, is among the leading causes of irreversible blindness in the world today. Electrical stimulation of spared retinal circuitry by retinal prosthetic devices holds promise for restoring vision, but results so far have been modest at best. Our understanding of how electrical stimulation engages the remaining retinal circuitry to perform basic visual computation is poor. To design more effective retinal prosthetic devices, we need to better understand how prosthetic stimulation activates the diseased retinal circuitry. Two major challenges to studying how sub-retina stimulation activates retinal circuitry are: 1) the lack of techniques to measure electrical activation of bipolar cells, and 2) an incomplete understanding of how retinal degeneration changes visual processing circuits. Here we use a new approach. By recording synaptic output of bipolar cells ex vivo, we can directly readout relevant bipolar cell activity, which is the first stage in sub-retinal prosthetic stimulation. By using a new retinal prosthetic technology, the nanowire detector array, to mimic light input to bipolar cells with high temporal and spatial precision, we can determine how basic computations such as contrast are altered during degeneration. The results from this proposal will be significant and will: 1.) Determine optimal stimulation strategies to restore vision with prosthetics 2.) Uncover basic physiological mechanisms that determine how spared retina responds to electrical stimulation, and 3.) Determine how prosthetics can engage basic computational circuitry in diseased retina to extract temporal contrast information from spatio- temporal patterns of electrical stimulation. These experiments will produce needed insight on the fundamental mechanisms underlying early visual computation and guide strategies to improve the design and execution of retinal prosthetic devices. The long-term goal of this work is to improve the design of retinal prosthetics for vision restoration, ultimately improving the quality of life for a broad patient population.