Final Activity Report Summary - REALRET (Real-time mammalian retina models) The recent advent of genetically encoded optical neuromodulators creates the opportunity for circuit-specific intervention in neurological diseases. One of the diseases most amenable to this approach is retinal degeneration (rd), where the progressive loss of photoreceptors leads to complete and irreversible blindness. We developed a method to specifically activate the ON pathway at the level of the second-order neurons, the bipolar cells. We genetically target a light-activated cation channel, channelrhodopsin-2 (ChR2), selectively to ON bipolar cells of degenerated retinas in vivo. Reporter gene function in retinal neurons was assessed using behavioural experiments, cortical recordings of visual-evoked potentials and extracellular spike recordings with multi-electrode array. We show that in the absence of classical photoreceptors, photosensitive ON bipolar cells induce light-evoked spiking activity in ganglion cells. The rescue of light sensitivity is selective - only circuits that signal light increments are functional, an increase in illumination only stimulates ON ganglion cells. Similar to healthy retinas, parallel processing in the time domain and modification of the information flow by inhibitory circuitry is demonstrated. Sustained and transient ganglion cells are activated in parallel. Although the intensity required stimulating ChR2 is several orders of magnitude greater than that required to stimulate endogenous photo-pigments, many of the response properties are conserved. The surprising functional preservation of the inner retinal synapses in our study suggests that targeting optical neuromodulators to second-order retinal neurons might be a feasible strategy to restore retinal function.