Foveal ganglion cell function in the living eye

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The fovea is a specialized region of the primate retina mediating color and high acuity visual perception. Foveal vision is highly susceptible to disease and is the primary target for therapies aiming to restore vision in the blind. However, our understanding of retinal ganglion cells (RGCs), the retinal output neurons that convey the retinal image to the brain, lags behind techniques to restore vision because we do not yet understand the full diversity of primate RGCs nor how they function in the fovea. Progress in these areas with conventional retinal physiology approaches has been limited by the difficulties of studying the fragile and densely packed fovea along with the challenges of reliably targeting rare RGCs in acute preparations. These obstacles can now be overcome with Functional Adaptive-optics Calcium Imaging in the Living Eye (FACILE), a powerful new technique enabling in vivo measurements of the light responses in hundreds of foveal RGCs expressing the calcium indicator GCaMP6s. This non-invasive, all-optical approach, which was developed in the laboratories of David Williams and William Merigan at the University of Rochester where my proposed postdoctoral training will occur, provides the unprecedented opportunity to record from the same foveal RGCs for months or years, allowing a more detailed characterization of the retinal output in the fovea than ever before. In Aim 1, I will determine the functional diversity of RGCs serving foveal vision by developing a stimulus battery and analysis pipeline to effectively and reliably classify the response properties of GCaMP6-expressing RGCs. In Aim Two, I will label six of the rarest RGC types with retrograde tracer injections to the superior colliculus (SC), then image their dendritic morphologies both in vivo and ex vivo. These results will create a detailed map of the topography of the foveal input to the superior colliculus, an evolutionarily ancient pathway mediating subconscious non-image-forming visual behaviors. The resulting map of rare GCaMP6-expressing RGCs will accelerate the classification in Aim 1 as many SC-projecting RGCs have never been characterized functionally and may have otherwise been lost in a region where midget RGCs make up over 90% of the retinal output. This project will produce a population-level account of foveal midget RGC function in the living eye that will guide progress in restoring visual perception. In addition, the insights gained into the diversity of foveal RGCs and the visual information they convey to the brain may ultimately enable the restoration all visual function, including the visually guided movements and reflexes mediated by rare SC-projecting RGCs.