Retinal foveal midget connectivity after acute photoreceptor loss

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Project Summary/Abstract Neuronal cell death due to injury or disease leads to circuit dysfunction and behavioral deficits. In the visual system, retinal photoreceptor death is a major cause of blindness. Current efforts to restore sight include replacing lost photoreceptors via stem-cell therapy, transplantation of differentiated neurons and inducing neuron production from glia. It is evident that designing strategies for successful integration of ‘new’ photoreceptors requires knowledge of the nature, extent and progression of neuronal remodeling upon photoreceptor loss. Although much has been learned from several non-primate models of injury and disease, we do not yet know about the circuit rearrangements that occur within the primate fovea, the region responsible for high acuity and color vision in humans and non-human primates. This project will fill this significant gap in knowledge by capitalizing on ex vivo fixed Macaque retinal tissue donated by collaborators at the RIKEN, Japan, in which cone photoreceptors in the fovea were ablated by laser- photocoagulation. We propose to generate 3D volumes of the tissue samples at ultrastructural resolution using serial block-face scanning electron microscopy (Aim 1) and reconstruct the foveal midget circuits, which normally underlie high-acuity vision (Aim 2). We will generate 3D volumes of foveal samples that received laser-photocoagulation 2 weeks, 2 months or 6 months prior to enucleation. Donated retinal tissue from unlasered eyes will serve as controls. Comparison of foveal cellular morphology and the midget connectomes across these samples will provide the first insights into the nature and progression of remodeling of this critical retinal synaptic pathway over time. Comparison of ON and OFF midget connectomes will also reveal whether or not there are differences in resilience and plasticity between these parallel retinal pathways, as discovered in rodent models of injury and disease. In addition to providing a basic understanding of how the foveal midget circuitry responds to acute cone loss, the EM volumes will also be a valuable resource for the retinal community for further analyses of the structure and connectivity of other primate retinal neurons and glia affected by cone loss. Knowledge gained from this project is an essential step towards halting synaptic miswiring and possibly diverting pathological changes that could lead to an environment in the primate fovea that is not conducive to circuit repair.