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Retinal foveal midget connectivity after acute photoreceptor loss

急性光感受器丧失后视网膜中心凹侏儒连接

基本信息

批准号：
10541889
负责人：
Rachel O Wong
金额：
$ 23.33万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541889
关键词：
3-Dimensional Ablation Acute Affect Animal Model Animals Area Behavioral Biochemical Blindness Brain Cell Death Cell Therapy Cell Transplantation Cells Cellular Morphology Cellular Structures Cessation of life Color Visions Communities Cone Data Set Disease Environment Exhibits Eye Face Functional disorder Future Hand Human Injury Japan Knowledge Learning Light Coagulation Lighting Location Macaca Modeling Molecular Molecular Analysis Morphology Nature Nervous System Neurodegenerative Disorders Neuroglia Neuronal Differentiation Neurons Output Pathologic Pathway interactions Pattern Photoreceptors Primates Privatization Procedures Production Replacement Therapy Research Personnel Resolution Resources Retina Retinal Cone Retinal Ganglion Cells Retinal Photoreceptors Rodent Model Sampling Scanning Electron Microscopy Sensory Structure Synapses Testing Time Tissue Fixation Tissue Sample Tissues Transplantation Trauma Vision Visual System Work cell replacement therapy cell type connectome design extrastriate visual cortex fovea centralis ganglion cell in vivo injured insight laser photocoagulation neural circuit neuron loss neuronal replacement neuronal survival nonhuman primate reconstruction repaired resilience retinal neuron sample fixation sight restoration stem cells

项目摘要

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.

项目总结/文摘