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：
10350118
负责人：
Rachel O Wong
金额：
$ 19.44万
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 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10350118
关键词：
3-Dimensional 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 Lasers Lead Learning Light Coagulation Lighting Location Macaca Modeling Molecular Molecular Analysis Morphology Nature Nervous system structure Neurodegenerative Disorders Neuroglia 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 structure 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 nonhuman primate reconstruction repaired resilience retinal neuron sample fixation sight restoration stem cells

3-Dimensional 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 Lasers Lead Learning Light Coagulation Lighting Location Macaca Modeling Molecular Molecular Analysis Morphology Nature Nervous system structure Neurodegenerative Disorders Neuroglia 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 structure 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 nonhuman primate reconstruction repaired resilience retinal neuron sample fixation sight restoration stem cells

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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.

项目摘要/摘要因损伤或疾病而导致的神经元细胞死亡会导致电路功能障碍和行为缺陷。在视觉系统，视网膜感受器死亡是失明的主要原因。当前恢复口味的努力包括通过干细胞疗法替换丢失的感光体，分化神经元的移植和诱导神经胶质的神经元产生。有证据表明，设计成功整合的策略 “新”光感受器需要了解神经元重塑的性质，程度和进展感光受体损失。虽然从几种非温和的伤害模型中学到了很多东西疾病，我们尚不知道灵长种中心内部发生的电路重排，负责人类和非人类隐私的高敏锐和色觉的地区。这个项目将通过利用由Vivo固定的猕猴永久性组织来填补知识的显着空白日本瑞肯（Riken）的合作者，在该合作者中，该动脉中锥体感受器被激光烧毁光凝。我们建议以超微结构分辨率生成3D卷使用串行块面扫描电子显微镜（AIM 1）并重建凹起的小块电路，通常是高敏感视觉的基础（AIM 2）。我们将生成3D卷的中央凹样样品在列举前2周，2个月或6个月接受激光 - 光凝。捐赠的视网膜来自非透明眼的组织将用作对照。凹形细胞形态和这些样品之间的侏儒连接群将提供对性质和进展的第一个见解随着时间的流逝，这种关键的视网膜突触途径的重塑。侏儒开机和关闭的比较连接组还将揭示是否存在弹性和可塑性差异这些平行的残留途径，如啮齿动物的损伤和疾病模型中所发现的。此外对中央凹侏儒电路如何应对急性锥体损失的基本了解，EM 对于剩余社区的进一步分析，卷也将是一个宝贵的资源以及其他原发性残留神经元和受锥体损失影响的神经胶质的连通性。从中获得的知识该项目是停止突触失误和可能转移病理的重要一步可能导致灵长类动脉中心环境的变化，该环境没有进行电路维修。