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

• 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
• 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

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/摘要 由于损伤或疾病导致的神经元细胞死亡导致回路功能障碍和行为缺陷。在 在视觉系统中，视网膜感光细胞死亡是致盲的主要原因。目前恢复视力的努力 包括通过干细胞疗法替换丢失光感受器，移植分化的神经元， 从神经胶质诱导神经元产生。很明显，设计战略，成功地整合 “新”光感受器需要了解神经元重塑的性质、程度和进展 光感受器丧失。尽管从几种非灵长类动物的损伤模型中已经学到了很多， 疾病，我们还不知道电路重排发生在灵长类动物的中央凹， 在人类和非人类灵长类动物中负责高敏锐度和颜色视觉的区域。该项目将 通过利用由捐赠的离体固定的猕猴视网膜组织来填补这一重大知识空白， 日本RIKEN的合作者，其中通过激光消融中央凹中的锥状光感受器， 光凝我们建议以超微结构分辨率生成组织样本的3D体积 使用串行块面扫描电子显微镜（Aim 1）并重建中央凹侏儒电路， 这通常是高敏锐度视力的基础（目标2）。我们将生成中央凹样本的3D体积， 分别于眼球摘除术前2周、2个月、6个月行激光光凝。捐赠视网膜 来自未激光照射的眼睛的组织将用作对照。视网膜中央凹细胞形态学与视网膜神经节细胞的比较 这些样本中的小型连接体将首次提供对自然和发展的见解， 随着时间的推移，这个关键的视网膜突触通路的重塑。ON和OFF侏儒的比较 连接体也将揭示是否有差异的弹性和可塑性之间 这些平行的视网膜通路，正如在啮齿动物损伤和疾病模型中发现的那样。除了 提供了对中央凹侏儒电路如何响应急性视锥细胞丢失的基本理解，EM 卷也将是一个宝贵的资源，为视网膜社区的进一步分析的结构 以及其他灵长类视网膜神经元和神经胶质细胞的连接受到视锥细胞损失的影响。获得的消息 这个项目是阻止突触错误连接的重要一步， 这些变化可能导致灵长类动物中央凹的环境不利于电路修复。