Retinal foveal midget connectivity after acute photoreceptor loss

项目摘要/摘要 由于损伤或疾病导致的神经细胞死亡会导致回路功能障碍和行为缺陷。在 视觉系统中，视网膜感光细胞死亡是导致失明的主要原因。目前为恢复视力所做的努力 包括通过干细胞疗法替换丢失的光感受器，移植分化的神经元和 诱导神经胶质细胞产生神经元。很明显，设计成功整合的战略 新的光感受器需要了解神经元重塑的性质、程度和进展 光感受器丧失时。尽管已经从几种非灵长类动物损伤模型中学到了很多东西 疾病，我们还不知道发生在灵长类中心凹内的回路重排， 负责人类和非人类灵长类动物高敏锐度和色觉的区域。这个项目将 通过利用由以下机构捐赠的体外固定猕猴视网膜组织来填补这一重大知识空白 日本理研院的合作者用激光消融了中心凹内的视锥感光细胞-- 光凝。我们建议在超微结构分辨率下生成组织样本的3D体积 使用连续块面扫描电子显微镜(AIM 1)并重建中心凹侏儒回路， 这通常是高敏锐度视力的基础(目标2)。我们将生成3D体积的中心凹样本 在摘除眼球前2周、2个月或6个月行激光光凝术。捐献视网膜 来自未激光眼睛的组织将作为对照。黄斑中心凹细胞形态与前房结构的比较 这些样本上的侏儒连接将提供对本质和进展的第一次洞察 随着时间的推移，这一关键的视网膜突触通路的重塑。启用和禁用侏儒的比较 连接还将揭示在弹性和可塑性方面是否存在差异 这些平行的视网膜通路，在啮齿动物的损伤和疾病模型中被发现。除了……之外 提供了对中心凹侏儒回路如何应对急性视锥细胞丢失的基本了解，EM 体积也将是视网膜社区进一步分析结构的宝贵资源 以及视锥细胞丢失影响的其他灵长类视网膜神经元和胶质细胞的连接性。从以下方面获得的知识 这个项目是阻止突触错误连接和可能转移病理性突触的关键一步 这些变化可能会导致灵长类中心凹的环境不利于电路修复。

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.