The Human Foveal Connectome

人类中心凹连接组

• 批准号: 10089446
• 负责人: DENNIS MICHAEL DACEY
• 金额: $ 45.22万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10089446
• 关键词: 3-Dimensional; Accounting; Address; Adult; Age related macular degeneration; Aging; Anatomy; Apical; Appearance; Architecture; Area; Axon; Biological Process; Catalogs; Cells; Cellular Morphology; Characteristics; Clinical; Complex; Cone; Data; Development; Disease; Electron Microscopy; Eye; Female; Floor; Functional disorder; Future; Goals; Health Status; Human; Image; Image Analysis; Individual; Lead; Link; Lipofuscin; Location; Machine Learning; Mediating; Melanosomes; Methods; Miniaturization; Mitochondria; Morphology; Muller' s cell; Neurobiology; Neurosciences; Optical Coherence Tomography; Organ Donor; Organelles; Outcome; Pathway interactions; Photoreceptors; Pigments; Process; Recovery; Research; Resources; Retina; Retinal Cone; Retinal Diseases; Rod; Services; Signal Transduction; Source; Structure; Structure of retinal pigment epithelium; Supporting Cell; Synapses; Technology; Testing; Time; Tissues; Variant; Vertebrate Photoreceptors; Vision; Visual Acuity; Visual Pathways; Work; cell type; clinical imaging; connectome; density; disorder of macula of retina; fovea centralis; ganglion cell; in vivo imaging; innovation; insight; macula; male; miniaturize; neural circuit; nonhuman primate; novel; pathology imaging; postsynaptic; programs; reconstruction; relating to nervous system; resilience; three dimensional structure; tool; visual performance

The complex relationship of cone photoreceptor cells with retinal circuits, Müller glia, and retinal pigment epithelial (RPE) cells is essential to normal vision. Yet for the cones in the very center of the fovea that mediate peak visual acuity these relationships are poorly characterized. A longstanding barrier to a comprehensive understanding of cellular and subcellular foveal structure is the myriad interactions among a great diversity of cell types embedded and miniaturized within a complex three-dimensional architecture. The broad long-term objective of this new research program is to elucidate foveal microstructure directly by application of new methods of volume electron microscopy (connectomics). We will utilize retinal tissue acquired from an innovative organ donor program that will permit pre-recovery optical coherence tomography (OCT) imaging to assess retinal health status and foveal pit morphology and to guide connectomic reconstruction. Preliminary data from two donor eyes demonstrates feasibility of complete reconstructions of foveal cones and their associated synaptic pathways, Müller cells, and RPE cells. The first reconstructions of cone microcircuits from an adult born preterm indicate that the critical cells and synaptic pathways for foveal vision differ dramatically in structure and localization anticipated from previous work on non-human primates. Therefore in Aim 1 we propose to localize, identify and reconstruct quantitatively the synaptic visual pathways that arise from the central-most foveal cones. We will characterize all of the bipolar and ganglion cell circuits arising from these cones and test the new hypothesis that the dominant “midget” pathway subserving spatial acuity may be highly variable across individuals in both circuitry and pit localization. We will further test the hypothesis that beyond the midget circuit the foveal center gives rise to over twenty distinct but as yet uncharacterized visual pathways. The first reconstructions of Müller cells revealed the intimate wrapping of cone axons and abundance of processes in the plexiform layer and foveal floor. In Aim 2 we propose complete reconstructions of Müller cells to test the hypotheses that the foveal floor contains a novel Müller cell type restricted to inner retina and that morphology of individual Müller cells and their foveal distribution accounts for the macular pigment distribution. The first reconstructions of RPE cells provided new insights on the distribution of organelles important in clinical OCT and autofluorescence imaging. Therefore, in Aim 3 we propose to reconstruct and enumerate organelles in RPE cells in the cone-only fovea and the mixed rod-cone perifovea. We will directly test the hypothesis that RPE organelle content and distribution differs between cone-only fovea and rod-rich perifovea, accounting for the appearance of OCT bands and for topography of autofluorescence signal in clinical imaging. This proposal combines expertise and innovation in neurobiology, pathology, imaging, and connectomics. Outcomes will impact retinal neurobiology, clinical image interpretation, and pathophysiology of macular diseases, especially age-related macular degeneration.

视锥细胞与视网膜回路、米勒神经胶质细胞和视网膜色素的复杂关系 上皮细胞（RPE）对于正常视力至关重要。然而，对于位于中央凹中央的视锥细胞来说， 峰值视力这些关系的特征很少。长期存在的阻碍全面发展的障碍 对细胞和亚细胞中心凹结构的理解是各种不同结构之间的无数相互作用 细胞类型嵌入并微型化在复杂的三维架构中。广泛的长期 这项新研究计划的目标是通过应用新方法直接阐明中央凹微观结构 体积电子显微镜方法（连接组学）。我们将利用从 创新的器官捐献计划，将允许恢复前光学相干断层扫描（OCT）成像 评估视网膜健康状况和中心凹形态并指导连接体重建。初步的 来自两只供体眼睛的数据证明了完全重建中央凹锥体及其 相关的突触通路、Müller 细胞和 RPE 细胞。锥形微电路的首次重建 成年早产儿表明，中央凹视力的关键细胞和突触通路在以下方面存在显着差异： 先前对非人类灵长类动物的研究预期的结构和定位。因此，在目标 1 中，我们 提出定量定位、识别和重建突触视觉通路 最中央的中央凹锥体。我们将描述所有双极细胞和神经节细胞电路的特征 这些视锥细胞并测试了新的假设，即促进空间敏锐度的主要“侏儒”通路可能是 个体之间的电路和凹坑定位差异很大。我们将进一步检验以下假设 在侏儒环路之外，中央凹中心产生了二十多个不同但尚未表征的视觉 途径。穆勒细胞的首次重建揭示了锥体轴突的紧密包裹和 丛状层和中央凹底有丰富的突起。在目标 2 中，我们建议完成 重建穆勒细胞以测试中央凹底包含一种新的穆勒细胞类型的假设 仅限于视网膜内部，单个穆勒细胞的形态及其中心凹分布解释了 黄斑色素分布。 RPE 细胞的首次重建提供了关于 RPE 细胞的新见解 细胞器的分布在临床 OCT 和自发荧光成像中很重要。因此，在目标 3 中，我们 提出重建和计数仅视锥中心凹和混合视锥细胞中 RPE 细胞的细胞器 视杆-锥体周围凹。我们将直接检验 RPE 细胞器含量和分布不同的假设 在仅视锥细胞的中央凹和富含视杆细胞的周围凹之间，解释了 OCT 条带的出现和 临床成像中自发荧光信号的形貌。该提案结合了专业知识和创新 神经生物学、病理学、成像和连接组学。结果将影响视网膜神经生物学、临床图像 黄斑疾病，特别是年龄相关性黄斑变性的解释和病理生理学。