The Human Foveal Connectome

人类中心凹连接组

• 批准号: 10558625
• 负责人: DENNIS MICHAEL DACEY
• 金额: $ 45.92万
• 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/10558625
• 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; Clinical assessments; Complex; Cone; Data; Development; Disease; Electron Microscopy; Epithelial Cells; 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; Pathology; Pathway interactions; Persons; 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; direct application; disorder of macula of retina; fovea centralis; ganglion cell; in vivo imaging; innovation; insight; macula; male; miniaturize; neural; neural circuit; nonhuman primate; novel; pathology imaging; postsynaptic; programs; reconstruction; 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.

锥形感光细胞与残留电路，müller胶质和视网膜色素的复杂关系 上皮（RPE）细胞对于正常视力至关重要。然而，对于中央凹的中心的锥体而言 峰值视力这些关系的特征很差。综合的长期障碍 了解细胞和亚细胞中央凹结构是多样性之间无数的相互作用 细胞类型嵌入并在复杂的三维体系结构中进行微型化。长期的 该新研究计划的目的是直接通过应用新的 体积电子显微镜（连接组学）的方法。我们将利用从一个 创新的器官捐赠计划，该计划将允许恢复前光学连贯性层析成像（OCT）成像 评估视网膜健康状况和中央凹坑形态，并指导连接组重建。初步的 来自两只捐赠者眼睛的数据证明了动脉锥及其完全重建的可行性 相关的合成途径，müller细胞和RPE细胞。锥微电路的第一批重建 一个成年的早产，表明临界细胞和凹起视力的突触途径在 以前关于非人类隐私的工作预期的结构和本地化。因此，在目标1中我们 提出定位，识别和重构的综合视觉途径 中央最中央锥。我们将表征所有由 这些锥体并检验了主要的假设，即主导的“侏儒”途径可能是空间敏锐的 电路和坑定位的个体之间的高度变化。我们将进一步检验以下假设 除了侏儒电路以外，凹起中心的中心产生了二十多个不同但尚未表征的视觉效果 途径。 Müller细胞的第一次重建揭示了锥形轴突和 在丛状层和凹室中的过程抽象。在AIM 2中，我们建议完成 Müller细胞的重建，以测试中央凹底底层包含新型Müller细胞类型的假设 仅限于内部视网膜，并且单个müller细胞的形态及其中央凹分布涉及 黄斑色素分布。 RPE单元的第一个重建提供了有关有关的新见解 细胞器的分布在临床OCT和自动荧光成像中很重要。因此，在目标3中我们 提议在仅圆锥体的RPE细胞中重建和枚举细胞器，并混合 杆孔perifovea。我们将直接检验RPE机构含量和分布差的假设 在仅圆锥形的中央凹和杆富的perifovea之间，占OCT频段的外观和 临床成像中自荧光信号的地形。该建议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。结果将影响残留的神经生物学，临床图像 黄斑疾病的解释和病理生理，尤其是与年龄有关的黄斑变性。