The Human Foveal Connectome

视锥感光细胞与视网膜环路、Müler神经胶质细胞和视网膜色素的复杂关系 视网膜色素上皮(RPE)细胞是正常视力所必需的。但对于位于中心凹正中心的视锥细胞来说， 最佳视觉敏锐度这些关系的特征很差。一个长期存在的障碍，全面 对细胞和亚细胞中心凹结构的理解是在各种不同的 在复杂的三维架构中嵌入和微型化的细胞类型。宽泛的长期 这一新的研究计划的目的是通过应用新的技术直接阐明中心凹的微结构 体积电子显微镜(连接组学)方法。我们将利用从 创新的器官捐赠者计划，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，并指导连接性重建。初步 来自两只供体眼的数据证实了完全重建黄斑中心凹圆锥和它们的可行性。 相关的突触通路、Müler细胞和RPE细胞。锥形微电路的首次重构 一名成年出生的早产儿表明，黄斑中心凹视觉的关键细胞和突触通路在 非人类灵长类动物的结构和本地化预期。因此，在目标1中，我们 建议对突触视觉通路进行定位、识别和定量重建 中央最中央的中心凹锥体。我们将描述所有双极和神经节细胞电路的特征 这些视锥细胞，并测试新的假设，即主导的“侏儒”通路可能是辅助空间敏锐度 在电路和凹坑本地化方面，个体差异很大。我们将进一步检验这一假设 在侏儒环路之外，中心凹产生了20多个截然不同但尚未确定特征的视觉。 小路。Müler细胞的第一次重建揭示了锥体轴突和 丛状层和中心凹底部突起丰富。在目标2中，我们建议完成 重建Müler细胞以检验中心凹底部含有一种新的Müler细胞类型的假设 限制在视网膜内，单个Müler细胞形态及其中心凹分布解释了 黄斑色素分布。RPE细胞的第一次重建提供了关于 细胞器的分布在临床OCT和自体荧光成像中具有重要意义。因此，在目标3中，我们 仅视锥中心凹和混合视锥中心凹RPE细胞细胞器的重建和计数 杆状圆锥形周卵窝体。我们将直接检验RPE细胞器内容和分布不同的假设 在仅视锥中心凹和富含视杆的周凹之间，解释了OCT条带的出现和 临床影像中自体荧光信号的地形图。这项建议结合了专业知识和创新 神经生物学、病理学、成像学和连接学。结果将影响视网膜神经生物学和临床影像 黄斑疾病，特别是老年性黄斑变性的解释和病理生理学。

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.