Synaptic Architecture and Mechanisms of Direction Selectivity in Primate Retina

灵长类视网膜突触结构和方向选择性机制

• 批准号: 10093434
• 负责人: DENNIS MICHAEL DACEY
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10093434
• 关键词: Amacrine Cells; Architecture; Area; Axon; Beds; Calcium; Calcium Signaling; Cell physiology; Cells; Clinical; Color; Coupling; Data; Dendrites; Detection; Development; Disease; Elements; Functional Imaging; Human; Image; Interneurons; Light; Link; Location; Macaca; Mediating; Methods; Modeling; Monkeys; Morphology; Motion; Motion Perception; Movement; Mus; Neurobiology; Ocular Physiology; Oryctolagus cuniculus; Outcome; Output; Pathway interactions; Physiological; Physiology; Population; Primates; Property; Radial; Research; Retina; Role; Series; Stimulus; Structure; Sum; Synapses; Testing; Time; Tracer; Trees; Vision; Vision research; Visual Pathways; cell type; cellular imaging; fovea centralis; ganglion cell; high resolution imaging; imaging modality; model development; neuromechanism; nonhuman primate; novel; postsynaptic; presynaptic; programs; receptive field; reconstruction; response; retinal imaging; sight restoration; starburst; starburst amacrine cell; synaptic inhibition; tool; tool development; visual neuroscience; visual processing

A major research challenge for neurobiology is to understand the neural mechanisms that give rise to an extreme diversity of parallel visual pathways and ultimately the contributions that these pathways make to our perception of motion, form and color. For motion perception the cell types, circuits and synaptic mechanisms that mediate selectivity to the direction of moving stimuli have been intensively studied in the non-primate mammal for decades and over a dozen distinct direction selective pathways are recognized in the mouse retina together with growing evidence for similarly diverse underlying neural mechanisms. The great complexity of the visual pathways found in the mouse is mirrored in the primate, yet surprisingly the abundant direction selective ganglion cells have not been previously identified. The broad long-term objective of this new research program is to elucidate for the first time the cell types, circuits, synaptic organization and underlying cellular mechanisms for direction selectivity in the macaque monkey retina, as an ideal model for human visual processing centered around the fovea. Our proposed research plan arises from a series of discoveries that opens a door to the first detailed study of both the visual physiology and synaptic organization of direction selective circuitry in the macaque retina. In preliminary studies we have identified the primate ON-OFF direction selective ganglion cell as the recursive bistratified type and have developed new methods that permit systematic targeting of this cell type for analysis. The synaptic physiology and directional tuning of this ganglion cell type are the focus of Aim 1 where we test the hypothesis that directional selectivity in the primate is radially aligned with respect to the fovea. Second, we have developed reliable methods for targeting the starburst amacrine cell type, the key retinal interneuron in the direction selective circuit, for both physiological analysis and connectomic circuit reconstruction for the first time. Preliminary data reveal novel features of starburst receptive field structure, directional tuning and connectivity providing the focus for Aim 2 where we test new hypotheses for the cellular origins of direction selectivity and its synaptic transfer to ganglion cells. Finally, we have discovered direction selectivity in the poly-axonal spiking A1 amacrine cell type and evidence for a functional link to ON-OFF direction selective ganglion cells. The focus of Aim 3 therefore is to test the hypotheses that the A1 cells unique axonal component provides synaptic input to both starburst and ON-OFF direction selective ganglion cells, and determine the role of the A1 cells unique dendro-axonal structure in direction selectivity. In sum the broad aim is to characterize the directional tuning properties of these three cell types, and to use connectomics for the first time to determine the underlying synaptic interactions that create direction selectivity in the primate retina. Outcomes will thus have a specific impact on understanding of mechanisms motion processing in human vision and more broadly on growing applications of the primate model for the development of tools and methods for vision restoration.

神经生物学的一个主要研究挑战是理解引起神经元变化的神经机制。 平行视觉通路的极端多样性以及这些通路最终对我们的贡献 对运动、形状和颜色的感知。对于运动感知，细胞类型、电路和突触机制 介导对移动刺激方向的选择性已在非灵长类动物中进行了深入研究 几十年来，小鼠中已识别出十多种不同的方向选择性途径 视网膜以及越来越多的证据表明类似不同的潜在神经机制。巨大的复杂性 小鼠中发现的视觉通路与灵长类动物中的相似，但令人惊讶的是丰富的方向 先前尚未鉴定出选择性神经节细胞。这项新研究的广泛长期目标 该计划旨在首次阐明细胞类型、电路、突触组织和底层细胞 猕猴视网膜的方向选择性机制，作为人类视觉的理想模型 处理以中央凹为中心。我们提出的研究计划源于一系列发现 为首次详细研究视觉生理学和方向突触组织打开了大门 猕猴视网膜中的选择性电路。在初步研究中，我们已经确定了灵长类动物的开关 方向选择性神经节细胞作为递归双层类型，并开发了新的方法，允许 系统地靶向该细胞类型进行分析。突触生理学和定向调节 神经节细胞类型是目标 1 的重点，我们测试灵长类动物的方向选择性这一假设 相对于中央凹径向对齐。其次，我们开发了可靠的方法来瞄准 星爆无长突细胞类型，方向选择电路中关键的视网膜中间神经元，对于生理学和 首次进行分析和连接电路重建。初步数据揭示了新特征 星爆感受野结构、定向调谐和连接性为我们的目标 2 提供了重点 测试方向选择性的细胞起源及其向神经节细胞的突触转移的新假设。 最后，我们发现了多轴突尖峰 A1 无长突细胞类型的方向选择性和证据 用于与开关方向选择性神经节细胞的功能链接。因此，目标 3 的重点是测试 假设 A1 细胞独特的轴突成分为星爆和开关提供突触输入 方向选择性神经节细胞，并确定 A1 细胞独特的树突轴突结构在 方向选择性。总之，主要目标是表征这三种细胞的定向调谐特性 类型，并首次使用连接组学来确定创建的潜在突触相互作用 灵长类动物视网膜的方向选择性。因此，结果将对理解产生具体影响 人类视觉中的运动处理机制以及更广泛的灵长类动物应用的增长 开发视力恢复工具和方法的模型。