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.

神经生物学面临的一个主要研究挑战是了解导致 平行视觉通路的极端多样性，以及最终这些通路对我们 对运动、形状和颜色的感知。运动知觉的细胞类型、回路和突触机制 在非灵长类动物中对运动刺激方向的中介选择性进行了深入的研究 数十年的哺乳动物和十几种不同的方向选择性通路在小鼠身上被识别 视网膜，以及越来越多的证据表明，类似的不同潜在神经机制。巨大的复杂性 在老鼠身上发现的视觉通路中的一部分反映在灵长类动物中，但令人惊讶的是，丰富的方向 以前还没有发现选择性神经节细胞。这项新研究的长期目标是 程序是首次阐明细胞类型、回路、突触组织和潜在的细胞 猕猴视网膜方向选择性的机制--人类视觉的理想模型 以中心凹为中心进行加工。我们提出的研究计划源于一系列发现 打开了第一个详细研究视觉生理学和方向突触组织的大门 猕猴视网膜中的选择性回路。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的双层类型，并发展了新的方法，允许 有系统地针对这种细胞类型进行分析。这一区域的突触生理和定向调节 神经节细胞类型是目标1的焦点，在那里我们测试了灵长类动物定向选择性的假设 与中心凹呈放射状对齐。第二，我们已经制定了可靠的方法来瞄准 星形爆发型无长突细胞，是视网膜中间神经元在方向选择回路中的关键，对于生理上的 首次进行了分析和连接电路重建。初步数据揭示了新的特征 星暴接受场结构、定向调谐和连通性为目标2提供了重点，我们 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说。 最后，我们发现了多轴突棘A1无长突细胞类型的方向选择性 用于与开关方向选择性神经节细胞的功能联系。因此，目标3的重点是测试 A1细胞独特的轴突成分为星暴和开关提供突触输入的假说 定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。总而言之，主要目标是表征这三个单元的定向调谐特性 类型，并首次使用连接学来确定创建 灵长类动物视网膜的方向选择性。因此，结果将对理解 人类视觉中的运动处理机制以及灵长类日益增长的应用 开发视力恢复工具和方法的模型。