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: 10525244
• 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/10525244
• 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; Mammals; 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; 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.

神经生物学的主要研究挑战是了解引起的神经机制 平行视觉途径的极端多样性，最终这些途径对我们的贡献 运动，形式和颜色的感知。为了运动感知细胞类型，电路和突触机制 对运动刺激方向的选择性已经进行了深入研究 哺乳动物数十年，在小鼠中识别出十几个不同方向的选择性途径 视网膜以及越来越多的基本神经机制的证据。巨大的复杂性 在鼠标中发现的视觉途径是在灵长类动物中反映的，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 程序将首次阐明细胞类型，电路，突触组织和潜在的细胞 猕猴视网膜中方向选择性的机制，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来自一系列发现 为视觉生理和突触组织的第一个详细研究打开了一扇门 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 方向选择性神经节细胞作为递归分类类型，并开发了允许的新方法 该细胞类型的系统靶向分析。突触生理和定向调整 神经节细胞类型是AIM 1的重点，我们测试了灵长类动物中定向选择性的假设 相对于中央凹面径向对齐。其次，我们开发了针对目标的可靠方法 starburst amacrine细胞类型，沿方向选择性电路的关键视网膜中间神经元，用于两种生理学 第一次分析和连接电路重建。初步数据揭示了新的特征 Starburst接受场结构，定向调整和连接性为AIM 2提供了重点2 测试新假设的方向选择性的细胞起源及其突触转移至神经节细胞。 最后，我们发现了在多轴尖峰A1无链氨酸细胞类型和证据中的方向选择性 对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单元独特的轴突组件为Starburst和On-Off提供突触输入 方向选择性神经节细胞，并确定A1细胞在独特的dendro轴结构中的作用 方向选择性。总之，广泛的目的是表征这三个单元的定向调谐特性 类型，并首次使用连接组来确定创建的基础突触相互作用 灵长类动物视网膜中的方向选择性。因此，结果将对理解有特定的影响 机制在人类视野中运动处理，以及更广泛的灵长类动物应用程序的应用 开发视觉恢复工具和方法的模型。