Synaptic Architecture and Mechanisms of Direction Selectivity in Primate Retina

神经生物学的一个主要研究挑战是了解引起神经元损伤的神经机制。 平行视觉通路的极端多样性，以及这些通路对我们大脑的最终贡献， 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 已经在非灵长类动物中深入研究了介导对运动刺激方向的选择性的 几十年来，在小鼠中识别出十几种不同的方向选择途径 视网膜以及越来越多的证据表明，类似的不同的潜在神经机制。极为复杂 在小鼠中发现的视觉通路在灵长类动物中也有反映，但令人惊讶的是， 选择性神经节细胞以前没有被鉴定。这项新研究的广泛的长期目标 该计划首次阐明了细胞类型，电路，突触组织和潜在的细胞 猕猴视网膜方向选择性的机制，作为人类视觉的理想模型 以中央凹为中心的处理。我们提出的研究计划源于一系列发现， 打开了一扇大门，第一次详细研究视觉生理学和突触组织的方向 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双层型，并已开发出新的方法，允许 系统地靶向该细胞类型用于分析。突触生理学和定向调节 神经节细胞类型是目标1的重点，我们在目标1中检验了灵长类动物的方向选择性 相对于中央凹径向对齐。第二，我们制定了可靠的方法， 星爆无长突细胞类型，方向选择回路中的关键视网膜中间神经元，对于生理和病理都是如此。 第一次分析和连接组学电路重建。初步数据显示， 星爆感受野结构、定向调谐和连通性为Aim 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传递的新假设。 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ON-OFF方向选择性神经节细胞的功能性连接。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ON-OFF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-轴突结构的作用， 方向选择性总而言之，主要目的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 灵长类视网膜的方向选择性因此，结果将对理解 机制运动处理在人类视觉和更广泛的日益增长的应用灵长类动物 模型的工具和方法的发展视力恢复。

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.