Molecular mechanisms underlying direction-selective circuit assembly and function in the mouse visual system

项目摘要 神经回路的精细化涉及一系列复杂的事件，包括神经元分化， 将神经元安置在适当的位置，神经过程生长和寻路，目标选择， 突触发生和突触细化。哺乳动物方向选择回路的研究进展 视觉系统依赖于这些步骤的精确执行，然而我们才刚刚开始了解 这些联系是如何建立起来的。这项提案的中心目标是了解分子 机制，允许DS电路的组件介导适当的视觉系统反应， 图像运动DS反应主要依赖于不同类型的双极细胞，星状无长突细胞 （SAC）和方向选择性视网膜神经节细胞（DSGCs）。这些神经元的发育，包括 它们的分化以及它们的形态学和突触接触的调节，是产生 功能性DS电路。在这里，我们建议利用我们最近的基因分析和额外的初步研究， 解决DS电路布线中关键未解决问题的调查结果。DSGCs的子类型被调整为运动， 不同的首选方向，这是由于不同的不对称布线的SAC到树突的 这些不同的DSGC亚型;然而，这种不对称SAC-DSGC布线的潜在基础是 未知我们已经鉴定了在DSGCs亚型中差异表达的基因， 辅助光学系统（AOS）的组件：仅在其首选的DSGCs（oDSGCs）上有所不同 方向偏好-在这种情况下是背侧对腹侧对象运动。分析这些差异 表达（DE）基因有可能揭示潜在的分子机制， 这些oDSGCs和突触布线的发展，决定了他们的方向调谐，因为 背侧oDSGCs和腹侧oDSGCs之间的中心差异是它们的首选方向的极性 调音本研究旨在验证oDSGCs中差异基因表达的假说， 被调谐以检测向上或向下运动的辅助光学系统（AOS）的指示 功能性DS电路的开发。

PROJECT SUMMARY The elaboration of neural circuits involves a complex series of events, including neuronal differentiation, settling of neurons in appropriate locations, neural process outgrowth and pathfinding, target selection, synaptogenesis and synapse refinement. Development of direction-selective (DS) circuits in the mammalian visual system relies on precise execution of each of these steps, however we are only beginning to understand how these connections are established. The central goal of this proposal is to understand the molecular mechanisms that allow components of DS circuits to mediate appropriate visual system responses to image motion. DS responses depend critically on distinct classes of bipolar cells, starburst amacrine cells (SACs), and direction-selective retinal ganglion cells (DSGCs). The development of these neurons, including their differentiation and the regulation of their morphology and synaptic contacts, is integral to the generation of functional DS circuitry. Here, we propose leveraging our recent gene profiling and additional Preliminary Findings to address key unresolved questions in DS circuit wiring. Subtypes of DSGCs are tuned to motion in distinct preferred directions, and this is due to differences in asymmetric wiring of SACs onto the dendrites of these different DSGC subtypes; however, the underlying basis of this asymmetric SAC-DSGC wiring is unknown. We have identified genes that are differentially expressed in subtypes of DSGCs that are components of the Accessory Optic System (AOS): On-DSGCs (oDSGCs) that differ only in their preferred directional preference–in this case for dorsal vs. ventral object motion. Analysis of these differentially expressed (DE) genes has the potential to reveal underlying molecular mechanisms governing the development of these oDSGCs and the synaptic wiring that determines their directional tuning, since the central difference between dorsal-oDSGCs and ventral-oDSGCs is the polarity of their preferred directional tuning. This proposal is focused on testing the hypothesis that differential gene expression in oDSGCs of the accessory optic system (AOS) tuned to detect either upward or downward motion instructs the development of functional DS circuits.