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

项目总结 神经回路的精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。哺乳动物的方向选择(DS)回路的发育 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理解 这些连接是如何建立的。这项提议的中心目标是理解分子 允许DS电路的组件调节适当的视觉系统反应的机制 图像运动。DS的反应严重依赖于不同类别的双极细胞，星状突起的无长突细胞 (SACs)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 它们的分化以及对它们的形态和突触接触的调节，是产生 功能DS电路。在这里，我们建议利用我们最近的基因图谱和其他初步的 解决DS电路布线中尚未解决的关键问题的发现。DSGC的子类型已调整为在 不同的优先方向，这是由于囊在树突上的不对称连接的不同 这些不同的DSGC子类型；然而，这种非对称SAC-DSGC布线的基本基础是 未知。我们已经确定了在DSGCs亚型中差异表达的基因 辅助光学系统(AOS)的组件：On-DSGCs(ODSGC)，仅在其首选组件上有所不同 方向偏好-在这种情况下，背部相对于腹部的物体运动。对这些问题的辨析 表达的(DE)基因有可能揭示潜在的分子机制控制 这些oDSGCs的发展和决定其方向调节的突触连接，因为 背侧DSGCs和腹侧ODSGCs的中心区别是它们的首选方向的极性 正在调音。这一建议的重点是检验oDSGCs中差异基因表达的假设 辅助光学系统(AOS)的调节以检测向上或向下运动指示 功能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.