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

小鼠视觉系统中方向选择性电路组装和功能的分子机制

• 批准号: 10467036
• 负责人: ALEX L KOLODKIN
• 金额: $ 45.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467036
• 关键词: Address; Antigen-Presenting Cells; Cell physiology; Cell surface; Cells; Cellular Morphology; Cellular Structures; Complex; Dendrites; Development; Dorsal; Event; Generations; Genes; Goals; Image; Integral Membrane Protein; Location; Mediating; Molecular; Morphology; Motion; Mus; Nerve Degeneration; Neuronal Differentiation; Neuronal Injury; Neurons; Optics; Pattern; Process; Protein Tyrosine Phosphatase; Proteins; Regulation; Research; Retina; Retinal Ganglion Cells; Series; Synapses; System; Testing; Tissue-Specific Gene Expression; Visual system structure; Work; differential expression; experimental study; ganglion cell; neural circuit; neuron development; object motion; preference; programs; receptor; relating to nervous system; response; selective expression; starburst amacrine cell; synaptogenesis; transcription factor; transcriptomics

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.

项目概要 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、 神经元在适当位置的安置、神经过程的生长和寻路、目标选择、 突触发生和突触细化。哺乳动物方向选择（DS）电路的发展 视觉系统依赖于每个步骤的精确执行，但是我们才刚刚开始了解 这些连接是如何建立的。该提案的中心目标是了解分子 允许 DS 电路的组件介导适当的视觉系统响应的机制 图像运动。 DS 反应主要取决于双极细胞、星爆无长突细胞的不同类别 （SAC）和方向选择性视网膜神经节细胞（DSGC）。这些神经元的发育，包括 它们的分化以及形态和突触接触的调节，对于生成 功能 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 电路接线中未解决的关键问题的研究结果。 DSGC 的亚型被调整为运动 不同的首选方向，这是由于 SAC 到树突上的不对称布线的差异 这些不同的 DSGC 亚型；然而，这种不对称 SAC-DSGC 接线的根本基础是 未知。我们已经鉴定出在 DSGC 亚型中差异表达的基因 附件光学系统 (AOS) 的组件：On-DSGC (oDSGC)，仅在其首选方面有所不同 方向偏好——在本例中是背侧与腹侧物体运动。对这些差异进行分析 表达（DE）基因有可能揭示控制基因的潜在分子机制 这些 oDSGC 的发育以及决定其方向调节的突触连线，因为 背侧-oDSGC 和腹侧-oDSGC 之间的主要区别是它们首选方向的极性 调整。该提案的重点是检验 oDSGC 中差异基因表达的假设 调整为检测向上或向下运动的辅助光学系统（AOS）的 功能DS电路的开发。