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: 10297113
• 负责人: ALEX L KOLODKIN
• 金额: $ 48.24万
• 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/10297113
• 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.

项目摘要 神经元电路的阐述涉及一系列复杂的事件，包括神经元分化， 在适当位置的神经元设置，神经process的产物和路径调查，目标选择， 突触发生和突触细化。哺乳动物中方向选择性（DS）电路的开发 视觉系统依赖于每个步骤的精确执行，但是我们才开始理解 如何建立这些连接。该提议的核心目标是了解分子 允许DS电路组件的机制调节适当的视觉系统响应 图像运动。 DS响应严重取决于双极细胞的不同类别，Starburst amacrine细胞 （SACS）和方向选择性残神经细胞（DSGC）。这些神经元的发展，包括 它们的分化以及对形态和突触接触的调节，是产生的组成部分 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其他初步 在DS电路接线中解决关键未解决问题的发现。 DSGC的亚型已调整为运动 不同的优选方向，这是由于SAC的不对称布线差异 这些不同的DSGC亚型；但是，这种不对称SAC-DSGC接线的基础是 未知。我们已经确定了在DSGC的亚型中表达不同的基因 附件光学系统（AOS）的组件：ON-DSGCS（ODSGC）仅在其首选中有所不同 方向偏好 - 在这种情况下，背侧与腹侧物体运动。对这些差异分析 表达的（de）基因有可能揭示有关管理的基本分子机制 这些ODSGC的开发以及决定其定向调整的突触接线，因为 背odsgc和腹侧odsgcs之间的核心差异是其首选方向的极性 调谐。该建议的重点是检验ODSGC中差异基因表达的假设 调谐的附件光学系统（AOS）的检测向上或向下运动指示 功能性DS电路的开发。