MAPPING RETINOTECTAL CIRCUITS FOR VISUAL-EVOKED INNATE BEHAVIORS

绘制视觉诱发先天行为的视网膜环路

• 批准号: 10300917
• 负责人: Xin Duan
• 金额: $ 75.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10300917
• 关键词: Anatomy; Animal Behavior; Area; Axon; Behavior; Behavioral; Binding; Bioinformatics; Brain; Complex; Data; Development; Electrophysiology (science); Engineering; Ensure; Freezing; Future; Genetic; Glycoproteins; Goals; Histology; Image; Individual; Instinct; Integrins; Knowledge; Label; Lead; Link; Maps; Measurement; Mediating; Methods; Midbrain structure; Molecular; Molecular Genetics; Motion; Mus; Nervous System Physiology; Neurons; Output; Play; Population; Resolution; Retina; Retinal Ganglion Cells; Role; Specificity; Synapses; System; Tectum Mesencephali; Tracer; Visual; Visual system structure; Wheat Germ Agglutinins; Work; axon growth; defense response; excitatory neuron; extracellular; ganglion cell; genetic analysis; genetic manipulation; inhibitory neuron; insight; nephronectin; neural circuit; optogenetics; postsynaptic; postsynaptic neurons; retinotectal; sequencing platform; single-cell RNA sequencing; superior colliculus Corpora quadrigemina; tool; visual processing

PROJECT SUMMARY The precise assembly of neural circuits ensures accurate neurological function and behavior. For example, to communicate specific aspects of the visual world to the brain, retinal ganglion cells (RGCs) find and form synaptic contacts with specific postsynaptic partners out of the heterogeneous neuronal population of retino-recipient areas in the brain. One such area is the superior colliculus (SC), which receives direct retinal inputs and sends commands for direct innate behaviors such as escape or prey capture. What are the molecular determinants for selective RGC to SC neuron wiring? How are parallel retinotectal circuits sorted onto different SC laminae and neuronal relays? How are distinct retinotectal circuits linked to defined visual evoked behaviors? This proposed study aims to answer these questions in the mouse visual system. To accomplish this goal, first, we will map out parallel retinotectal circuits. We have established an integrated anterograde-tracing and sequencing platform, Trans-Seq, that defines the outputome of a genetically- defined RGC subtype. We applied Trans-Seq to all RGC subtypes globally, α-RGCs, and On-Off direction- selective-ganglion-cells and reconstructed their differential outputomes onto superficial superior-collicular (sSC) neuron subtypes. We propose to apply Trans-Seq to other major RGC subtypes representing different visual features. The proposed studies will determine retinotectal circuit convergence and divergence at neuron subtype resolution. Second, we aim to understand cellular and molecular mechanisms regulating specific retinotectal circuit wiring. We have analyzed α-RGC specific outputomes and revealed a selective sSC neuron subtype, Nephronectin-positive-wide-field neurons (NPWFs). The α-RGC-to-NPWF circuit was genetically validated using imaging, electrophysiology, and retrograde tracing. We propose to study how Nephronectin mediates α-RGC selective axonal lamination onto the deep sSC layer and whether Nephronectin determines the subsequent synaptic specificity from α-RGCs to NPWFs. We will also investigate what molecular mechanisms mediate Nephronectin binding and lead to a selective mammalian retinotectal circuit assembly. Third, we will link specific retinotectal circuits to defined visual evoked behaviors. We propose to combine genetic and optogenetic tools established above to determine whether the α-RGC-to-NPWF circuit contributes to visual evoked innate behaviors, such as looming triggered defense responses. We will also examine whether molecular determinants for connectivity, such as Nephronectin, regulate this behavioral output via these retinotectal circuits. Our circuit mapping platform builds a precise connectivity map at neuronal subtype resolution. Further, this work will align the precise neuronal wiring diagram to innate visual evoked behaviors, informing future functional and behavioral analysis. The new knowledge gained here may include molecular principles underlying mammalian circuit wiring relevant beyond the visual system.

项目摘要 神经元电路的精确组装确保了准确的神经功能和行为。为了 例如，为了将视觉世界的特定方面传达给大脑，残留的神经节细胞（RGC）查找和 与特定的突触后伴侣形成突触接触，来自异质神经元种群 大脑中的视网膜接收区域。这样一个区域是上丘（SC），它接收直接残留 输入并发送命令，以直接先天行为，例如逃生或猎物捕获。什么是分子 选择性RGC的决定因素？如何平行视网膜直直直截止电路分类在不同的 SC laminae和神经元中继？如何将明显的视网膜直直直截止电路链接到定义的视觉诱发行为？ 这项拟议的研究旨在在鼠标视觉系统中回答这些问题。 为了实现这一目标，首先，我们将绘制平行的视网膜直直直肠电路。我们已经建立了 集成的地前追踪和测序平台Trans-Seq，该平台定义了一般的输出组 定义的RGC亚型。我们在全球所有RGC亚型，α-RGC和On-Off Toriesct-on-Off-Off-Off-Off-Off-Off-Off- 选择性缠绕细胞并将其差分输出量重建到浅表超典型（SSC）上 神经元亚型。我们建议将trans-seq应用于代表不同视觉的其他主要RGC亚型 特征。拟议的研究将确定神经元亚型的视网膜直肠电路收敛和差异 解决。其次，我们旨在了解调节特定视网膜直肠的细胞和分子机制 电路接线。我们已经分析了α-RGC特异性型组，并揭示了选择性的SSC神经元亚型， 肾上腺素阳性全场神经元（NPWFS）。使用α-RGC到NPWF电路通过使用遗传验证 成像，电生理和逆行跟踪。我们建议研究肾琴素如何介导α-RGC 选择性轴突层压层到深SSC层，以及肾膦菌素是否确定后续序列 从α-RGC到NPWFS的突触特异性。我们还将研究哪些分子机制介导 肾上腺素结合并导致选择性的哺乳动物视网膜直肠电路组件。第三，我们将链接特定 视网膜直肠电路定义的视觉诱发行为。我们建议结合遗传学和光遗传学工具 在上面建立的以确定α-rgc-to-npwf电路是否有助于视觉诱发的先天 行为，例如损失触发防御反应。我们还将检查分子确定器是否 对于连通性，例如肾膦素，可以通过这些视网膜直肠电路调节这种行为输出。 我们的电路映射平台在神经元亚型分辨率下构建了精确的连接图。此外， 这项工作将使精确的神经元接线图与先天的视觉唤起行为保持一致，从而告知未来 功能和行为分析。这里获得的新知识可能包括基础的分子原理 哺乳动物电路接线在视觉系统之外相关。