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MAPPING RETINOTECTAL CIRCUITS FOR VISUAL-EVOKED INNATE BEHAVIORS

绘制视觉诱发先天行为的视网膜环路

基本信息

批准号：
10676764
负责人：
Xin Duan
金额：
$ 75.36万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/10676764
关键词：
Anatomy Animal Behavior Area Axon Behavior Behavioral Binding Bioinformatics Brain Communication 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 Motion Mus Nervous System Physiology Neurons Output Population Resolution Retina Retinal Ganglion Cells Role Sorting Specificity Synapses System Tectum Mesencephali Tracer Visual Visual System Wheat Germ Agglutinins Work axon growth defense response empowerment excitatory neuron extracellular ganglion cell genetic analysis genetic manipulation inhibitory neuron insight nephronectin neural circuit neuronal circuitry optogenetics postsynaptic postsynaptic neurons retinotectal sequencing platform single-cell RNA sequencing superior colliculus Corpora quadrigemina tool visual processing

项目摘要

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.

项目摘要神经回路的精确组装确保了准确的神经功能和行为。为例如，为了将视觉世界的特定方面传达给大脑，视网膜神经节细胞（RGC）找到并形成突触接触特定的突触后伙伴的异质神经元群体大脑中的视网膜受体区域。其中一个这样的区域是上级丘（SC），其接收直接视网膜电图。输入并发送指令，以进行直接的先天行为，如逃跑或捕获猎物。什么是分子选择性RGC到SC神经元布线的决定因素？平行的视网膜顶盖回路是如何分类到不同的 SC板层和神经元中继？不同的视网膜顶盖回路是如何与定义的视觉诱发行为联系在一起的？这项研究旨在回答小鼠视觉系统中的这些问题。为了实现这个目标，首先，我们将绘制平行的视网膜顶盖回路。我们建立了一个整合的顺向追踪和测序平台，Trans-Seq，它定义了一个基因的输出组，定义RGC亚型。我们将Trans-Seq应用于全球所有RGC亚型、α-RGC和开-关方向- 选择性神经节细胞，并将其分化的输出细胞重建到浅上丘（sSC）上神经元亚型我们建议将Trans-Seq应用于代表不同视觉特征的其他主要RGC亚型，功能.这项研究将确定视网膜顶盖回路在神经元亚型上的会聚和发散分辨率其次，我们的目标是了解细胞和分子机制，调节特定的视网膜顶盖，电路布线我们已经分析了α-RGC特异性输出组，并揭示了选择性sSC神经元亚型，肾连接素阳性宽视野神经元（NPWF）。α-RGC至NPWF回路的遗传学验证采用成像、电生理和逆行追踪。我们打算研究肾连蛋白如何介导α-RGC 选择性轴突层压到深sSC层，以及肾连蛋白是否决定了随后的从α-RGCs到NPWF的突触特异性。我们还将研究什么样的分子机制介导肾连蛋白结合并导致选择性哺乳动物视网膜顶盖电路组装。第三，我们将具体视网膜顶盖回路到定义的视觉诱发行为。我们建议将联合收割机遗传学和光遗传学工具结合起来确定α-RGC至NPWF回路是否有助于视觉诱发先天性行为，如迫在眉睫的触发防御反应。我们还将研究分子决定因素是否连接，如肾连蛋白，通过这些视网膜顶盖回路调节这种行为输出。我们的电路映射平台以神经元亚型分辨率构建精确的连接图。此外，本发明的目的是，这项工作将使精确的神经元接线图与先天视觉诱发行为相一致，为未来的研究提供信息。功能和行为分析。这里获得的新知识可能包括潜在的分子原理哺乳动物的电路布线相关的视觉系统以外。