Role of insect olfactory receptors and cell adhesion molecules in circuit organization

昆虫嗅觉受体和细胞粘附分子在电路组织中的作用

• 批准号: 2006471
• 负责人: Pelin Volkan
• 金额: $ 123.44万
• 依托单位: Duke University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2006471&HistoricalAwards=false
• 关键词: Role; insect; olfactory; receptors; cell

Axons (the long, tube-like extensions of nerve cells that carry electrical and molecular signals) are a particularly critical feature of brain circuit architecture. This project examines how functionally diverse populations of nerve cells coordinate their axonal architecture during fruit fly brain development to produce precisely-organized brain circuits. Fruit flies have more than 50 different types (classes) of olfactory receptor neurons that make precise axonal connections to the first upstream processing station in the brain. This project combines molecular, cell-biological and developmental techniques with genomic, bioinformatics and statistical approaches to identify the mechanisms through which olfactory receptor neurons form class-specific axonal connections with their targets. Understanding how olfactory receptor neurons decide upon which class-specific combinations of path-finding and cell adhesion molecules to express on their cell surfaces will further understanding of how the physical wiring diagram at the initial stage of brain odor-processing circuitry gets set up. This research will also lead to fundamental insights into evolutionarily-conserved mechanisms that assemble brain cells with highly-diverse functional properties into functionally integrated brain circuits, and further understanding of how the structure of olfactory circuits and olfactory behaviors evolves along with changes in olfactory receptor sequence, expression pattern and function. This award also supports advanced research training for graduate, undergraduate, and high school students, as well as scientific outreach programs for 6th-12th grade students attending schools in low-income areas with a high percentage of students from groups who are traditionally underrepresented in science, technology, engineering and mathematics.As neurons are born, they organize their axons into large tracts (clumps of axons) that extend for long distances. Once axons arrive at a target site, they defasciculate from these main tracts, sort themselves out based on their molecular and/or functional identity, and selectively synapse with target cells. Combinations of genes encoding cell adhesion molecules (CAMs) act as adhesive or repulsive cues to regulate axonal behavior. Nevertheless, how diverse neuronal populations coordinate axonal organization to regulate circuit architecture remains unclear. The Drosophila olfactory system provides an excellent model to investigate molecular mechanisms of axonal organization. Olfactory receptor neurons (ORNs) of the same class express the same olfactory receptor (OR) genes, and their axons converge onto class-specific glomeruli in the antennal lobes to synapse with projection neurons (PNs). Previous research has identified interacting CAM families expressed in ORN class-specific combinations. Genetic perturbations of a subset of CAMs in differentiated ORNs exhibited defects in glomerular position, morphology and context; simultaneous disruption of function in ORN classes targeting neighboring glomeruli resulted in similar defects with reduced expression of some CAMs. This project tests the hypothesis that signaling in ORNs regulate the expression of CAM combinations to organize axonal projections to class-specific glomeruli. First, the function of OR signaling pathways and ORN activity in glomerular organization will be tested. Next, transcriptional changes in CAMs will be studied in OR mutant flies using RNA profiling. Finally, developmental and genetic analyses will be used to elucidate the ORN-specific function of CAMs in axonal and glomerular organization.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

轴突（神经细胞的长管状延伸，携带电信号和分子信号）是大脑回路结构的一个特别重要的特征。本项目研究功能多样的神经细胞群体如何在果蝇大脑发育过程中协调其轴突结构，以产生精确组织的大脑回路。果蝇有50多种不同类型的嗅觉受体神经元，它们与大脑中的第一个上游处理站进行精确的轴突连接。该项目将分子、细胞生物学和发育技术与基因组学、生物信息学和统计学方法相结合，以确定嗅觉受体神经元与其靶点形成类特异性轴突连接的机制。了解嗅觉受体神经元如何决定在其细胞表面表达哪些类别特异性的寻路分子和细胞粘附分子的组合，将进一步了解大脑气味处理电路初始阶段的物理布线图是如何建立的。这项研究还将导致对进化保守机制的基本见解，将具有高度多样性功能特性的脑细胞组装成功能集成的脑回路，并进一步了解嗅觉回路和嗅觉行为的结构如何沿着嗅觉受体序列，表达模式和功能的变化。该奖项还支持研究生、本科生和高中生的高级研究培训，以及低收入地区6 - 12年级学生的科学推广计划，这些学生中有很高比例来自传统上在科学、技术、工程和数学方面代表性不足的群体。随着神经元的诞生，它们将轴突组织成大片（轴突丛），延伸很长的距离。一旦轴突到达靶点，它们就从这些主要的神经束中解束，根据它们的分子和/或功能特性进行分类，并选择性地与靶细胞突触。编码细胞粘附分子（CAM）的基因组合作为粘附或排斥的线索来调节轴突行为。然而，不同的神经元群体如何协调轴突组织来调节电路结构仍不清楚。果蝇嗅觉系统为研究轴突组织的分子机制提供了一个很好的模型。同一类别的嗅觉受体神经元（ORN）表达相同的嗅觉受体（OR）基因，它们的轴突会聚到触角叶中的类别特异性肾小球上，与投射神经元（PN）形成突触。以前的研究已经确定了ORN类特异性组合中表达的相互作用CAM家族。在分化的ORN中CAM的一个子集的遗传扰动表现出肾小球位置，形态和背景的缺陷;同时破坏ORN类靶向邻近肾小球的功能导致类似的缺陷与一些CAM的表达减少。该项目测试的假设，即信号在ORN调节CAM组合的表达，以组织轴突投射到类特异性肾小球。首先，将测试OR信号通路和ORN活性在肾小球组织中的功能。接下来，将使用RNA分析在OR突变果蝇中研究CAM中的转录变化。最后，发育和遗传分析将用于阐明CAMs在轴突和肾小球组织中的ORN特异性功能。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。