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

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。该项目研究了在果蝇大脑发育过程中，不同功能的神经细胞如何协调它们的轴突结构，以产生精确组织的大脑回路。果蝇有50多种不同类型（类别）的嗅觉受体神经元，它们与大脑中第一个上游处理站形成精确的轴突连接。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目标形成特定类别轴突连接的机制。了解嗅觉受体神经元如何决定在其细胞表面表达哪种特定类别的寻径和细胞粘附分子组合，将进一步了解大脑气味处理电路初始阶段的物理接线图是如何建立的。该研究还将有助于深入了解具有高度多样化功能特性的脑细胞组装成功能完整的脑回路的进化保守机制，并进一步了解嗅觉回路结构和嗅觉行为如何随着嗅觉受体序列、表达模式和功能的变化而进化。该奖项还支持面向研究生、本科生和高中生的高级研究培训，以及面向低收入地区学校6至12年级学生的科学推广项目，这些学校的学生中有很大一部分来自传统上在科学、技术、工程和数学领域代表性不足的群体。当神经元诞生时，它们将轴突组织成长长的束（轴突丛）。一旦轴突到达目标部位，它们就会从这些主要束中流出，根据它们的分子和/或功能身份进行分类，并选择性地与目标细胞发生突触。编码细胞粘附分子（CAMs）的基因组合作为粘附或排斥信号来调节轴突行为。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。同类嗅觉受体神经元（orn）表达相同的嗅觉受体（OR）基因，它们的轴突会聚到类特异性的触角叶肾小球上，与投射神经元（PNs）发生突触。先前的研究已经确定了相互作用的CAM家族在ORN类特异性组合中表达。分化性肾小球肾小球中CAMs亚群的遗传扰动表现出肾小球位置、形态和环境的缺陷；同时，针对邻近肾小球的ORN类功能破坏导致了类似的缺陷，一些CAMs的表达减少。本项目验证了orn中的信号调节CAM组合的表达以组织轴突投射到特定类别肾小球的假设。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，我们将利用RNA分析技术研究OR突变果蝇中CAMs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。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.