Assembly of the Central Olfactory Networks in Drosophila

描述（由申请人提供）：从昆虫到哺乳动物，表达相同气味受体的嗅觉受体神经元（orn）将其轴突投射到触角叶/嗅球的特定肾小球目的地，在中枢神经系统的这些第一嗅觉结构中创建气味图。在果蝇中，50类嗅投射神经元的轴突与50类二级嗅投射神经元（PNs）的树突精确匹配，形成触角叶的50个肾小球。因此，嗅觉信息从外围的感觉器官忠实地传递到更高的大脑中心，使先天和习得的嗅觉行为成为可能。由于这项资助的支持，我们在过去十年的研究已经使果蝇的触角叶成为最容易理解的电路之一，就布线特异性的分子、细胞和发育基础而言。我们提供了单细胞分辨率的线路过程的详细描述，发现PN树突在ORN轴突入侵之前预模式天线叶。我们已经发现了PN树突-树突相互作用和ORN轴突-轴突相互作用，以及PN-ORN突触伴侣匹配在布线过程中的贡献。我们已经确定了几种转录因子和细胞表面受体在上述细胞环境中指导布线特异性。我们还创造了新的工具来分析单肾小球和单个神经元的特异性。在这篇论文中，我们提出了一系列的分子遗传学实验，目的是识别细胞表面密码，指导50类orn和pn之间的精确匹配。我们将研究调节ORN轴突的细胞表面蛋白，以选择其到达目的地肾小球的特定轨迹，靶向触角叶的特定区域，并与特定的突触后伙伴PNs匹配。重点将放在基于rnai的筛选上，以识别细胞表面蛋白。我们将进行深入的机制研究，将它们的作用置于适当的细胞和发育背景下。我们期望完成这项拨款中提出的实验将大大丰富和扩展我们对嗅觉电路组装的逻辑和机制的理解。这些研究将有助于我们理解发育神经生物学的一个核心问题：在发育过程中，神经回路的布线特异性是如何实现的。通过揭示苍蝇嗅觉回路的分子和内在机制，我们已经为在哺乳动物大脑中构建更复杂的神经回路提供了洞见，并在神经回路布线和人类大脑紊乱之间建立了联系。

DESCRIPTION (provided by applicant): From insects to mammals, olfactory receptor neurons (ORNs) expressing the same odorant receptor target their axonal projections to specific glomerular destinations in the antennal lobe/olfactory bulb, creating an odor map in these first olfactory structures of the central nervous system. In the fly, axons of 50 classes of ORNs match precisely with the corresponding dendrites of 50 classes of second order olfactory projection neurons (PNs) to form the 50 glomeruli of the antennal lobe. Olfactory information is thus faithfully delivered from sensory organs in the periphery to higher brain centers, enabling innate and learned olfactory behavior. Thanks to the support of this grant, our studies over the past ten years have made the Drosophila antennal lobe one of the best-understood circuits in terms of the molecular, cellular, and developmental underpinnings of wiring specificity. We have provided a detailed description of the wiring process with single-cell resolution, finding that PN dendrites pre-pattern the antennal lobe prior to ORN axon invasion. We have uncovered the contributions of PN dendrite-dendrite interactions and ORN axon-axon interactions, as well as PN-ORN synaptic partner matching in the wiring process. We have identified several transcription factors and cell surface receptors that instruct wiring specificity in the above cellular contexts. We have also created novel tools to analyze wiring specificity with single-glomerular and single neuron precision. In this renewal, we propose a series of molecular genetic experiments with the aim of identifying the cell surface code that instructs the precise matching between 50 classes of ORNs and PNs. We will study cell surface proteins that regulate ORN axons in choosing their specific trajectories en route to their destined glomeruli, targeting to specific areas of the antennal lobe, and matching with specific postsynaptic partner PNs. An emphasis will be placed on RNAi-based screens to identify cell surface proteins. We will follow up with in-depth mechanistic studies to place their actions in the proper cellular and developmental context. We expect that completion of the proposed experiments in this grant will significantly enrich and expand our understanding of the logic and mechanisms of olfactory circuit assembly. These studies will contribute to our understanding of a central problem in developmental neurobiology: how wiring specificity of neural circuits is achieved during development. By uncovering the molecules and mechanisms inherent to the fly olfactory circuit, we have already provided insight into constructing more complex neural circuits in the mammalian brain, and established links between neural circuit wiring and disorders of the human brain.