Assembly of the Central Olfactory Networks in Drosophila

描述(申请人提供)：从昆虫到哺乳动物，表达相同气味受体的嗅觉感受器神经元(ON)将它们的轴突投射汇聚到触角叶/嗅球中特定的肾小球目标，在中枢神经系统的这些第一嗅觉结构中创建了气味图谱。在果蝇中，触角叶投射神经元(PNS，相当于脊椎动物的二尖瓣/簇状细胞)将树突发送到肾小球并与ORN轴突突触；PN轴突随后将嗅觉信息传递给高等大脑中枢蘑菇体和侧角。在过去的五年里，由于前一笔拨款的支持，我们在理解果蝇嗅觉回路中的连接特异性是如何建立的方面取得了重大进展，无论是在细胞和发育事件及其分子机制方面。在这次更新中，我们提出了一系列分子、遗传和生化实验，以继续我们的努力，以了解每个PN或ORN在50个可选区域中选择一个区域来靶向其树突或轴突的机制，最终导致形成一个刻板的和高精度的回路，供苍蝇感知和区分气味和信息素。我们利用候选基因方法和正向遗传筛选来识别这些靶向过程所需的分子，然后研究它们的详细作用机制。重点将放在研究配体和受体，引导PN树突和ORN轴突到触角叶的适当区域，并促进它们的突触匹配。我们预计，完成这项拨款中的拟议实验将极大地丰富和扩大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一些重要的神经生物学问题，包括神经元命运的指定、树突的引导和靶向，以及嗅觉回路和神经回路的组装逻辑。我们的研究还将深入了解嗅觉信息是如何沿着中枢通路传递和转化的。公共卫生相关性了解神经回路在正常发育过程中是如何连接的，是了解病理性连接的性质的先决条件，病理性连接是许多人类神经和精神疾病的基础。此外，昆虫嗅觉系统组织和发展的知识可以用来帮助设计抗击疟疾的战略，疟疾是由蚊子传播的，蚊子主要利用嗅觉寻找配偶和人类宿主。

DESCRIPTION (provided by applicant): From insects to mammals, olfactory receptor neurons (ORNs) expressing the same odorant receptors converge their axonal projections to specific glomerular targets in the antennal lobe/olfactory bulb, creating an odor map in these first olfactory structures of the central nervous system. In the fruit fly Drosophila, antennal lobe projection neurons (PNs, equivalent to vertebrate mitral/tufted cells) send dendrites to glomeruli and synapse with ORN axons; PN axons then relay the olfactory information to higher brain centers the mushroom body and the lateral horn. Over the past five years and thanks to the support of the previous grant, we have made significant progress towards understanding how wiring specificity in the Drosophila olfactory circuit is established, both in terms of cellular and developmental events and their molecular mechanisms. In this renewal, we propose a series of molecular, genetic and biochemical experiments to continue our effort in understanding the mechanisms by which each PN or ORN chooses one of 50 alternative areas to target its dendrites or axons, ultimately resulting in the formation of a stereotyped and highly precise circuit for flies to sense and discriminate odors and pheromones. We utilize both candidate gene approaches and forward genetic screen to identify molecules that are required for these targeting processes, and then investigate their detailed mechanisms of action. Emphasis will be placed on studying ligands and receptors that guide PN dendrites and ORN axons to appropriate areas in the antennal lobe and faciliate their synaptic matching. 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 number of important neurobiological questions, including neuronal fate specification, dendritic guidance and targeting, and the logic of the assembly of the olfactory circuits and neural circuits in general. Our studies will also provide insight into how olfactory information is transferred and transformed along the central pathways. PUBLIC HEALTH RELEVANCE Understanding how neural circuits are wired during normal development is a prerequisite for understanding the nature of pathological wiring, which underlie many human neurological and psychiatric disorders. In addition, knowledge of insect olfactory system organization and development can be used to help design strategies to combat malaria, transmitted by mosquitos that utilize primarily olfaction to find their mates and human host.