Formation of an Olfactory Sensory Map

这项提议的长期目标是了解产生大脑中神经元精确连接的分子和细胞机制。嗅觉系统为轴突引导提供了一个很好的模型，因为大量功能不同的神经元必须适当地连接，以便大脑感知和区分气味。实验将在果蝇Drosphila Blackogaster身上进行，它有一个功能复杂但解剖学上简单的嗅觉系统。这种模式遗传有机体的完整基因组序列的获得使在基因、分子、神经元和行为水平上研究嗅觉成为可能。大约1300个嗅觉神经元连接到大脑中的43个嗅觉小球，产生嗅觉感觉图。气味识别很可能是由一个新的气味受体基因家族介导的，这些基因编码60个不同的跨膜区G蛋白偶联受体。在初步研究中，P.I.对所有表达给定受体的神经元进行了基因标记，并证明了这些神经元的轴突可以精确地汇聚到大脑中的一个或两个肾小球。这些研究导致了一种假设，即嗅觉神经元本身的功能特性是大脑目标选择的决定因素。为了验证这一假说，本研究提出了以下具体目标：(1)嗅轴突引导的发展分析。(2)幼虫触角神经在成人嗅神经轴突引导中的作用。(3)气味受体蛋白在目标识别中的作用。(4)突触活动对嗅觉映射形成的影响。一种遗传方法将被用来追踪发育中的动物的嗅觉轴突投射，这些动物的幼虫嗅觉神经元已经被有条件地消融，并且表达给定受体的神经元错误表达第二气味受体或突触活动的细胞自主阻滞剂。这些研究与健康相关的是，调节轴突寻路的细胞和分子因素可能直接应用于神经和精神疾病的发育基础上。

The long term goals of this proposal are to understand the molecular and cellular mechanisms that generate the precise connectivity of neurons in the brain. The olfactory system provides an excellent model for axon guidance because a large number of functionally distinct neurons must be wired appropriately for the brain to perceive and discriminate odors. Experiments will be carried out in the fruit fly, Drosphila melanogaster, which has a functionally sophisticated but anatomically simple olfactory system. The availability of the complete genome sequence of this model genetic organism makes it possible to study olfaction at the level of genes, molecules, neurons, and behavior. Approximately 1300 olfactory neurons are wired to 43 olfactory glomeruli in the brain, generating an olfactory sensory map. Odorant recognition is likely to be mediated by a large family of novel odorant receptor genes, which encode 60 different seven transmembrane domain G protein-coupled receptors. In preliminary studies, the P.I. has genetically labeled all neurons expressing a given receptor and demonstrated that axons from these neurons converge with precision to one or two glomeruli in the brain. These studies have led to the hypothesis that functional properties of the olfactory neuron itself are determinants in target selection in the brain. To test this hypothesis, the following specific aims are proposed: (1) Developmental analysis of olfactory axon guidance. (2) Role of the larval antennal nerve as a pioneer fiber in adult olfactory axon guidance. (3) Contribution of the odorant receptor protein to target recognition. (4) Influence of synaptic activity on the formation of the olfactory map. A genetic approach will be used to trace olfactory axon projections in developing animals, in animals whose larval olfactory neurons have been conditionally ablated, and in which neurons expressing a given receptor misexpress a second odorant receptor or a cell- autonomous blocker of synaptic activity. The health relatedness of these studies is that cellular and molecular factors that regulate axonal pathfinding may have direct application to neurological and psychiatric disorders with a developmental basis.