Formation of an Olfactory Sensory Map

这项提议的长期目标是了解产生大脑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极好的模型，因为大脑必须将大量功能不同的神经元适当地连接起来才能感知和区分气味。实验将在果蝇（Drosphila melanogaster）身上进行，这种果蝇具有功能复杂但解剖结构简单的嗅觉系统。这种模式遗传生物的全基因组序列的可用性使得在基因、分子、神经元和行为水平上研究嗅觉成为可能。大约1300个嗅觉神经元与大脑中的43个嗅觉肾小球相连，形成嗅觉感觉图。气味识别可能是由一大家族新的气味受体基因介导的，这些基因编码60种不同的7种跨膜结构域G蛋白偶联受体。在初步研究中，P.I.对所有表达特定受体的神经元进行了遗传标记，并证明这些神经元的轴突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中目标选择的决定因素。为了验证这一假设，本文提出了以下具体目标：(1)嗅觉轴突引导的发育分析。(2)触角神经作为先锋纤维在成虫嗅轴突引导中的作用。(3)气味受体蛋白对目标识别的贡献。(4)突触活动对嗅觉图谱形成的影响。遗传学方法将用于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被有条件地切除，以及表达特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。这些研究与健康的关系是，调节轴突寻路的细胞和分子因素可能直接应用于具有发育基础的神经和精神疾病。

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.