The Olfactory Nerve

嗅觉神经

• 批准号: 9118166
• 负责人: Charles A Greer
• 金额: $ 35.14万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-13 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118166
• 关键词: Address; Adhesions; Adult; Antibodies; Attention; Axon; Behavior; Brain; Cells; Cilia; Code; Complex; Confocal Microscopy; Development; Distal; Electron Microscopy; Epithelium; Exhibits; Fascicle; Gene Family; Genetic; Genetic Translation; Growth Cones; Health; Heterogeneity; Individual; Knowledge; Lead; Life; Ligand Binding; Messenger RNA; Molecular; Mus; Muscle fasciculation; Natural regeneration; Neuraxis; Neuroglia; Neurons; Nose; Odorant Receptors; Odors; Olfactory Epithelium; Olfactory Nerve; Pathway interactions; Perception; Population; Process; Property; Sensory; Side; Signal Transduction; Site; Smell Perception; Specificity; Structure-Activity Relationship; Surface; Testing; Varicosity; axon growth; axon regeneration; insight; neurogenesis; olfactory bulb; olfactory bulb glomeruli; olfactory sensory neurons; receptor; receptor expression; sensory system; spatial relationship

DESCRIPTION (provided by applicant): The perception of odorous molecules begins in the olfactory epithelium when odorant ligands bind to molecular receptors expressed on the cilia of the olfactory sensory neurons (OSNs). Buck and Axel (1991) were the first to describe the large family of genes coding for the odorant receptors, now known to number ~1,200 in mice. An OSN expresses only 1 odorant receptor. OSNs expressing the same receptor do not cluster together but rather are broadly distributed across the epithelium. Thus the olfactory epitheium is a complex mosaic of neurons each of which expresses only 1 of 1,200 possible odorant receptors. As their axons exit the epithelium they initially fasciculate with nearest neighbors, no necessarily with axons from other neurons expressing the same odorant receptor. However, as they progress over the surface of the olfactory bulb and a point of glomerular convergence, the axons undergo a profound topographical reorganization such that all of the axons coming from neurons expressing the same odorant receptor converge into only 2/3 glomeruli/olfactory bulb. This process of reorganization of axons and convergence into specific glomeruli poses a significant wiring problem, perhaps the most complex wiring problem found among sensory systems. It is widely accepted that the odorant receptors themselves contribute to the convergence of homotypic axons but the process of fasciculation and axon behavior remains poorly understood. Despite a concerted effort to identify the molecular substrates of sensory axon growth, coalescence and targeting, we remain woefully ignorant of the most fundamental aspects of OSN axon organization: When does the initial fasciculation of axons begin, the processes of defasciculation and reorganization? When do homotypic axons expressing the same odorant receptor show evidence of irreversible adhesion? What is the relationship of individual axons to the olfactory ensheathing cells along the course of the olfactory nerve and olfactory nerve layer? How are growth cones distributed and organized in the fascicles both during early development when the pathway is established and in the adult during ongoing axogenesis? Where and when is the odorant receptor mRNA expressed in axons? Does local axonal translation of mRNA occur, and if so under what conditions and where? To begin addressing these significant gaps in our knowledge we are proposing 3 specific aims: Aim 1 - Test the hypothesis that adhesion of homotypic axons does not occur until they are proximal to the site of glomerular convergence; Aim 2 - Test the hypothesis that the growth cones of olfactory sensory neuron axons are not homogeneously distributed within fascicles; and Aim 3 - Test the hypotheses that odorant receptor mRNAs and the translational components are locally compartmentalized in the olfactory nerve/sensory axons.

描述（由申请人提供）：当气味配体与嗅觉感觉神经元（OSN）纤毛上表达的分子受体结合时，气味分子的感知开始于嗅觉上皮。 Buck 和 Axel (1991) 首次描述了编码气味受体的基因大家族，目前已知小鼠体内有约 1,200 个基因。一个 OSN 仅表达 1 个气味受体。表达相同受体的 OSN 不会聚集在一起，而是广泛分布在上皮细胞中。因此，嗅觉上皮是一个复杂的神经元镶嵌体，每个神经元仅表达 1,200 种可能的气味受体中的一种。当它们的轴突离开上皮时，它们最初与最近的邻居发生成束，不一定与表达相同气味受体的其他神经元的轴突发生成束。然而，当它们在嗅球表面和肾小球汇聚点上前进时，轴突经历了深刻的拓扑重组，使得来自表达相同气味受体的神经元的所有轴突仅汇聚到 2/3 肾小球/嗅球中。轴突重组和汇聚成特定肾小球的过程引起了严重的接线问题，这可能是感觉系统中发现的最复杂的接线问题。人们普遍认为气味受体本身有助于同型轴突的汇聚，但束颤和轴突行为的过程仍然知之甚少。尽管我们共同努力确定感觉轴突生长、合并和靶向的分子底物，但我们仍然对 OSN 轴突组织的最基本方面一无所知：轴突的初始束化何时开始，解束和重组过程是什么时候？表达相同气味受体的同型轴突何时表现出不可逆粘附的证据？沿着嗅神经和嗅神经层的各个轴突与嗅鞘细胞的关系是什么？在早期发育过程中，当通路建立时，以及在成人正在进行的轴突发生过程中，生长锥在束中是如何分布和组织的？气味受体 mRNA 在轴突中何时何地表达？ mRNA 的局部轴突翻译是否会发生？如果会发生，则在什么条件下以及在何处发生？为了开始解决我们知识中的这些重大差距，我们提出了 3 个具体目标： 目标 1 - 检验同型轴突在接近肾小球会聚部位之前不会发生粘附的假设；目标 2 - 检验嗅觉感觉神经元轴突的生长锥在束内分布不均匀的假设；目标 3 - 测试气味受体 mRNA 和翻译成分在嗅觉神经/感觉轴突中局部划分的假设。