The olfactory stimulation-dependent birth of neurons that express specific odorant receptors

表达特定气味受体的神经元的嗅觉刺激依赖性诞生

• 批准号: 10735173
• 负责人: Stephen Santoro
• 金额: $ 44.23万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735173
• 关键词: Acceleration; Adult; Affect; Bar Codes; Birth; Birth Rate; Cell Proliferation; Failure; Gene Expression; Genes; Genetic; Genome; Health; Human; Individual; Laboratories; Life; Link; Maps; Mitotic; Modeling; Nervous System; Neurons; Odorant Receptors; Odors; Olfactory Epithelium; Olfactory dysfunction; Process; Proliferating; Quality of life; Receptor Gene; Sensory; Signal Transduction; Testing; Work; experience; experimental study; in situ sequencing; insight; nerve stem cell; neurogenesis; olfactory sensory neurons; olfactory stimulus; postmitotic; progenitor; selective expression; sex; single cell sequencing

Project Summary/Abstract The olfactory epithelium is one of three major regions within the mammalian nervous system where new neurons are added throughout life. In humans, a failure to maintain olfactory sensory neurogenesis is associated with olfactory dysfunction, which afflicts an estimated 12.4 percent of adults in the U.S. and can adversely affect health and quality of life. A key barrier to treating olfactory dysfunction is our incomplete understanding of how persistent olfactory sensory neurogenesis is regulated and maintained. A related deficiency lies in our understanding of why neurogenesis persists within the olfactory epithelium. Life-long olfactory sensory neurogenesis is presumed to function solely to replace damaged olfactory sensory neurons. However, work from our laboratory has demonstrated that the birthrates of neurons that express a fraction of odorant receptors are accelerated upon stimulation by specific odors, leading to the central hypothesis of this proposal: that persistent neurogenesis within the olfactory epithelium serves, in part, an adaptive function. Our results are not readily explained by the current model of olfactory sensory neurogenesis, which predicts that the relative birthrates of neurons expressing each of the hundreds of different receptor genes encoded in the genome are determined stochastically by a process in which each post-mitotic neural precursor randomly ‘chooses’ a single odorant receptor gene for expression. Accordingly, the relative birthrates of distinct olfactory sensory neuron ‘subtypes’ are expected to be impervious to olfactory experience. The overall objective of this proposal is to determine how odor stimulation selectively accelerates the birthrates of specific olfactory sensory neuron subtypes. Our working model is that a fraction of subtypes have a special capacity, upon stimulation by odors with potential salience, to amplify themselves by selectively promoting the proliferation of mitotic neural progenitors that are of the same lineage and predisposed toward the same subtype fate. This model will be tested through three specific aims. Aim 1 will test the hypothesis that olfactory stimuli that selectively promote the neurogenesis of specific neuron subtypes are discrete, salient odors that selectively stimulate those subtypes. This will be tested by identifying, via a selective single-cell sequencing-based approach, the scope of neuron subtypes whose birthrates are accelerated by sex-specific odors. Aim 2 will test the hypothesis that some mitotic neural progenitors are predisposed toward specific odorant receptor fates that can be selectively amplified via cell proliferation. This will be tested by mapping the subtype fates of individual progenitors using genetic barcoding and in situ sequencing strategies. Aim 3 will test the hypothesis that mature olfac- tory sensory neurons of specific subtypes have a special capacity to promote the proliferation of progenitors within the same lineage via odor stimulation-dependent signaling. This will be tested through functional analyses of genes that have been found to be selectively expressed by neuron subtypes that undergo stimulation-dependent neurogenesis. The proposed experiments are expected to elucidate key aspects of persistent olfactory sensory neurogenesis, including how it is regulated, why it occurs, and how it may be manipulated to enhance human health.

项目摘要/摘要 嗅觉上皮是新神经元的哺乳动物神经系统中的三个主要区域之一 一生增加。在人类中，无法维持嗅觉神经发生与嗅觉有关 功能障碍，影响美国估计有12.4％的成年人，并可能对健康和质量产生不利影响 生活。治疗嗅觉功能障碍的关键障碍是我们对持久性嗅觉的不完全理解 感觉神经发生受调节和维护。相关的缺陷在于我们对为什么神经发生的理解 在嗅觉上皮中持续存在。终身嗅觉的感觉神经发生仅发挥作用 更换受损的嗅觉感觉神经元。但是，我们实验室的工作证明了出生率 在特定的气形上刺激时，表达大量气形受体的神经元会加速，导致 该提议的核心假设：嗅觉上皮内的持续神经发生，部分是 自适应功能。当前的嗅觉感觉神经发生模型不容易解释我们的结果，该模型 预测神经元的相对出生率表达了数百种不同受体基因中的每一个 基因组是通过一个随机“选择”的有丝分裂后神经元前体的过程随机确定的 一个用于表达的单个气形受体基因。彼此之间，不同嗅觉神经元的相对出生率 预计“亚型”将不受嗅觉体验。该提议的总体目的是确定 气味刺激如何选择性地加速了特定的嗅觉感觉神经元亚型的出生率。我们的工作 模型是，一小部分亚型具有特殊的能力，在被潜在的显着性刺激时， 通过选择性促进具有相同谱系的有丝分裂神经祖细胞的增殖来扩大自己 并倾向于相同的亚型命运。该模型将通过三个特定目标进行测试。 AIM 1将测试 有选择地促进特定神经元亚型神经发生的嗅觉刺激是离散的假设 有选择地刺激这些亚型的明显气味。通过选择性单细胞识别，将通过识别来测试这一点 基于测序的方法，即神经元亚型的范围，其出生率被性别特定的气味加速。目的 2将检验以下假设：某些有丝分裂神经祖细胞倾向于特定的异味受体命运 可以通过细胞增殖来选择这一点。这将通过映射个体的亚型命运来测试 祖细胞使用遗传条形码和原位测序策略。 AIM 3将检验以下假设：成熟的Olfac- 特定亚型的保守感官神经元具有促进祖细胞增殖的特殊能力 通过气味刺激依赖性信号传导相同的谱系。这将通过对基因的功能分析来测试 已经发现，经历模拟依赖性神经发生的神经元亚型选择性表达。这 提出的实验有望阐明持续性嗅觉神经发生的关键方面，包括 它的调节方式，为什么发生以及如何被操纵以增强人类健康。