The Role of Microglia in Neuroblast Migration in the Olfactory System

小胶质细胞在嗅觉系统神经母细胞迁移中的作用

• 批准号: 9911029
• 负责人: Sarah Meller
• 金额: $ 2.98万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911029
• 关键词: Ablation; Address; Adult; Affect; Anosmia; Apoptosis; Area; Astrocytes; Blood Vessels; Brain; Brain Injuries; CCL2 gene; CXCL12 gene; Cell Death; Cell Therapy; Cells; Cerebral Dominance; Cerebral Ventricles; Data; Deafferentation procedure; Destinations; Development; Dichloromethylene Diphosphonate; Dissociation; Embryo; Exhibits; Fluorescent in Situ Hybridization; Generations; Hydroxydopamines; Immune; Immunohistochemistry; Immunotoxins; Impairment; Injections; Injury; Insulin-Like Growth Factor I; Interneurons; Life; Liposomes; Location; Mediating; Microglia; Modeling; Morphology; Mus; Nervous System Trauma; Neurodevelopmental Disorder; Neurons; Olfactory Nerve; Olfactory Pathways; Phagocytosis; Pharmacology; Play; Positioning Attribute; Process; Radial; Recovery; Role; Route; Shapes; Site; Smell Perception; Source; Stream; Stroke; Testing; Therapeutic; Tube; chemokine; functional status; granule cell; improved; in vivo; insight; migration; nervous system disorder; neural circuit; neuroblast; neurogenesis; neuron loss; olfactory bulb; osteopontin; postnatal development; postnatal period; prenatal; progenitor; recruit; regenerative; response; scaffold; sensory input; subventricular zone

Project Summary: The Role of Microglia in Neuroblast Migration in the Olfactory System The olfactory system is unique in both its vulnerability to environmental insults and its regenerative capacity. Interneuron cell death in the olfactory bulb is ameliorated by the replacement of these cells with new neurons capable of integrating into previously established neural circuits. Microglia may be pivotal to this process, as they are first-line responders to cell death and are responsible for clearing debris. There has also been growing appreciation in recent years for the role these immune cells play in establishing neural circuits during development. Moreover, there is evidence that microglia may recruit neuroblasts targeted to the olfactory bulb to sites of injury following stroke. The mechanisms by which microglia may influence neuroblast migration is not well understood, but the olfactory system offers a tractable model. Thus, this project will explore the hypothesis that microglia influence neuroblast migration during development and in response to cell death in the olfactory bulb. Three independent questions examining how microglia may affect neuroblast migration in the olfactory system are addressed here. Aim 1 will characterize the distribution and morphology of microglia in the developing olfactory system. It is hypothesized that microglia morphology reflects functional states, and preliminary studies show that microglia exhibit a greater range of morphologies during the early postnatal period, including the presence of small “ameboid” cells along the path of migrating neuroblasts. These “ameboid” cells may play a functional role in neuroblast migratory streams. Aim 2 will test the hypothesis that microglia depletion results in arrested neuroblast migration during development. Preliminary data indicates that microglia closely associate with migrating neuroblasts in the olfactory system during development and prior to the formation of the astrocytic and vascular scaffold that guides these cells in adulthood. If microglia depletion results in neuroblasts clumping and dying before they reach their final destination in the olfactory bulb, it would suggest a functional role for microglia facilitating neuroblast migration during this developmental period. Aim 3 will test the hypothesis that microglia secrete molecules that influence neuron migration. Fluorescence in situ hybridization and immunohistochemical approaches will be used to examine the expression of microglia-secreted molecules along the path of neuroblast migration, both during development and in response to neuron cell death in the olfactory bulb. Understanding how microglia mediate neuroblast migration in the olfactory system will not only increase our understanding of olfaction but may pave the way for better therapies to mitigate neurodevelopmental disorders and neurologic injury.

项目摘要：小胶质细胞在嗅觉系统神经母细胞迁移中的作用 嗅觉系统在其对环境损害的脆弱性和再生能力方面是独特的。 嗅球中的中间神经元细胞死亡通过用新的神经元替换这些细胞而得到改善 能够整合到先前建立的神经回路中。小胶质细胞可能是这一过程的关键， 它们是细胞死亡的第一线反应者，并负责清除碎片。此外， 近年来，人们对这些免疫细胞在建立神经回路中所起的作用表示赞赏， 发展此外，有证据表明，小胶质细胞可能会招募神经母细胞针对嗅球 中风后受伤的部位。小胶质细胞可能影响成神经细胞迁移的机制是 虽然我们还不太了解，但嗅觉系统提供了一个易于处理的模型。因此，本项目将探讨 小胶质细胞在发育过程中影响成神经细胞迁移和对细胞死亡反应假说 嗅球 三个独立的问题探讨小胶质细胞如何影响嗅觉系统中的神经母细胞迁移 都在这里。目的1将描述小胶质细胞的分布和形态， 发展嗅觉系统。假设小胶质细胞形态反映功能状态， 初步研究表明，小胶质细胞在出生后早期表现出更大范围的形态 期间，包括小的“阿米巴样”细胞的存在沿着迁移的神经母细胞的路径。这些 “阿米巴样”细胞可能在成神经细胞迁移流中发挥功能性作用。目标2将检验假设 在发育过程中，小胶质细胞的缺失导致神经母细胞迁移受阻。初步数据 表明小胶质细胞与嗅觉系统中迁移的成神经细胞密切相关， 在星形胶质细胞和血管支架形成之前， 成年如果小胶质细胞的消耗导致神经母细胞在达到最终的生长阶段之前聚集并死亡， 目的地在嗅球，这将表明小胶质细胞促进成神经细胞迁移的功能作用 在这个发展时期。目标3将测试小胶质细胞分泌分子的假设， 影响神经元迁移。荧光原位杂交和免疫组织化学方法将在 用于检测小胶质细胞分泌分子沿着成神经细胞迁移路径的表达， 在发育过程中和对嗅球中神经元细胞死亡的反应中。了解小胶质细胞如何 在嗅觉系统中介导成神经细胞迁移不仅会增加我们对嗅觉的理解， 可能为更好的治疗方法铺平道路，以减轻神经发育障碍和神经损伤。