Opposing Roles for Microglia in the Young and Aged Neurogenic Niche

项目摘要 神经干细胞/祖细胞产生成熟的神经元、星形胶质细胞和少突胶质细胞 在生活中。然而，神经发生在衰老过程中迅速下降， 年龄依赖性神经干细胞功能障碍尚不清楚。室-室下区（V-subventricular zone，V-subventricular zone） SVZ）位于侧脑室，是小鼠中最大的神经干细胞库。 个脑袋我们已经发现，小胶质细胞，大脑的先天免疫细胞， 定位在整个年轻和老年V-SVZ利基。在衰老过程中，小胶质细胞经历了 从静息状态到促炎状态的形态学和表型转变。 初步数据表明，来自年轻小胶质细胞的分泌分子支持增殖， 体外神经元分化。相比之下，从老年小鼠中分离出的小胶质细胞似乎失去了 这对体外增殖的影响。总的来说，这些数据表明小胶质细胞在一个关键的年龄- 在调节神经发生中的依赖性作用。尽管小胶质细胞在 神经母细胞的吞噬作用，它们对B型神经干细胞的影响，C型转运 扩增细胞和小生境细胞结构基本上是未知的。使用三维图像 分析小生境细胞结构和流式细胞仪（FACS），我们将测试 小胶质细胞在年轻和老年神经原生态位中具有相反作用的假说。 在目标1中，我们将从年轻的神经原性胶质细胞中分离和遗传性地耗尽小胶质细胞。 利基和询问对神经发生，B，C型和神经母细胞存活的影响， 以及数量、增殖和靠近血管室的位置。在目标2中，我们将使用 异时输注来自年轻和老年小胶质细胞的分泌分子，以直接测试 这些分子在神经发生中具有相反的作用。在目标3中，我们将测试是否减轻 老年小胶质细胞的炎性表型恢复神经干/祖细胞功能。我们将 我还探索了小胶质细胞衍生的分泌分子的新分子候选物， 或阻碍神经发生。了解小胶质细胞激活状态如何调节 神经发生会产生深远的影响V-SVZ神经网络被广泛接受， 干细胞及其后代有助于大脑修复。因此，了解小胶质细胞 在组织内稳态和衰老过程中有助于神经发生， 了解神经发生，但将有助于在使用神经干/祖细胞的最终目标 脑细胞治疗

Project Summary Neural stem cell/progenitors cells give rise to mature neurons, astrocytes and oligodendrocytes throughout life. However, neurogenesis rapidly declines during aging and the mechanism for age-dependent neural stem cell dysfunction is not clear. The ventricular-subventricular zone (V- SVZ), lining the lateral ventricle, is home to the largest pool of neural stem cells in the murine brain. We have found that microglia, the innate immune cells of the brain, are prominently positioned throughout the young and aged V-SVZ niche. During aging, microglia undergo a morphological and phenotypical shift from a resting state to a pro-inflammatory state. Preliminary data suggest that secreted molecules from young microglia support proliferation and neuronal differentiation in vitro. In contrast, microglia isolated from aged mice appear to lose this influence on proliferation in vitro. Together, these data suggest microglia play a critical age- dependent role in regulating neurogenesis. Although microglia are known to be important in phagocytosis of neuroblasts, their influence on type B neural stem cells, type C transit amplifying cells and niche cytoarchitecture is essentially unknown. Using 3-dimensional image analysis of niche cytoarchitecture and flow activated cell sorting (FACS), we will test the hypothesis that microglia have opposing roles in the young and aged neurogenic niche. In aim 1, we will pharmacologically and genetically deplete microglia from the young neurogenic niche and interrogate the impact on neurogenesis, Type B, C and neuroblast cell survival as well as number, proliferation and position near the vascular compartment. In aim 2, we will use heterochronic infusion of secreted molecules from young and aged microglia to directly test if these molecules have opposing roles in neurogenesis. In aim 3, we will test if mitigating the inflammatory phenotype of aged microglia restores neural stem/progenitor cell function. We will also explore novel molecular candidates for microglia derived secreted molecules that support or hinder neurogenesis. Understanding how the microglia activation state regulates neurogenesis will have far-reaching consequences. It is widely accepted that V-SVZ neural stem cells and their progeny contribute to brain repair. Thus, understanding how microglia contribute to neurogenesis during tissue homeostasis and aging will not only further our basic understanding of neurogenesis but will help in the eventual goal of using neural stem/progenitor cells in brain therapeutics.