Origins, properties, and therapeutic potential of cells that repopulate the microglia-depleted adult brain

摘要： 我们发现成年人大脑中的小胶质细胞依赖于通过集落刺激因子1的信号传导 受体（CSF 1 R），并确定了几种CSF 1 R抑制剂，进入大脑，导致 消除大部分的小胶质细胞。这一引人注目的现象已被广泛复制，现在是一个 标准领域探索小胶质细胞在健康和疾病中的功能，临床试验正在进行中。 计划/执行结果。我们还发现，只要我们继续下去， 治疗，但停药后，小胶质细胞组织的再增殖迅速发生， 整个大脑中的细胞在约14天内形成新的小胶质组织。我们发现我们可以用它来 在损伤后或老化中“重置”发炎的小胶质细胞组织，并促进功能恢复/认知。在这 继续，我们试图了解这些再生细胞的来源和性质， 小胶质细胞，并研究它们如何调节神经元基因表达，以恢复老年大脑的活力， 恢复幼年动物的长时程增强。此外，我们描述了第二个较慢的来源， 小胶质细胞再增殖，起源于特定的脑龛-吻侧迁移流（RMS）， 相关的突出轴突束。这种“替代性”的重新繁殖只有在完全的 消除小胶质细胞。这些“替代”细胞来自这些大脑小生境中的未知细胞， 最终可以从白色物质束中爆发出来并填充皮层/大脑。这些细胞永远不会达到 小胶质细胞的数量、形态或基因表达，但类似于RMS中发现的小胶质细胞， 促神经发生和增加的吞噬能力比其他小胶质细胞。我们会确定 这些“替代”细胞的数量，以及用它们填充大脑的后果，包括它们是否有任何 治疗潜力，在阿尔茨海默病的小鼠模型中。

Abstract: We discovered microglia in the adult brain are dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R), and identified several CSF1R inhibitors that crossed into the brain, leading to the elimination of most of the microglia. This remarkable phenomenon has been widely replicated and is now a standard in the field to explore microglial function in health and disease, and clinical trials are being conducted/planned as a result. We also found that we could eliminate microglia for as long as we continued treatment, but upon drug withdrawal, repopulation of the microglial tissue occurred rapidly from proliferating cells throughout the brain that formed a new microglial tissue in ~14 days. We found we could use this to “reset” the inflamed microglial tissue after injury or in aging, and promote functional recovery/cognition. In this continuation, we seek to understand the source and properties of these repopulating cells that become microglia, and study how they modulate neuronal gene expression to rejuvenate the aged brain and fully restore long-term potentiation to that of a young animal. In addition, we describe a second slower source of microglial repopulation, that originates in specific brain niches – the rostral migratory stream (RMS) and associated projecting axonal tracts. This “alternative” repopulation is only unmasked by the complete elimination of microglia. These “alternative” cells arise from unknown cells within these brain niches, and eventually can break out from the white matter tracts and fill the cortex/brain. These cells never attain the numbers, morphologies, or gene expression of microglia, but resemble microglia found in the RMS, which have pro-neurogenesis and increased phagocytotic capabilities than other microglia. We will determine the source of these “alternative” cells, and the consequences of filling the brain with them, including if they have any therapeutic potential, in a mouse model of Alzheimer's disease.