Mitochondrial metabolism in astrocytes - impact on hippocampal neurogenesis and gliogenesis

新神经元的不断生成和整合到现有的神经回路中是成年人大脑可塑性的关键贡献，并且仅限于前脑中的特定神经发生龛-其中之一是海马体。在这里，神经元的产生是通过一个刻板的发育序列来实现的，这需要精确的调节机制来防止常驻神经干细胞（NSCs）的衰竭或不受控制的生长。最近，我发现线粒体电子传递和氧化磷酸化在调节海马神经源性谱系的进展中起着关键作用，特别是在中间祖细胞状态。破坏NSCs和星形胶质细胞中的这些通路可诱导过早衰老表型，而增强线粒体功能可显著改善衰老过程中的神经发生。我的数据确定了线粒体功能是改善老年海马神经发生缺陷的潜在目标，并支持了特定阶段的代谢程序在功能上与NSC谱系中的不同步骤相关联的新兴概念。与其他干细胞系统一样，干细胞及其后代与其微环境的相互作用对海马神经发生的调节至关重要。星形胶质细胞是神经源性壁龛的关键组成部分，为新神经元的产生提供了必要的局部微环境。从获得的结果中出现的一个有趣的问题是，海马神经发生的缺陷是由NSCs的线粒体功能障碍引起的，还是由于生态位星形胶质细胞的代谢变化引起的。在项目1中，我将在两种不同的小鼠模型中诱导条件Tfam缺失- nsc特异性cre驱动和特定于小众星形胶质细胞的cre驱动-并研究对神经源性谱系进展的影响。这些研究将为小生境星形胶质细胞的线粒体代谢是否以及如何影响海马神经发生提供重要的见解。此外，我将研究线粒体代谢在胶质细胞发生和胶质细胞谱系进展中的潜在调节功能的新方面。项目2将评估来自成年海马NSCs和局部星形胶质细胞祖细胞的新星形胶质细胞的产生、存活和成熟是否需要完整的线粒体复杂机制，或者这是否是神经元谱系的特定标志。总之，这些研究将为星形胶质细胞线粒体代谢对成人海马神经发生和胶质发生的调节功能提供重要的见解。

The continuous generation and integration of new neurons into existing circuitries is a key contribution to an adult's brain plasticity and is restricted to specific neurogenic niches in the forebrain - one of them is the hippocampus. Here, the production of neurons is achieved through a stereotypic developmental sequence that requires precise regulatory mechanisms to prevent exhaustion or uncontrolled growth of resident neural stem cells (NSCs). Recently, I discovered a critical role of mitochondrial electron transport and oxidative phosphorylation in regulating progression of the hippocampal neurogenic lineage specifically at the intermediate progenitor cell state. Disrupting these pathways in NSCs and astrocytes induces premature ageing phenotypes while enhancing mitochondrial function significantly improves neurogenesis during ageing. My data identify mitochondrial function as a potential target to ameliorate neurogenesis defects in the aged hippocampus and support the emerging notion that stage-specific metabolic programs are functionally linked to distinct steps within the NSC lineage. Like in other stem cell systems, interaction of stem cells and stem cell progeny with their microenvironment is critical for regulation of hippocampal neurogenesis. Astrocytes are key components of the neurogenic niches and provide the necessary local microenvironment for the generation of new neurons. An intriguing question emerging from the obtained results is if the defects in hippocampal neurogenesis are caused by mitochondria dysfunction in NSCs or due to metabolic changes in niche astrocytes. In project 1 I will induce conditional Tfam deletion in two different mouse models - a NSC-specific Cre-driver and a Cre-driver specific for niche astrocytes - and investigate the impact on neurogenic lineage progression. These studies will give important insights into whether and how mitochondrial metabolism in niche astrocytes affects hippocampal neurogenesis. Furthermore, I will investigate the novel aspect of a potential regulatory function of mitochondrial metabolism in gliogenesis and glial lineage progression. Project 2 will assess if generation, survival and maturation of new astrocytes from adult hippocampal NSCs and local astrocyte progenitors require intact mitochondrial complex machinery or if this is a specific hallmark of the neuronal lineage. Together, these studies will provide important insights into a regulatory function of mitochondrial metabolism in astrocytes on neurogenesis and gliogenesis in the adult hippocampus.