Mitochondrial metabolism in astrocytes - impact on hippocampal neurogenesis and gliogenesis

星形胶质细胞的线粒体代谢 - 对海马神经发生和胶质细胞生成的影响

• 批准号: 222167634
• 负责人: Dr. Ruth Beckervordersandforth
• 金额: --
• 依托单位: Institut für Biochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/222167634?language=en
• 关键词: Mitochondrial; metabolism; astrocytes; impact; hippocampal

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.

不断产生新神经元并将其整合到现有的回路中，是成年人大脑可塑性的关键贡献，并仅限于前脑中特定的神经源性缝隙--其中之一是海马体。在这里，神经元的产生是通过一种刻板的发育序列实现的，这需要精确的调控机制来防止常驻神经干细胞(NSCs)耗尽或不受控制的生长。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，特别是在中间前体细胞状态。破坏神经干细胞和星形胶质细胞中的这些途径会导致过早衰老的表型，同时增强线粒体功能显着改善衰老过程中的神经发生。我的数据确定线粒体功能是改善老年海马区神经发生缺陷的潜在靶点，并支持新出现的概念，即特定阶段的代谢程序在功能上与NSC谱系中的不同步骤有关。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控至关重要。星形胶质细胞是神经源性小生境的关键组成部分，为新神经元的产生提供必要的局部微环境。从所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神经干细胞中的线粒体功能障碍引起的，还是由于壁龛星形胶质细胞的代谢变化引起的。在项目1中，我将在两个不同的小鼠模型中诱导条件性Tfam缺失--一个是NSC特异性的CRE驱动程序，另一个是针对小生境星形胶质细胞的CRE驱动程序--并研究其对神经源性谱系进展的影响。这些研究将为研究利基星形胶质细胞中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神经胶质发生和神经胶质细胞谱系发展中的潜在调节功能的新方面。项目2将评估从成年海马神经干细胞和局部星形胶质细胞前体细胞产生、存活和成熟的新星形胶质细胞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一个特殊标志。总之，这些研究将为了解星形胶质细胞线粒体代谢对成年海马区神经发生和胶质形成的调节作用提供重要的见解。