Metabolic heterogeneity of astrocytes in grey and white matter of the brain

星形胶质细胞对大脑能量代谢至关重要。然而，灰色和白色物质的环境以及对这些细胞的要求是非常不同的。灰质中的星形胶质细胞主要接触突触、血管等星形胶质细胞，而白色质星形胶质细胞主要接触轴突（在朗维尔结处）、少突胶质细胞及其髓鞘。在功能上，灰质内的神经元的主要任务是在突触处传输和计算信息;白色物质束被专门化以允许可靠的轴突电位沿沿着长距离传播。我们假设，这些不同的环境和要求导致星形胶质细胞在不同的基础以及刺激的能量代谢，包括不同的信号调节的代谢异质性。此外，我们假设代谢反馈信号在这些细胞中是不同的。因此，本项目旨在揭示灰质和白色物质星形胶质细胞中的区别性代谢事件、潜在的调节原则以及它们与脑功能的生理相关性。这些目标将使用最先进的方法来解决，包括采用基因编码的荧光传感器和钙成像的代谢物的成像急性分离的大脑切片从小鼠比较皮质和胼胝体。灰质和白色物质中星形胶质细胞之间代谢差异的潜在机制将通过不同脑区之间的细胞移植以及代谢表型与基因表达谱的相关性来建立。我们希望确定星形胶质细胞在灰色和白色物质之间的差异，在基础能量代谢以及影响星形胶质细胞能量代谢的主要调控机制，但也提供反馈，从代谢到信号事件。此外，我们期望获得有关星形胶质细胞代谢表型如何在大脑不同区域指定的见解。总之，该项目旨在全面了解星形胶质细胞代谢、其调节以及不同脑区和脑区内的异质性。这些见解将使我们更深入地了解大脑能量代谢如何嵌入大脑生理学，以实现大脑功能。

Astrocytes crucially contribute to brain energy metabolism. However, the environment and therefore the requirements for these cells are very different in grey and white matter. Astrocytes in grey matter mainly contact synapses, blood vessels and other astrocytes, while white matter astrocytes mainly contact axons (at the node of Ranvier), oligodendrocytes and their myelin. Functionally, the major task for neurons within grey matter is transmission and computation of information at synapses; white matter tracts are specialized to allow reliable axon potential propagation along axons for long distances. We hypothesize that these diverse environments and requirements result in metabolic heterogeneity of astrocytes in respect to different basal as well as stimulated energy metabolism including regulation by different signals. In addition, we hypothesize that metabolic feedback to signaling is different in these cells. Therefore, this project aims at unraveling the discriminative metabolic events in astrocytes of grey and white matter, the underlying regulatory principles as well as their physiological relevance for brain function. These objectives will be addressed using state-of-the-art methodology including imaging of metabolites employing genetically encoded fluorescent sensors and calcium imaging in acutely isolated brain slices from mice comparing cortex and corpus callosum. Mechanisms underlying metabolic differences between astrocytes in grey and white matter will be established using cell transplantations between different brain regions as well as by correlation of metabolic phenotypes with gene expression profiles. We expect to identify differences between astrocytes in grey and white matter in basal energy metabolism as well as in the main regulatory mechanisms affecting astrocytic energy metabolism, but also providing feedback from metabolism to signaling events. In addition, we expect obtaining insights on how the astrocytic metabolic phenotype is specified in different areas of the brain. In summary, the proposed project aims at establishing a comprehensive picture of astrocytic metabolism, its regulation, and heterogeneity in different but also within brain regions. These insights will allow a deeper understanding of how brain energy metabolism is embedded in brain physiology to enable brain function.