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起着至关重要的作用。然而，环境以及对这些细胞的要求在灰质和白质中是非常不同的。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，而白质星形胶质细胞主要接触轴突(Ranvier结节)、少突胶质细胞及其髓鞘。从功能上讲，灰质内神经元的主要任务是在突触上传输和计算信息；白质束是专门化的，允许轴突沿着轴突进行可靠的长距离传播。我们假设，这些不同的环境和需求导致星形胶质细胞在不同的基础和刺激能量代谢方面的代谢异质性，包括不同信号的调节。此外，我们假设这些细胞对信号的代谢反馈是不同的。因此，本项目旨在解开灰质和白质星形胶质细胞的区别代谢事件、潜在的调节原理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，包括使用基因编码的荧光传感器对代谢物进行成像，以及在从小鼠急性分离的脑片中进行钙成像，比较皮质和胼胝体。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，将建立脑灰质和白质星形胶质细胞代谢差异的潜在机制。我们期望确定灰质和白质星形胶质细胞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方面的差异，同时也提供代谢对信号事件的反馈。此外，我们希望获得关于星形细胞代谢表型如何在大脑不同区域指定的见解。总之，拟议的项目旨在建立一个全面的图像星形细胞代谢，它的调节，以及异质性在不同的，但也在大脑区域内。这些洞察力将使我们更深入地了解大脑能量代谢是如何嵌入到大脑生理中来实现大脑功能的。

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.