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，在灰质和白质中，环境和对这些细胞的需求是非常不同的。灰质星形胶质细胞主要接触突触、血管等星形胶质细胞，白质星形胶质细胞主要接触轴突（Ranvier结）、少突胶质细胞及其髓鞘。功能上，灰质内神经元的主要任务是突触传递和计算信息；白质束是专门用来允许可靠的轴突电位沿轴突长距离传播的。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，本项目旨在揭示灰质和白质星形胶质细胞的区别代谢事件，潜在的调节原理及其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，包括利用遗传编码荧光传感器对代谢物进行成像，以及在小鼠急性分离的脑切片中比较皮层和胼胝体的钙成像。脑灰质和白质星形胶质细胞代谢差异的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。我们期望发现灰质和白质星形胶质细胞在基础能量代谢中的差异，以及影响星形胶质细胞能量代谢的主要调节机制，同时也提供从代谢到信号事件的反馈。此外，我们期望获得星形细胞代谢表型是如何在大脑的不同区域指定的见解。总之，该项目旨在建立星形细胞代谢的全面图景，其调控，以及大脑不同区域的异质性。这些见解将使我们更深入地了解大脑能量代谢是如何嵌入大脑生理学中以实现大脑功能的。

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.