Objectives: Increased glucose uptake in the activated region of the brain known as neurometabolic coupling has long been widely accepted in functional neuroimaging. A fundamental question is how and which cell plays a key role in the immediate uptake of glucose during brain activation. Here, we suggest the key role of the endothelium in the enhancement of glucose utilization using single-cell level analysis. Methods: Public single-cell RNA-sequencing data were acquired from the mouse brains of visual stimulation and those of chemical stimulation by pentylenetetrazole (PTZ). Various cells including neurons, glial cells and endothelial cells were identified by marker genes. Differentially expressed genes according to the activation were analyzed for each cell type. RNA levels of glucose transporters and genes related to glycolysis were investigated according to the activation in each cell type. Functional in vivo glucose uptake during brain activation was analyzed by FDG PET in 8-week-old C57BL/6 mouse. FDG PET was acquired after the seizure induction by PTZ with or without GLUT1 inhibition. Results: GLUT1 expression was significantly increased in Nr2f2-expressing endothelial cell clusters after neuronal activation, regardless of stimulation methods. GLUT3 and glycolysis were not significantly changed in neurons and glial cells in both activation studies. In vivo study with FDG PET revealed relatively increased glucose uptake in the whole brain cortex after the seizure induction. Compared with the brain with chemical stimulation only, FDG uptake was relatively decreased in the brain when GLUT1 inhibitor was administered before the chemical stimulation.
Conclusions: Endothelial cells play a key role in immediate increases in glucose uptake during brain activation by upregulation of GLUT1.
Bae, S., Choi, Y., Choi, H., & Lee, D. S. (2020).