Cerebral perfusion and metabolic response of astrocytes and neurons during locomotion

The hemodynamic response links neural oxidative metabolism changes to increased cerebral blood flow during brain activity1. Although Roy and Sherrington introduced this concept over a century ago (1890), the exact cellular mechanisms remain unclear. This study demonstrates how local blood supply increases correlate with the metabolic response of individual brain cells during locomotion. Using Raman microspectroscopy, we observed an elevation in oxygen saturation levels (sO2) in cortical venules but not in arterioles, which were already near saturation. The increased sO2 in the venules was accompanied by vasodilation, indicating blood oversupply in the local brain area, a phenomenon known as functional hyperemia. We then analyzed the metabolic response of individual neurons and astrocytes to locomotion. In neurons, the levels of reduced cytochromes of c and b types [cyt c,b (Fe2+)] rapidly decreased at the onset of locomotion. This suggests an increase in the activity of the mitochondrial respiratory chain (electron transport chain, ETC) in response to heightened energy demands in these cells2. In contrast, because astrocytes rely less on oxidative phosphorylation for their energy metabolism than neurons3, we did not observe an initial decrease in reduced cytochromes in these cells. However, as locomotion continued, the cyt c,b (Fe2+) levels steadily increased in both cell types. In neurons, this led to a slow recovery from the initial drop, while in astrocytes, the increase exceeded baseline levels. Consequently, we observed an overload of electrons in the astrocytic ETC. The distinct responses of astrocytic and neuronal mitochondria to locomotion may reflect differences in the organization of the ETC in the two cell types4. Furthermore, astrocytes may shift to glycolysis under increased neuronal activity5,6. This difference also resulted in hydrogen peroxide (H202) production in astrocytic mitochondria but not neuronal mitochondria. Since H202 is a signaling molecule critical for cognitive function in the brain7, we speculate that astrocytic mitochondria act as signaling hubs during exercise.