Regulation of blood flow in activated human brain by cytosolic NADH/NAD+ ratio - PubMed (original) (raw)

Regulation of blood flow in activated human brain by cytosolic NADH/NAD+ ratio

Andrei G Vlassenko et al. Proc Natl Acad Sci U S A. 2006.

Abstract

It has been known for more than a century that increases in neuronal activity in the brain are reliably accompanied by changes in local blood flow. More recently it has been appreciated that these blood flow increases are accompanied by increases in glycolysis that are much greater than the increases in oxidative phosphorylation. It has been proposed by us and others that this activity-induced increase in glycolysis mediates the increase in blood flow by mechanisms linked through the near-equilibrium relationship between cytosolic NADH/NAD+ and the lactate/pyruvate ratios. Here we show in awake human subjects that by transiently raising blood pyruvate concentration during local increases in functional brain activity, a maneuver designed to reduce the cytosolic NADH/NAD+ ratio, the expected blood flow response measured with positron-emission tomography is significantly attenuated. This result provides critical additional support for the hypothesis that, like in anesthetized rodents, the cytosolic NADH/NAD+ ratio of awake human subjects links activity-induced increases in glycolysis to signaling pathways for the regulation of blood flow.

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.

Fig. 1.

Blood values for glucose, lactate, pyruvate, and lactate/pyruvateratio. Inset illustrates the start time of pyruvate injection (red dashed line) and the PET scan (red bar). The values are means for six subjects. The values and SDs for all measures are presented in Table 2.

Fig. 2.

Fig. 2.

Correlation between pyruvate-attenuated CBF increases and percent changes in plasma lactate, pyruvate, and lactate/pyruvate ratio obtained from averaging the measured values just before and immediately after the PET scan.

Fig. 3.

Fig. 3.

Proposed model of regulation of blood flow in physiologicallystimulated human brain. Neuronal firing is associated with intermittent release of glutamate into the synaptic cleft to activate postsynaptic glutamate receptors. There is subsequent rapid glutamate uptake by astrocytes, conversion of glutamate to glutamine, and release of glutamine out of astrocytes. Glutamine is taken up by neurons for conversion back to glutamate. Glutamate uptake involves activation of Na+/K+-ATPase. Glutamate uptake and cycling in astrocytes is ATP-consuming and stimulates glycolysis. Increased glycolysis leads to increased production of NADH and a rise in the cytosolic NADH/NAD+ ratio. Regeneration of NAD+ is critical for continuation of glycolysis, and several mechanisms are recruited, including (i) malate–aspartate electron shuttle to mitochondria, (ii) conversion of pyruvate to lactate, and (iii) signaling pathways that promote an increase in brain blood flow. However, astrocytes have fewer mitochondria and lack important components of the malate–aspartate shuttle compared with neurons. Lactate produced from pyruvate will egress from astrocytes and may be taken up by neurons or removed by the increased blood flow. The impact of activated neurons in the regulation of blood flow is likely to be less than that of astrocytes, because neurons may increase ATP production without a large rise in the NADH/NAD+ ratio because of simultaneous increase in both glycolysis and oxidative phosphorylation, and they have more effective pathways of NAD+ regeneration.

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