Imaging brain activation: simple pictures of complex biology.

Elucidation of biochemical, physiological, and cellular contributions to metabolic images of brain is important for interpretation of images of brain activation and disease. Discordant brain images obtained with [(14)C]deoxyglucose and [1- or 6-(14)C]glucose were previously ascribed to increased glycolysis and rapid [(14)C]lactate release from tissue, but direct proof of [(14)C]lactate release from activated brain structures is lacking. Analysis of factors contributing to images of focal metabolic activity evoked by monotonic acoustic stimulation of conscious rats reveals that labeled metabolites of [1- or 6-(14)C]glucose are quickly released from activated cells as a result of decarboxylation reactions, spreading via gap junctions, and efflux via lactate transporters. Label release from activated tissue accounts for most of the additional [(14)C]glucose consumed during activation compared to rest. Metabolism of [3,4-(14)C]glucose generates about four times more [(14)C]lactate compared to (14)CO(2) in extracellular fluid, suggesting that most lactate is not locally oxidized. In brain slices, direct assays of lactate uptake from extracellular fluid demonstrate that astrocytes have faster influx and higher transport capacity than neurons. Also, lactate transfer from a single astrocyte to other gap junction-coupled astrocytes exceeds astrocyte-to-neuron lactate shuttling. Astrocytes and neurons have excess capacities for glycolysis, and oxidative metabolism in both cell types rises during sensory stimulation. The energetics of brain activation is quite complex, and the proportion of glucose consumed by astrocytes and neurons, lactate generation by either cell type, and the contributions of both cell types to brain images during brain activation are likely to vary with the stimulus paradigm and activated pathways.