Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging

Despite striking advances in functional brain imaging, the cellular and mol ecular mechanisms that underlie the signals detected by these techniques ar e still largely unknown. The basic physiological principle of functional im aging is represented by the tight coupling existing between neuronal activi ty and the associated local increase in both blood flow and energy metaboli sm. Positron emission tomography (PET) signals detect blood flow, oxygen co nsumption and glucose use associated with neuronal activity; the degree of blood oxygenation is currently thought to contribute to the signal detected with functional magnetic resonance imaging, while magnetic resonance spect roscopy (MRS) identifies the spatio-temporal pattern of the activity-depend ent appearance of certain metabolic intermediates such as glucose or lactat e. Recent studies, including those of neurotransmitter-regulated metabolic fluxes in purified preparations and analyses of the cellular localization o f enzymes and transporters involved in energy metabolism, as well as in viv o microdialysis and MRS approaches have identified the neurotransmitter glu tamate and astrocytes, a specific type of glial cell, as pivotal elements i n the coupling of synaptic activity with energy metabolism. Astrocytes are ideally positioned to sense increases in synaptic activity and to couple th em with energy metabolism. Indeed they possess specialized processes that c over the surface of intraparenchymal capillaries, suggesting that astrocyte s may be a likely site of prevalent glucose uptake. Other astrocyte process es are wrapped around synaptic contacts which possess receptors and reuptak e sites for neurotransmitters. Glutamate stimulates glucose uptake into ast rocytes. This effect is mediated by specific glutamate transporters present on these cells. The activity of these transporters, which is tightly coupl ed to the synaptic release of glutamate and operates the clearance of gluta mate from the extracellular space, is driven by the electrochemical gradien t of Na+. This Na+-dependent uptake of glutamate into astrocytes triggers a cascade of molecular events involving the Na+/K+-ATPase leading to the gly colytic processing of glucose and the release of lactate by astrocytes. The stoichiometry of this process is such that for one glutamate molecule take n up with three Na+ ions, one glucose molecule enters an astrocyte, two ATP molecules are produced through aerobic glycolysis and two lactate molecule s are released. Within the astrocyte, one ATP molecule fuels one 'turn of t he pump' while the other provides the energy needed to convert glutamate to glutamine by glutamine synthase. Evidence has been accumulated from struct ural as well as functional studies indicating that, under aerobic condition s, lactate may be the preferred energy substrate of activated neurons. Inde ed, in the presence of oxygen, lactate is converted to pyruvate, which can be processed through the tricarboxylic acid cycle and the associated oxidat ive phosphorylation, to yield 17 ATP molecules per lactate molecule. These data suggest that during activation the brain may transiently resort to aer obic glycolysis occurring in astrocytes, followed by the oxidation of lacta te by neurons. The proposed model provides a direct mechanism to couple syn aptic activity with glucose use and is consistent with the notion that the signals detected during physiological activation with F-18-deoxyglucose (DG )-PET may reflect predominantly; uptake of the tracer into astrocytes. This conclusion does not question the validity of the 2-DG-based techniques , rather it provides a cellular and molecular basis for these functional br ain imaging techniques.