Brain energy metabolismBackground The energy requirements of the brain are amazingly high; indeed, while representing only 2% of the body mass, its oxygen and glucose utilization account for approximately 20% of those of the whole organism, almost ten times more than those predicted on a mass basis . A similar mismatch is observed for blood flow destined to the brain, which represents over 10% of cardiac output. In addition to these quantitative aspects, brain metabolism has other distinctive features, in particular its regional variability and the nature of its cellular determinants. At the macroscopic level, one regional variability is manifested by the difference in energy metabolism between grey and white matter (Clarke and Sokoloff, 1994). But a much finer feature of brain metabolism is that its regional variability is strongly determined by the ever-changing spatially and temporally specified levels of synaptic activity. Thus one of the founding principles of brain physiology is that metabolism and flow are tightly coupled with neuronal activity; this fact has been appreciated since the turn of the 19th century when Sherrington proposed that "âŠthe brain possess an intrinsic mechanism by which its vascular supply can be varied locally in correspondence with local variations of functional activity" (Roy and Sherrington, 1890).The pioneering work of Louis Sokoloff and his colleagues in the 1970s and 1980s using the 2-deoxyglucose (2-DG) autoradiographic technique and its in vivo extension to humans with 18-fluoro-DG imaging of glucose utilization by positron emission tomography (PET) (Sokoloff et al., 1977), has clearly demonstrated a similar coupling between neuronal activity and glucose metabolism. Indeed, this tight relationship between neuronal activity with blood flow and metabolism has provided the basis for the functional brain imaging techniques that are now widely in use by cognitive neuroscientists and clinicians (Mazziotta et al., 2000). Thus local changes in glucose utilization, blood flow and oxygen utilization for PET and, mostly, variations in the level of hemoglobin oxygenation for functional magnetic resonance imaging (fMRI) during wellThe coupling between synaptic activity and glucose utilization (neurometabolic coupling) is a central physiological principle of brain function that has provided the basis for 2-deoxyglucose-based functional imaging with positron emission tomography (PET). Astrocytes play a central role in neurometabolic coupling, and the basic mechanism involves glutamate-stimulated aerobic glycolysis; the sodium-coupled reuptake of glutamate by astrocytes and the ensuing activation of the Na-K-ATPase triggers glucose uptake and processing via glycolysis, resulting in the release of lactate from astrocytes. Lactate can then contribute to the activity-dependent fuelling of the neuronal energy demands associated with synaptic transmission. An operational model, the 'astrocyteneuron lactate shuttle', is supported experimentally by a large body of evidence, which provides a molecu...