Lactate efflux and the neuroenergetic basis of brain function

In the unstimulated brain energy is primarily supplied by the oxidation of glucose. However the oxygen-to-glucose index (OGI), which is the ratio of metabolic rates of oxygen to glucose, CMR(O2)/CMR(glc), diverges from the theoretical value of 6 as activity is increased. In vivo measurements of brain lactate show its concentration to increase with stimulation. The decreasing OGI with stimulation had led to the suggestion that activation, unlike resting activity, is supported by anaerobic glycolysis. To date a unifying concept that accommodates glucose oxidation at rest with lactate generation and OGI decrease during stimulation of brain is lacking. Furthermore, energetics that change with increasing activity are not consistent with a neuroenergetic model that has been proposed from 1-(13)C-glucose MRS experiments. That model, based upon in vivo MRS measurements and cellular studies by Pellerin and Magistretti, showed that glutamate neurotransmitter cycling was coupled to glucose oxidation over a wide range of brain activities from rest down to deep anesthesia. Here we reconcile these paradoxical observations by suggesting that anaerobic glucose consumption (which can provide energy rapidly) increases with activation to meet the power requirements of millisecond neuronal firing. It is proposed, in accord with our neuroenergetic model, that the extra glucose mobilized rapidly for glial clearance of glutamate, is not needed for the oxidative processes that are responsible for neuronal firing and glutamate release, and consequently it is effluxed as lactate. A stoichiometric relation between OGI and lactate concentration is derived from the neuroenergetic model, showing that the enhanced glucose uptake during activation is consistent with neuronal activity being energetically supported by glucose oxidation.