Your Brain on Oxygen: From Glucose to Lactate to Carbon Dioxide and Water

Two seminal studies were published almost simultaneously in 1988 in the same scientific journal. Both spurred the field of brain energy metabolism research in new directions, culminating in long-lasting debates that appear to split its practitioners into two factions that seem unwilling to agree on what metabolic processes are responsible for providing adenosine triphosphate (ATP) to the active brain. The first study used rat hippocampal slices to demonstrate the ability of lactate to support neuronal function as the sole oxidative mitochondrial substrate. The second study demonstrated that upon brain stimulation, glucose consumption is not accompanied by oxygen consumption i.e., a non-oxidative glucose utilization or what has become known as “aerobic glycolysis.” Consequently, for almost four decades, researchers in this field have been divided between those who profess that non-oxidative glucose metabolism supports neural activity and those who profess that this activity is supported by oxidative lactate metabolism. Hypotheses for both concepts were offered, “The Efficiency Tradeoff Hypothesis” and the “Astrocyte Neuron Lactate Shuttle Hypothesis,” respectively. To bridge the gap between the two groups, a recent Editorial was published, authored by over twenty leading investigators. The editorial received two separate responses from investigators who support the non-oxidative glucose consumption as the main source of energy to support neuronal activity, signaling that the gap has not being bridged. The present review attempts to cover the principal disagreements that divide this utmost important field of research with the aim of uncovering points of agreement and possible hurdles that, if removed, could close this rift.