Cerebral Oxygen/Glucose Ratio is Low during Sensory Stimulation and Rises above Normal during Recovery: Excess Glucose Consumption during Stimulation is Not Accounted for by Lactate Efflux from or Accumulation in Brain Tissue

Abstract

Functional activation stimulates CMRglc more than CMRO2 and raises lactate levels in brain. This has been interpreted as evidence that brain work is supported mainly by energy derived from anaerobic glycolysis. To determine if lactate production accounts for the "excess" glucose consumption, cerebral arteriovenous differences were measured in conscious rats before, during, and 15 minutes after sensory stimulation; the brains were rapidly frozen in situ immediately after completion of blood sampling and assayed for metabolite levels. The molar O2/glucose uptake ratio fell from 6.1+/-1.1 (mean+/-SD) before stimulation to 5.0+/-1.1 during activation (P<0.01); lactate efflux from brain to blood was detectable at rest but not during stimulation. By 15 minutes after activation, O2 and lactate arteriovenous differences normalized, whereas that for glucose fell, causing the O2/glucose ratio to rise above preactivation levels to 7.7+/-2.6 (P<0.01). Brain glucose levels remained stable through all stages of activity. Brain lactate levels nearly doubled during stimulation but normalized within 15 minutes of recovery. Brain glycogen content fell during activation and declined further during recovery. These results indicate that brain glucose metabolism is not in a steady state during and shortly after activation. Furthermore, efflux from and increased content of lactate in the brain tissue accounted for less than 54% of the "excess" glucose used during stimulation, indicating that a shift to anaerobic glycolysis does not fully explain the disproportionately greater increases in CMRglc above that of CMRO2 in functionally activated brain. These results also suggest that the apparent dissociation between glucose utilization and O2 consumption during functional activation reflects only a temporal displacement; during activation, glycolysis increases more than oxidative metabolism, leading to accumulation of products in intermediary metabolic pools that are subsequently consumed and oxidized during recovery.

Neurohumoral responses during prolonged exercise in humans

“…Two possibilities are that glucose-derived molecules, such as amino acids (e.g., glutamate), are synthesized during the early recovery phase or that brain glycogen stores are replenished (17,29,53). This notion is supported by the observations that cerebral activation is associated with a reduced brain glycogen content in rats (17,36,37,56) and a reduced oxygento-carbohydrate consumption ratio in the brain for several minutes after cerebral activation in rats (sensory stimulation; Ref. 36) and humans (Wisconsin Card Sorting Test; Ref.…”

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

“…Reduction of pyruvate to lactate results in a rise in tissue lactate levels, which has been demonstrated in animals (22,23) and in humans with magnetic resonance spectroscopy (24-27) during brain activation. It has been proposed that a third pathway for regeneration of NAD ϩ occurs during activation, which increases NADH oxidation through signaling pathways that promote production of nitric oxide with subsequent increase in blood flow (8,11).…”

Localized in vivo13C NMR spectroscopy of the brain

“…146 The concept of uncoupled oxygen metabolism has been supported by studies reporting small increases in brain lactate during focal activation 147,148 that initially were very controversial 149 and that are very difficult to perform. The relatively small magnitude of change in brain lactate is difficult to reconcile with the reported large uncoupling between oxygen and glucose consumption 150 and explanations linking the lactate increase to brain glycogen at present appear unlikely (see above). To address this question, it is useful to measure the TCA cycle activity in the brain.…”