A Temporary Local Energy Pool Coupled to Neuronal Activity: Fluctuations of Extracellular Lactate Levels in Rat Brain Monitored with Rapid‐Response Enzyme‐Based Sensor

Abstract

A successfully developed enzyme-based lactate microsensor with rapid response time allows the direct and continuous in vivo measurement of lactic acid concentration with high temporal resolution in brain extracellular fluid. The fluctuations coupled to neuronal activity in extracellular lactate concentration were explored in the dentate gyrus of the hippocampus of the rat brain after electrical stimulation of the perforant pathway. Extracellular glucose and oxygen levels were also detected simultaneously by coimplantation of a fast-response glucose sensor and an oxygen electrode, to provide novel information of trafficking of energy substances in real time related to local neuronal activity. The results first give a comprehensive picture of complementary energy supply and use of lactate and glucose in the intact brain tissue. In response to acute neuronal activation, the brain tissue shifts immediately to significant energy supply by lactate. A local temporary fuel "reservoir" is established behind the blood-brain barrier, evidenced by increased extracellular lactate concentration. The pool can be depleted rapidly, up to 28% in 10-12 s, by massive, acute neuronal use after stimulation and can be replenished in approximately 20 s. Glutamate-stimulated astrocytic glycolysis and the increase of regional blood flow may regulate the lactate concentration of the pool in different time scales to maintain local energy homeostasis.

Is Brain Lactate Metabolized Immediately after Neuronal Activity through the Oxidative Pathway?

“…This study and several others (e.g., De Bruin et al, 1990;Kuhr et al, 1988;Van der Kuil and Korf, 1991;Krugers et al, 1992) show that lactate is formed under conditions of enhanced neural activity which is-at least in part-associated with lower extracellular glucose. The time course of hippocampus lactate after a single stimulation (lasting 5 secs; Hu and Wilson, 1997) and detected with the biosensors is very similar to that seen with continuous flow analysis of microdialysates in rats, subjected to a single electroconvulsive stimulus with an intact entorhinalhippocampal glutamatergic pathway (Krugers et al, 1992). Modelling shows that such a time course can best be described by a very rapid (nearly immediate) increase of intracellular lactate that is subsequently released into the extracellular compartment via a carrier-mediated process (Kuhr et al, 1988).…”

Elevated brain lactate responses to neural activation in panic disorder: a dynamic 1H-MRS study

“…It should be noted that there is some evidence that a slight, transient decrease in local pO 2 may occur during the first few hundred milliseconds of neural activation. 39 However, if this occurs, it would be quickly supplanted by a longer lasting hyperemia and increase in oxygen availability. 44,45 Thus, even if a transient hypoxia occurs at the beginning of visual stimulation, it cannot be the cause of the sustained elevation of lactate observed in the PD patients.…”

“…However, it is now known that lactate accumulation occurs regularly under aerobic conditions in the brain and other tissues and that lactate is an important metabolic fuel. 35,36 Although its exact role as a metabolic fuel is not yet fully understood, studies have shown that lactate is the end product of glycogenolysis in astroglia, 37,38 that accumulation of lactate in brain parenchyma is a normal occurrence during neural activation under fully aerobic conditions 39,40 and that lactate is a significant substrate for neuronal oxidative metabolism. 36,41 The hypoxia model of PD interprets the exaggerated brain lactate responses to alkalosis as confirmation that alkalosisinduced vasoconstriction has caused hypoxia in the PD patients.…”

“…In vivo studies in both animals and humans have shown that neural activation is accompanied by increased glycolysis under fully aerobic conditions (aerobic glycolysis) and results in an increase in local brain lactate concentration. 39,40,42,43,45 Thus, the 'metabolism' model predicts that the characteristically exaggerated lactate responses of PD patients will be observed in the visual cortex during visual stimulation. We used 1H-MRS measures of visual cortex lactate responses to visual stimulation in PD patients and healthy comparisons subjects to test the contrasting predictions of these two models.…”

Brain lactate responses during visual stimulation in fasting and hyperglycemic subjects: A proton magnetic resonance spectroscopy study at 1.5 Tesla

“…Recent studies have suggested that lactate might serve a similar role in brain energy metabolism (Pellerin et al, 1998;Schurr, 2005). In vivo measures of brain lactate with microsensors in rats (Hu and Wilson, 1997) and with proton magnetic resonance spectroscopy (1H-MRS) in humans (Prichard et al, 1991;Sappey-Marinier et al, 1992;Frahm et al, 1996) have demonstrated brain lactate increases during neuronal activation. These 1H-MRS studies suggests that noninvasive measures of activity-stimulated lactate responses can be used to study brain function in humans.…”