BrainFuel

Glucose is a key energy source for all eukaryotic cells. Its metabolism through the Embden-Meyerhof pathway (glycolysis) and the Krebs’ cycle (or tricarboxylic acid cycle) coupled to oxidative phosphorylation provides ATPs and redox equivalents necessary for cells to face their essential tasks. In contrast, lactate has been considered for a long time as a waste product of glucose metabolism, arising during anaerobic conditions. Its appearance has been often considered as a sign of cell (or tissue) suffering. However, recent advances demonstrated that lactate is not only formed under normal (aerobic) conditions, but it is exchanged between different cell types to be used as an oxidative substrate for energy production, thus sustaining cell activities. The concept of lactate shuttling, first proposed by George Brooks in muscle, has been extended to other tissues and organs, including the brain. Indeed, it was described that astrocytes, a specialized glial cell type of the central nervous system, are endowed with the capacity to enhance their aerobic glycolysis in proportion with the level of synaptic (neuronal) activity. Lactate produced and released by astrocytes under such circumstances is taken up by neurons and oxidized to face their high energy needs. The process has been described as the Astrocyte-Neuron Lactate Shuttle (ANLS). Since its inception 25 years ago, this concept has generated a fierce controversy. Despite mounting evidence of its existence, its relative contribution and precise roles in phenomena ranging from synaptic transmission to neural network activity and cognitive performances have remained elusive. In parallel, the usefulness of glucose as the predominant brain energy substrate has not been questioned. More to the contrary, glucose use was shown to be essential for specific neuronal processes. Thus, two opposing (but not mutually exclusive) hypotheses have emerged to account for the bioenergetic changes necessary to fuel processes giving rise to cognition: the “direct glucose” neuronal use and the “ANLS”. The ambition of the present proposal is to tackle this arduous problem of evaluating these two hypotheses within the same framework. For this purpose, it was agreed to focus on the rat whisker-to-barrel system and target the somatosensory cortical S1BF area for all investigations. Our strategy will make use of validated viral vector tools and siRNAs to downregulate the expression in a cell-specific manner the key transporters for glucose (on neurons) and for lactate (on neurons or astrocytes). Then, investigations will be carried out first to assess at the electrophysiological level in thalamocortical slices the relative importance of glucose and astrocyte-derived lactate to sustain synaptic transmission and plasticity mechanisms. In parallel, nuclear magnetic resonance spectroscopy, magnetic resonance imaging (including a novel technique to assess oxidative metabolism) and positron emission tomography will be used to determine the contribution of each substrate in the metabolic and hemodynamic responses triggered by the functional activation of local neuronal networks. Finally, the role of each energy supply source in learning and memory processes will be evaluated using a novel and validated behavioral task (a textured version of the novel object recognition task). Through this panel of parallel explorations at different scales but in the same system, we expect to shed light on a puzzling question for biochemists and other scientists alike: What fuels your thoughts ? The answer to this question is not a mere curiosity but has far reaching implications. Indeed, it might call for a reappraisal of the interpretation of functional brain imaging, as most of these techniques consider metabolic responses as surrogate markers for neuronal activity. Moreover, as metabolic dysfunctions have been identified as being early events in numerous neurological disorders, novel therapeutic strategies could be designed.