The 48th Annual Meeting of the Japan Neuroscience Society

Chairperson: Akira Sato (Carl Zeiss Co., Ltd.)

Co-sponsored by Carl Zeiss Co., Ltd.

Understanding brain energy metabolism is fundamental to deciphering its computational efficiency and plasticity. The discovery of the astrocyte-neuron lactate shuttle (ANLS) revolutionized our perspective on neuroenergetics, shifting the focus from glucose to lactate as a key neuronal energy substrate. Recent findings underscore the role of astrocytic, glycogen-derived lactate in memory formation and synaptic stabilization. To directly investigate the structural changes occurring during learning and their dependence on astrocytic energy metabolism, we performed 3D ultrastructural reconstructions from Serial Block Face Scanning Electron Microscopy (SBF-EM) on adult mice brains subjected to novel-object recognition (NOR) training. Inhibition of glycogenolysis using 1,4-Dideoxy-1,4-imino-D-arabinitol hydrochloride (DAB) led to impairments in memory consolidation and synaptic plasticity, which were reversed by intrahippocampal lactate administration. Expected morphological evidence of the increase in spine density and size in brain undergoing long term memory potentiation was coupled with the appearance of glycogen clusters in perisinaptic astrocytic processes, prevented by DAB treatment. Surprisingly exogenous l-lactate injection restored spine density, but not their size, nor glycogen accumulation. Additionally, 3D analyses of dendritic mitochondria highlighted an impairment in mitochondrial fission, also rescued by lactate administration. To further investigate the spatial relationships between glycogen granules, axons, dendrites, synapses, and mitochondria, we leveraged computational tools and virtual reality-based interactive visualization. These approaches, reminiscent of early microscopy pioneers like Golgi and Ramón y Cajal, enhance our ability to analyze the intricate astrocyte-neuron interactions in an immersive and quantitative manner. Our findings indicate that astrocytic glycogen-derived lactate plays a critical role in synaptic plasticity and brain energy metabolism, offering new insights into neuronal function and potential therapeutic avenues for neurological disorders.