Metabolic Trajectories in Human Neocortical Development

The shift from glycolysis to oxidative phosphorylation is a key step in neural differentiation. Yet, the timing of metabolic rewiring in the development from progenitors to neurons remains elusive, especially in human corticogenesis. To bridge this gap, here we adopted a unique cell platform based on neocortex-derived human neuroepithelial stem cells, modeling their physiological transition into functional neurons in a four-month longitudinal study. Using quantitative proteomics, combined with NAD(P)H fluorescence lifetime imaging in living cells, we investigated the entire differentiation process and described how metabolic pathways drive cortical neuron maturation. The prevalent metabolic adaptations were then confirmed in cerebro-cortical organoids and in a human neocortical specimen. This study provides a spatio-temporal map of neocortical metabolism during development and offers a framework to investigate human neurometabolic disorders.