Mapping energy metabolism systems in the human brain

Abstract Energy metabolism involves a network of biochemical reactions that generate ATP, utilizing substrates such as glucose and oxygen supplied via cerebral blood flow. Energy substrates are metabolized in multiple interrelated pathways that are cell- and organelle-specific. These pathways not only generate energy but are also fundamental to the production of essential biomolecules required for neuronal function and survival. How these complex biochemical processes are distributed over the cortex is integral to understanding the structure and function of the brain. Here, using curated gene sets and whole-brain transcriptomics, we generate maps of five fundamental energy metabolic pathways: glycolysis, pentose phosphate pathway, tricarboxylic acid cycle, oxidative phosphorylation and lactate metabolism. We find consistent divergence between primarily energy-producing pathways and anabolic pathways, particularly in unimodal sensory cortices. We then explore the spatial alignment of these maps with multi-scale structural and functional attributes, including metabolic uptake, neurophysiological oscillations, cell type composition, laminar organization and macro-scale connectivity. Finally, we show that metabolic pathways exhibit unique developmental trajectories from the fetal stage to adulthood. The primary energy-producing pathways peak in late childhood, while the anabolic pentose phosphate pathway shows pronounced expression in the fetal stage and declines throughout life. Together, these results highlight the rich biochemical complexity of energy metabolism organization in the brain. Competing Interest Statement The authors have declared no competing interest.