# Five energy metabolism pathways show distinct regional distributions and lifespan trajectories in the human brain

## TL;DR

This study maps five energy metabolism pathways in the human brain, revealing their spatial and developmental patterns and how they relate to brain structure and function.

## Contribution

The study provides the first comprehensive mapping of five energy metabolism pathways in the human cortex and their developmental trajectories.

## Key findings

- Energy-producing and anabolic pathways show distinct spatial divergence, especially in sensory cortices.
- Metabolic pathways correlate with cellular and laminar organization, indicating higher energy demands in large pyramidal cells.
- Primary energy pathways peak in childhood, while the pentose phosphate pathway is more active prenatally and declines with age.

## Abstract

Energy metabolism involves a series 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 spatially distributed across 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 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. We find that energy pathways exhibit unique relationships with the cellular and laminar organization of the cortex, pointing to the higher energy demands of large pyramidal cells and efferent projections. Finally, we show that metabolic pathways exhibit distinct developmental trajectories from the fetal stage to adulthood. The primary energy-producing pathways peak in childhood, while the anabolic pentose phosphate pathway shows greater prenatal expression and declines throughout life. Together, these results highlight the rich biochemical complexity of energy metabolism organization in the brain.

Energy metabolism involves the activity of distinct biochemical processes that are key for cellular function, but their distribution across cortex is poorly understood. This study maps five energy metabolism pathways in the human brain, linking metabolic organization with brain structural and functional properties, as well as developmental dynamics.