Cellular and molecular underpinnings of functional networks in the human brain

Abstract

Understanding how cellular and molecular architecture underpins the large-scale organization of human brain function is a central challenge in neuroscience. By integrating transcriptomic (microarray and single-nucleus RNA-sequencing), molecular imaging, and neuroimaging datasets, we observe spatial correspondences indicating that the distributions of diverse cell types, neurotransmitter systems, and mitochondrial phenotypes align with intrinsic connectivity networks (ICNs). These associations extend beyond local correspondence to reflect network-level structure: inter-ICN similarity networks derived from cellular and molecular profiles recapitulate static and dynamic patterns of functional network connectivity (FNC), mirroring canonical functional domains. Mediation analyses reveal that specific ICNs mediate the relationship between microscale cell-type architecture and domain-specific cognitive processes, while FNCs capture mediating pathways linking cell-type and neurotransmitter similarity networks to cognitive organization. Together, our findings show that the brains functional architecture systematically aligns with cellular and molecular organization, which may constrain functional network formation and contribute to the neural basis of cognition.