Cellular and molecular underpinnings of functional networks in the human brain

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 data and single-nucleus RNA-sequencing [sn-RNA] data), molecular imaging, and neuroimaging datasets, we present converging evidence that the spatial distribution of diverse cell types, neurotransmitter systems, and mitochondrial phenotypes are systematically aligned with intrinsic connectivity networks (ICNs)—the macroscale scaffolding of brain function. These associations extend beyond local correspondence to reflect network-level structure: inter-ICN similarity networks derived from cellular and molecular profiles significantly recapitulate both static and dynamic patterns of functional network connectivity (FNC), mirroring the established division of ICNs into canonical functional domains. Importantly, these cellular and molecular profiles not only co-localize with ICNs and FNC but also appear to support their role as intermediaries linking microscale biological substrates to cognitive function. Mediation analyses reveal that specific ICNs statistically mediate the relationship between microscale cell-type architecture and domain-specific cognitive and behavioral processes. Moreover, dynamic FNC, particularly in specific transient states, captures the mediating pathways linking cell-type and neurotransmitter similarity networks to cognitive network organization. Taken together, our findings suggest that the brain’s functional architecture is systematically aligned with cellular and molecular organization, which may act as a biological constraint guiding functional network formation and shaping the neural basis of cognition.