Spatiomolecular mapping reveals anatomical organization of heterogeneous cell types in the human nucleus accumbens

The nucleus accumbens (NAc) is a key component of the mesolimbic dopamine system that is implicated in several neuropsychiatric disorders. The NAc contains transcriptomically distinct medium spiny neuron (MSN) subtypes, but their spatial organization remains unclear. We generated a spatiomolecular atlas of the human NAc by integrating paired single-cell and spatial transcriptomics of postmortem NAc tissue. We identified transcriptionally unique cell populations and spatial domains (SpDs), including D1 islands composed of discrete MSN subtypes enriched for dopamine receptor D1 (DRD1) and OPRM1. We demonstrated continuous spatial gene expression gradients across the NAc and evolutionary conservation of spatial features. We also identified SpDs associated with risk for psychiatric and addiction-related traits and spatially mapped risk-associated ligand-receptor interactions. Finally, we predicted enrichment of drug-responsive transcriptional programs in both SpDs and cell types. Collectively, we provide a spatiomolecular framework for understanding the relevance of the human NAc in neuropsychiatric diseases.