biostudies-literatureTran MNNIDA NIH HHSNIMH NIH HHSNHGRINHGRI NIH HHSNational Institute of Mental HealthLieber Institute for Brain DevelopmentNational Institute on Drug Abuse3088-3103.e5https://www.ebi.ac.uk/biostudies/studies/S-EPMC8564763biostudies-literatureUnknown109(19)Single-cell gene expression technologies are powerful tools to study cell types in the human brain, but efforts have largely focused on cortical brain regions. We therefore created a single-nucleus RNA-sequencing resource of 70,615 high-quality nuclei to generate a molecular taxonomy of cell types across five human brain regions that serve as key nodes of the human brain reward circuitry: nucleus accumbens, amygdala, subgenual anterior cingulate cortex, hippocampus, and dorsolateral prefrontal cortex. We first identified novel subpopulations of interneurons and medium spiny neurons (MSNs) in the nucleus accumbens and further characterized robust GABAergic inhibitory cell populations in the amygdala. Joint analyses across the 107 reported cell classes revealed cell-type substructure and unique patterns of transcriptomic dynamics. We identified discrete subpopulations of D1- and D2-expressing MSNs in the nucleus accumbens to which we mapped cell-type-specific enrichment for genetic risk associated with both psychiatric disease and addiction.NeuronSingle-nucleus transcriptome analysis reveals cell-type-specific molecular signatures across reward circuitry in the human brain.PMC8564763R01 MH123183R01 DA0420901R01MH123183R01DA042090R00 HG009007R00HG009007Collado-Torres LKleinman JEMaynard KRTippani MHuuki LASadashivaiah VTran MNHicks SCHyde TMMontgomery KDMartinowich KSpangler AHancock DBJaffe AEBarry BKfalseSingle-nucleus transcriptome analysis reveals cell-type-specific molecular signatures across reward circuitry in the human brain.Single-cell gene expression technologies are powerful tools to study cell types in the human brain, but efforts have largely focused on cortical brain regions. We therefore created a single-nucleus RNA-sequencing resource of 70,615 high-quality nuclei to generate a molecular taxonomy of cell types across five human brain regions that serve as key nodes of the human brain reward circuitry: nucleus accumbens, amygdala, subgenual anterior cingulate cortex, hippocampus, and dorsolateral prefrontal cortex. We first identified novel subpopulations of interneurons and medium spiny neurons (MSNs) in the nucleus accumbens and further characterized robust GABAergic inhibitory cell populations in the amygdala. Joint analyses across the 107 reported cell classes revealed cell-type substructure and unique patterns of transcriptomic dynamics. We identified discrete subpopulations of D1- and D2-expressing MSNs in the nucleus accumbens to which we mapped cell-type-specific enrichment for genetic risk associated with both psychiatric disease and addiction.2021-01-01T00:00:00Z2021 Oct2025-04-18T17:16:44.123Z2025-04-07T04:46:28.84ZS-EPMC85647633458278510.1016/j.neuron.2021.09.001