Spatiomolecular mapping reveals anatomical organization of heterogeneous cell types in the human nucleus accumbens
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE325489 | GEO | 2026/03/30
REPOSITORIES: GEO
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Project description:The nucleus accumbens (NAc) is a key component of the mesolimbic dopamine system that critically regulates many behaviors related to reward and motivation. The NAc is implicated in several neuropsychiatric disorders, including major depressive disorder, schizophrenia, and substance use disorder. Rodent studies have identified spatial organization of heterogeneous medium spiny neuron (MSN) subtypes across the NAc core and shell, but the extent to which this cellular diversity and spatial organization is conserved in the human brain remains unclear. Here, we generated a spatiomolecular atlas of NAc cell types and spatial domains by integrating spatial transcriptomics and single-nucleus RNA sequencing data from postmortem NAc tissue from 10 neurotypical adult donors. We identified 20 transcriptionally unique cell populations and 8 spatial domains, including specialized D1 islands composed of distinct dopamine receptor 1 (DRD1) MSN subtypes, which were enriched for OPRM1. In contrast to a discrete core vs. shell division, we observed continuous spatial gradients of gene expression across MSN domains, suggesting a more complex organization of DRD1 and DRD2 MSNs. Cross-species comparisons demonstrated conservation of MSN subtypes and spatial features between human, rodent, and nonhuman primate NAc. Genetic enrichment analysis with stratified linkage disequilibrium score regression revealed specific spatial domains associated with risk for psychiatric and addiction-related traits. To investigate this further, we spatially mapped ligand-receptor interactions involving neuropsychiatric risk genes. Finally, we leveraged existing rodent NAc data to identify drug-responsive transcriptional programs and predict their spatial distribution in the human NAc. Collectively, we provide a spatiomolecular framework for understanding the human NAc and its relevance to neuropsychiatric disease.
2025-09-10 | GSE307587 | GEO
Project description:The nucleus accumbens (NAc) is a key component of the mesolimbic dopamine system that critically regulates many behaviors related to reward and motivation. The NAc is implicated in several neuropsychiatric disorders, including major depressive disorder, schizophrenia, and substance use disorder. Rodent studies have identified spatial organization of heterogeneous medium spiny neuron (MSN) subtypes across the NAc core and shell, but the extent to which this cellular diversity and spatial organization is conserved in the human brain remains unclear. Here, we generated a spatiomolecular atlas of NAc cell types and spatial domains by integrating spatial transcriptomics and single-nucleus RNA sequencing data from postmortem NAc tissue from 10 neurotypical adult donors. We identified 20 transcriptionally unique cell populations and 8 spatial domains, including specialized D1 islands composed of distinct dopamine receptor 1 (DRD1) MSN subtypes, which were enriched for OPRM1. In contrast to a discrete core vs. shell division, we observed continuous spatial gradients of gene expression across MSN domains, suggesting a more complex organization of DRD1 and DRD2 MSNs. Cross-species comparisons demonstrated conservation of MSN subtypes and spatial features between human, rodent, and nonhuman primate NAc. Genetic enrichment analysis with stratified linkage disequilibrium score regression revealed specific spatial domains associated with risk for psychiatric and addiction-related traits. To investigate this further, we spatially mapped ligand-receptor interactions involving neuropsychiatric risk genes. Finally, we leveraged existing rodent NAc data to identify drug-responsive transcriptional programs and predict their spatial distribution in the human NAc. Collectively, we provide a spatiomolecular framework for understanding the human NAc and its relevance to neuropsychiatric disease.
2025-09-10 | GSE307586 | GEO
Project description:GSEA using both edgeR and voom statistics revealed that the ES of two types of corticothalamic neurons, CTX.Glt25d2-positive layer 5b and CTX.Ntsr1-positive layer 6 neurons, were downregulated by both NAc D1- and D2-RNB. In contrast, the ES of CTX.S100a10 corticostriatal neurons were upregulated and downregulated by NAc D1- and D2-RNB, respectively. These data show that cortical neurons are asymmetrically regulated by subcortical pathways in the mPFC-NAc-VP/SNr-MD/VD-mPFC circuit.
2019-01-03 | GSE124583 | GEO
Project description:We used RNAseq to evaluate changes in nucleus accumbens (NAc) D1 and D2 translatomes from fentanyl abstinent mice.
2022-07-31 | GSE209969 | GEO
Project description:Background: Depression is the leading cause of disability which produces enormous health and economic burdens. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activities of D1- or D2-type medium spiny neurons (MSNs). Methods: To separate D1- or D2-MSN specific transcriptomes in the NAc, RiboTag (RT) mice were crossed with D1- or D2-Cre lines and subjected to chronic social defeat stress. The cell-type specifically tagged ribosome-mRNA complex was pulled down by anti-HA antibody, and purified RNAs were subjected to RNA sequencing. Sequencing data were analyzed and defined differentially expressed genes (DEGs) were validated with RNAscope and viral overexpression in vivo. Results: Both MSN subtypes express distinct gene expression profiles according to stress groups. The DEGs are correlated with depression relevant gene ontology terms. Behavioral susceptibility and resilience are also correlated with subsets of DEGs, especially in D1-MSNs. Conclusions: Distinct subsets of genes are modulated in a cell-type specific manner in the NAc of depressed mice. Here we provided valuable transcriptome data sets for future studies on depression.
2021-07-09 | GSE147640 | GEO
Project description:Substance use disorders (SUDs) induce widespread molecular dysregulation in nucleus accumbens (NAc), a brain region pivotal for coordinating motivation and reward, which is linked to neural and behavioral disturbances promoting addiction. Despite the overlapping symptomatology of SUDs, different drug classes exert partly unique influences on neural circuits, cell types, physiology, and gene expression. To better understand common and divergent molecular mechanisms governing SUD pathology, we characterized the cell-type-specific restructuring of the NAc transcriptional landscape after psychostimulant or opioid exposure. We combined fluorescence-activated nuclei sorting and RNA sequencing to profile NAc D1 and D2 medium spiny neurons (MSNs) across cocaine exposure paradigms, including initial exposure, prolonged withdrawal after repeated exposure, and re-exposure post-withdrawal. Our analyses reveal that D1 MSNs display many convergent transcriptional responses across the two drugs, whereas D2 MSNs manifest highly divergent responses, with morphine causing far more adaptations in this cell type.
2024-10-09 | GSE272823 | GEO
Project description:Substance use disorders (SUDs) induce widespread molecular dysregulation in nucleus accumbens (NAc), a brain region pivotal for coordinating motivation and reward, which is linked to neural and behavioral disturbances promoting addiction. Despite the overlapping symptomatology of SUDs, different drug classes exert partly unique influences on neural circuits, cell types, physiology, and gene expression. To better understand common and divergent molecular mechanisms governing SUD pathology, we characterized the cell-type-specific restructuring of the NAc transcriptional landscape after psychostimulant or opioid exposure. We combined fluorescence-activated nuclei sorting and RNA sequencing to profile NAc D1 and D2 medium spiny neurons (MSNs) across morphine exposure paradigms, including initial exposure, prolonged withdrawal after repeated exposure, and re-exposure post-withdrawal. Our analyses reveal that D1 MSNs display many convergent transcriptional responses, whereas D2 MSNs manifest highly divergent responses, with morphine causing far more adaptations in this cell type.
2025-03-04 | GSE276374 | GEO
Project description:In the ‘incubation of cocaine craving’ model of relapse, rats self-administer cocaine and then experience a prolonged abstinence period. After this prolonged abstinence period, rats exhibit a progressive intensification (incubation) of cue-induced craving, and the expression of incubated craving depends on plasticity of excitatory synaptic transmission in nucleus accumbens (NAc) core medium spiny neurons (MSN). Previously, we found that the maintenance of this plasticity depends on ongoing protein translation, and that regulation of translation is altered after incubation of cocaine craving. Here we used male and female rats that express Cre recombinase in either dopamine D1 receptor- or adenosine 2a (A2a) receptor-expressing MSN to express a GFP-tagged ribosomal protein in a cell-type specific manner, enabling us to use Translating Ribosome Affinity Purification (TRAP) to isolate actively translating mRNAs from both MSN subtypes for analysis by RNA-Seq. We compared rats that self-administered saline or cocaine. Saline rats were assessed on abstinence day (AD) 1, while cocaine rats were assessed on AD1 or AD40-50. For both D1 and A2a MSN, there were few differentially translated (DT) genes between saline and cocaine AD1 groups. In contrast, a pronounced divergence was observed between cocaine rats on AD1 and AD40, and this was far more robust in D1 MSN. Finally, all comparisons revealed sex differences in translating mRNAs. This study, the first to combine TRAP-seq, transgenic rats, and a cocaine self-administration paradigm, identifies translating mRNAs specifically linked to incubation of cocaine craving in D1 and A2a MSN of the NAc core.
2025-04-29 | GSE263646 | GEO
Project description:Major depressive disorder (MDD) disproportionately affects women, yet the molecular mechanisms underlying female vulnerability remain poorly understood. The nucleus accumbens (NAc), a reward circuitry hub, is central to stress- and depression-related pathology. While NAc medium spiny neuron (MSN) transcriptional adaptations have been characterized in stressed male rodents, much less is known about female adaptations. To address this, we exposed female D1-Cre-RiboTag and A2A-Cre-RiboTag mice to chronic witness defeat stress (CWDS) and classified them as high- or low-social interactors. Ribosome-associated mRNA was isolated from MSN subtypes and analyzed by RNA sequencing, differential gene expression analysis (DEG), and weighted gene co-expression network analysis (WGCNA). Cross-species consensus WGCNA with male mouse and human transcriptomic datasets was performed to identify conserved, sex-specific signatures. We detected 9 differentially expressed genes (DEGs) in D1-MSNs and 630 in A2A-MSNs (FDR < 0.05). In D1-MSNs, DEGs were primarily upregulated in low interactors and enriched for energy homeostasis and cell adhesion. A2A-MSN DEGs included upregulated structural genes and downregulated neurotransmission-related genes. WGCNA identified 9 significant D1- and 5 significant A2A-MSN modules, with the most impacted enriched for PI3K-Akt-mTOR signaling and regulated by Nf1. Consensus analysis revealed a stress-associated, sex- and subtype-specific module enriched for PI3K-Akt-mTOR signaling conserved across mice and humans. These findings reveal female-specific MSN transcriptional adaptations to chronic social stress and implicate PI3K-Akt-mTOR signaling as a convergent molecular pathway. By highlighting MSN subtype-specific vulnerabilities, this work suggests potential therapeutic targets for alleviating stress-induced pathology in women with MDD.
2026-05-06 | GSE315159 | GEO
Project description:The growing therapeutic promise of repeated, low-dose ketamine treatment across various psychopathologies-including depression and drug addiction-warrants clarity on its potential addictive properties and their associated mechanisms in both sexes. Accordingly, the present work examined the effects of repeated low-doses ketamine in male and female rats on behavioral sensitization to the locomotor activating effects of ketamine, as well as the associated molecular profiles in dopamine D1- and D2-receptor-expressing medium spiny neurons (D1- and D2-MSNs) of the nucleus accumbens (NAc). Following intra-NAc infusion of a Cre-inducible RiboTag virus, locomotor activity was measured in adult Drd1a-iCre and Drd2-iCre male and female rats in either diestrus or proestrus following repeated administration of ketamine (0, 10, or 20 mg/kg, i.p.) to evaluate the development of locomotor sensitization. Female-but not male-rats developed sensitization to the locomotor-activating effects of ketamine, occurring more rapidly in proestrus than in diestrus females at the lower dose tested. To examine enduring context- and cell-type-specific changes in translating mRNAs associated with sensitization to ketamine, RNA sequencing was performed on polyribosome-bound mRNA of D1- and D2-MSNs isolated from the NAc of sensitized females in a drug-free state. A greater number of differentially expressed genes were observed selectively in D1-MSNs of ketamine-treated proestrus compared to diestrus females, which were broadly related to regulation of transcription and epitranscriptional modification. These findings provide novel evidence of cell-type-specific and estrous-cycle-dependent molecular profiles responsive to intermittent ketamine treatment in female rats and identify post-transcriptional mechanisms with relevance to ketamine's effects on behavioral plasticity.
2026-01-27 | GSE303789 | GEO