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Single-nucleus transcriptome analysis reveals cell-type-specific molecular signatures across reward circuitry in the human brain
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Abstract
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.
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“snRNA-seq overcomes the need for intact cell dissociation, thereby minimizing dissociation-associated challenges and providing a more physiologically accurate representation of the brain’s cellular heterogeneity[12, 14, 15].”
From Comparative analysis of nuclei isolation methods for brain single-nucleus RNA sequencing (2026) · cites this paper as [15]
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Metadata
- Authors
- Tran, M. N., Maynard, K. R., Spangler, A., Huuki, L. A., Montgomery, K. D., Sadashivaiah, V., Tippani, M., Barry, B. K., Hancock, D. B., Hicks, S. C., Kleinman, J. E., Hyde, T. M., Collado-Torres, L., Jaffe, A. E., & Martinowich, K.
- Affiliations
- Johns Hopkins University (US)
- RTI International (US)
- Corresponding author
- Jaffe, Andrew E.
- Martinowich, Keri
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 109
- Issue
- 19
- Pages
- 3088-3103.e5
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC8564763
- OpenAlex
- W3203631316
- Cited by
- 219
- References
- 116
- Citations by year
- 2026: 34 · 2025: 42 · 2024: 61 · 2023: 53 · 2022: 25 · 2021: 4
- FWCI
- 11.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 370 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NHGRI (R00HG009007)
- Lieber Institute for Brain Development (1R01MH123183)
- National Institute of Mental Health
- National Institute on Drug Abuse (R01DA042090)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- single-nucleus transcriptomics, nucleus accumbens, amygdala, subgenual anterior cingulate cortex, hippocampus, dorsolateral prefrontal cortex, interneurons, medium spiny neurons, cell type-specific gene expression
- MeSH terms
- Mental Disorders, Brain, Brain Mapping, Cell Nucleus, gamma-Aminobutyric Acid, Humans, Interneurons, Nerve Net, Neurons, Reward, Sequence Analysis, RNA, Substance-Related Disorders, Gene Expression Profiling, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing
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