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.
“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]
The Methods describe sequencing nuclei isolated from frozen brain tissue, supporting the point that intact cell dissociation was not required. The paper does not establish that this minimizes dissociation-associated challenges or provides a more physiologically accurate representation of cellular heterogeneity; the Discussion instead notes incomplete transcriptomic capture and that some cell populations were not captured by the protocols. Page numbers were not available in our copy. (LLM, conf=0.85)
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Unraveling Psychiatric Disorders through Neural Single-Cell Transcriptomics Approaches
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Specification of claustro-amygdalar and palaeocortical neurons and circuits
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Self-citationHippocampal neurogenesis in adult primates: a systematic review
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Strategies for cellular deconvolution in human brain RNA sequencing data
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Self-citationRecent advances in deciphering hippocampus complexity using single-cell transcriptomics
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Cell-type specific profiling of histone post-translational modifications in the adult mouse striatum
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Self-citationThyroid hormone action in adult neurogliogenic niches: the known and unknown
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A single-nucleus transcriptomic atlas of medium spiny neurons in the rat nucleus accumbens
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Self-citationRegional and aging-specific cellular architecture of non-human primate brains
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Self-citationSingle-Cell RNA Sequencing and Its Applications in the Study of Psychiatric Disorders
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Self-citationOmics Approaches to Investigate the Pathogenesis of Suicide
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Self-citationDifferential expression of NPAS4 in the dorsolateral prefrontal cortex following opioid overdose
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Self-citationTranscriptomic and morphologic vascular aberrations underlying FCDIIb etiology
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Transcriptomic Analysis of the Human Habenula in Schizophrenia
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Self-citationNeural cell isolation from adult macaques for high-throughput analyses and neurosphere cultures
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- 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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