A single-nucleus transcriptomic atlas of medium spiny neurons in the rat nucleus accumbens.
Medium spiny neurons
Nucleus accumbens
Rat
Single cell transcriptomics
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
06 Aug 2024
06 Aug 2024
Historique:
received:
16
05
2024
accepted:
02
08
2024
medline:
7
8
2024
pubmed:
7
8
2024
entrez:
6
8
2024
Statut:
epublish
Résumé
Neural processing of rewarding stimuli involves several distinct regions, including the nucleus accumbens (NAc). The majority of NAc neurons are GABAergic projection neurons known as medium spiny neurons (MSNs). MSNs are broadly defined by dopamine receptor expression, but evidence suggests that a wider array of subtypes exist. To study MSN heterogeneity, we analyzed single-nucleus RNA sequencing data from the largest available rat NAc dataset. Analysis of 48,040 NAc MSN nuclei identified major populations belonging to the striosome and matrix compartments. Integration with mouse and human data indicated consistency across species and disease-relevance scoring using genome-wide association study results revealed potentially differential roles for MSN populations in substance use disorders. Additional high-resolution clustering identified 34 transcriptomically distinct subtypes of MSNs definable by a limited number of marker genes. Together, these data demonstrate the diversity of MSNs in the NAc and provide a basis for more targeted genetic manipulation of specific populations.
Identifiants
pubmed: 39107568
doi: 10.1038/s41598-024-69255-0
pii: 10.1038/s41598-024-69255-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
18258Subventions
Organisme : NIDA NIH HHS
ID : R21 DA057458
Pays : United States
Organisme : NIDA NIH HHS
ID : R21 DA055846
Pays : United States
Organisme : NIDA NIH HHS
ID : DP1 DA054394
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA030056
Pays : United States
Organisme : Pennsylvania Department of Health
ID : Nonformula Tobacco Settlement Act Grant
Organisme : BLRD VA
ID : I01 BX004820
Pays : United States
Organisme : Tobacco-Related Disease Research Program
ID : T32IR5226
Informations de copyright
© 2024. The Author(s).
Références
Schmidt, H. D. & Pierce, R. C. Cocaine-induced neuroadaptations in glutamate transmission: Potential therapeutic targets for craving and addiction. Ann. N. Y. Acad. Sci. 1187, 35–75. https://doi.org/10.1111/j.1749-6632.2009.05144.x (2010).
doi: 10.1111/j.1749-6632.2009.05144.x
pubmed: 20201846
pmcid: 5413205
Schmidt, H. D., Anderson, S. M. & Pierce, R. C. Stimulation of D1-like or D2 dopamine receptors in the shell, but not the core, of the nucleus accumbens reinstates cocaine-seeking behaviour in the rat. Eur. J. Neurosci. 23, 219–228. https://doi.org/10.1111/j.1460-9568.2005.04524.x (2006).
doi: 10.1111/j.1460-9568.2005.04524.x
pubmed: 16420431
Gibson, G. D., Millan, E. Z. & McNally, G. P. The nucleus accumbens shell in reinstatement and extinction of drug seeking. Eur. J. Neurosci. 50, 2014–2022. https://doi.org/10.1111/ejn.14084 (2019).
doi: 10.1111/ejn.14084
pubmed: 30044017
Kravitz, A. V., Tye, L. D. & Kreitzer, A. C. Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nat. Neurosci. 15, 816–818. https://doi.org/10.1038/nn.3100 (2012).
doi: 10.1038/nn.3100
pubmed: 22544310
pmcid: 3410042
Enoksson, T., Bertran-Gonzalez, J. & Christie, M. J. Nucleus accumbens D2- and D1-receptor expressing medium spiny neurons are selectively activated by morphine withdrawal and acute morphine, respectively. Neuropharmacology 62, 2463–2471. https://doi.org/10.1016/j.neuropharm.2012.02.020 (2012).
doi: 10.1016/j.neuropharm.2012.02.020
pubmed: 22410393
O’Neal, T. J., Bernstein, M. X., MacDougall, D. J. & Ferguson, S. M. A conditioned place preference for heroin is signaled by increased dopamine and direct pathway activity and decreased indirect pathway activity in the nucleus accumbens. J. Neurosci. 42, 2011–2024. https://doi.org/10.1523/JNEUROSCI.1451-21.2021 (2022).
doi: 10.1523/JNEUROSCI.1451-21.2021
pubmed: 35031576
pmcid: 8916759
Lobo, M. K. et al. Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science 330, 385–390. https://doi.org/10.1126/science.1188472 (2010).
doi: 10.1126/science.1188472
pubmed: 20947769
pmcid: 3011229
O’Neal, T. J., Nooney, M. N., Thien, K. & Ferguson, S. M. Chemogenetic modulation of accumbens direct or indirect pathways bidirectionally alters reinstatement of heroin-seeking in high- but not low-risk rats. Neuropsychopharmacology 45, 1251–1262. https://doi.org/10.1038/s41386-019-0571-9 (2020).
doi: 10.1038/s41386-019-0571-9
pubmed: 31747681
Beutler, L. R. et al. Balanced NMDA receptor activity in dopamine D1 receptor (D1R)- and D2R-expressing medium spiny neurons is required for amphetamine sensitization. Proc. Natl. Acad. Sci. U. S. A. 108, 4206–4211. https://doi.org/10.1073/pnas.1101424108 (2011).
doi: 10.1073/pnas.1101424108
pubmed: 21368124
pmcid: 3054029
James, A. S. et al. Opioid self-administration results in cell-type specific adaptations of striatal medium spiny neurons. Behav. Brain Res. 256, 279–283. https://doi.org/10.1016/j.bbr.2013.08.009 (2013).
doi: 10.1016/j.bbr.2013.08.009
pubmed: 23968589
Calipari, E. S. et al. In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward. Proc. Natl. Acad. Sci. U. S. A. 113, 2726–2731. https://doi.org/10.1073/pnas.1521238113 (2016).
doi: 10.1073/pnas.1521238113
pubmed: 26831103
pmcid: 4791010
Flanigan, M. & LeClair, K. Shared motivational functions of ventral striatum D1 and D2 Medium Spiny Neurons. J. Neurosci. 37, 6177–6179. https://doi.org/10.1523/JNEUROSCI.0882-17.2017 (2017).
doi: 10.1523/JNEUROSCI.0882-17.2017
pubmed: 28659329
pmcid: 5490058
Floresco, S. B. The nucleus accumbens: An interface between cognition, emotion, and action. Annu. Rev. Psychol. 66, 25–52. https://doi.org/10.1146/annurev-psych-010213-115159 (2015).
doi: 10.1146/annurev-psych-010213-115159
pubmed: 25251489
Di Chiara, G. Nucleus accumbens shell and core dopamine: Differential role in behavior and addiction. Behav. Brain Res. 137, 75–114. https://doi.org/10.1016/s0166-4328(02)00286-3 (2002).
doi: 10.1016/s0166-4328(02)00286-3
pubmed: 12445717
Zahm, D. S. Functional-anatomical implications of the nucleus accumbens core and shell subterritories. Ann. N. Y. Acad. Sci. 877, 113–128. https://doi.org/10.1111/j.1749-6632.1999.tb09264.x (1999).
doi: 10.1111/j.1749-6632.1999.tb09264.x
pubmed: 10415646
Li, Z. et al. Cell-type-specific afferent innervation of the nucleus accumbens core and shell. Front. Neuroanat. 12, 84. https://doi.org/10.3389/fnana.2018.00084 (2018).
doi: 10.3389/fnana.2018.00084
pubmed: 30459564
pmcid: 6232828
Smith, R. J., Lobo, M. K., Spencer, S. & Kalivas, P. W. Cocaine-induced adaptations in D1 and D2 accumbens projection neurons (a dichotomy not necessarily synonymous with direct and indirect pathways). Curr. Opin. Neurobiol. 23, 546–552. https://doi.org/10.1016/j.conb.2013.01.026 (2013).
doi: 10.1016/j.conb.2013.01.026
pubmed: 23428656
pmcid: 3681928
Soares-Cunha, C. et al. Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion. Mol. Psychiatry 25, 3241–3255. https://doi.org/10.1038/s41380-019-0484-3 (2020).
doi: 10.1038/s41380-019-0484-3
pubmed: 31462765
Rossi, L. M. et al. Role of nucleus accumbens core but not shell in incubation of methamphetamine craving after voluntary abstinence. Neuropsychopharmacology 45, 256–265. https://doi.org/10.1038/s41386-019-0479-4 (2020).
doi: 10.1038/s41386-019-0479-4
pubmed: 31422417
Durst, M., Könczöl, K., Balázsa, T., Eyre, M. D. & Tóth, Z. E. Reward-representing D1-type neurons in the medial shell of the accumbens nucleus regulate palatable food intake. Int. J. Obes. (Lond.) 43, 917–927. https://doi.org/10.1038/s41366-018-0133-y (2019).
doi: 10.1038/s41366-018-0133-y
pubmed: 29907842
Brimblecombe, K. R. & Cragg, S. J. The striosome and matrix compartments of the striatum: A path through the labyrinth from neurochemistry toward function. ACS Chem. Neurosci. 8, 235–242. https://doi.org/10.1021/acschemneuro.6b00333 (2017).
doi: 10.1021/acschemneuro.6b00333
pubmed: 27977131
Cui, Y. et al. Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward. Nat. Neurosci. 17, 254–261. https://doi.org/10.1038/nn.3622 (2014).
doi: 10.1038/nn.3622
pubmed: 24413699
pmcid: 4008330
Crittenden, J. R. & Graybiel, A. M. Basal Ganglia disorders associated with imbalances in the striatal striosome and matrix compartments. Front. Neuroanat. 5, 59. https://doi.org/10.3389/fnana.2011.00059 (2011).
doi: 10.3389/fnana.2011.00059
pubmed: 21941467
pmcid: 3171104
He, J. et al. Transcriptional and anatomical diversity of medium spiny neurons in the primate striatum. Curr. Biol. 31, 5473-5486.e5476. https://doi.org/10.1016/j.cub.2021.10.015 (2021).
doi: 10.1016/j.cub.2021.10.015
pubmed: 34727523
pmcid: 9359438
Tran, M. N. et al. Single-nucleus transcriptome analysis reveals cell-type-specific molecular signatures across reward circuitry in the human brain. Neuron 109, 3088-3103.e3085. https://doi.org/10.1016/j.neuron.2021.09.001 (2021).
doi: 10.1016/j.neuron.2021.09.001
pubmed: 34582785
pmcid: 8564763
Chen, R. et al. Decoding molecular and cellular heterogeneity of mouse nucleus accumbens. Nat. Neurosci. 24, 1757–1771. https://doi.org/10.1038/s41593-021-00938-x (2021).
doi: 10.1038/s41593-021-00938-x
pubmed: 34663959
pmcid: 8639815
Savell, K. E. et al. A dopamine-induced gene expression signature regulates neuronal function and cocaine response. Sci. Adv. 6, eaba4221. https://doi.org/10.1126/sciadv.aba4221 (2020).
doi: 10.1126/sciadv.aba4221
pubmed: 32637607
pmcid: 7314536
Phillips, R. A. et al. Distinct subpopulations of D1 medium spiny neurons exhibit unique transcriptional responsiveness to cocaine. Mol. Cell. Neurosci. 125, 103849. https://doi.org/10.1016/j.mcn.2023.103849 (2023).
doi: 10.1016/j.mcn.2023.103849
pubmed: 36965548
pmcid: 10898607
Avey, D. et al. Single-cell RNA-seq uncovers a robust transcriptional response to morphine by glia. Cell Rep. 24, 3619-3629.e3614. https://doi.org/10.1016/j.celrep.2018.08.080 (2018).
doi: 10.1016/j.celrep.2018.08.080
pubmed: 30257220
pmcid: 6357782
Reiner, B. C. et al. Single nucleus transcriptomic analysis of rat nucleus accumbens reveals cell type-specific patterns of gene expression associated with volitional morphine intake. Transl. Psychiatry 12, 374. https://doi.org/10.1038/s41398-022-02135-1 (2022).
doi: 10.1038/s41398-022-02135-1
pubmed: 36075888
pmcid: 9458645
Phan, B. N. et al. Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder. Nat. Commun. 15, 878. https://doi.org/10.1038/s41467-024-45165-7 (2024).
doi: 10.1038/s41467-024-45165-7
pubmed: 38296993
pmcid: 10831093
Steuernagel, L. et al. HypoMap-a unified single-cell gene expression atlas of the murine hypothalamus. Nat. Metab. 4, 1402–1419. https://doi.org/10.1038/s42255-022-00657-y (2022).
doi: 10.1038/s42255-022-00657-y
pubmed: 36266547
pmcid: 9584816
Yao, Z. et al. A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation. Cell 184, 3222-3241.e3226. https://doi.org/10.1016/j.cell.2021.04.021 (2021).
doi: 10.1016/j.cell.2021.04.021
pubmed: 34004146
pmcid: 8195859
BICCN. A multimodal cell census and atlas of the mammalian primary motor cortex. Nature 598, 86–102. https://doi.org/10.1038/s41586-021-03950-0 (2021).
doi: 10.1038/s41586-021-03950-0
Toikumo, S. et al. Multi-ancestry meta-analysis of tobacco use disorder prioritizes novel candidate risk genes and reveals associations with numerous health outcomes. medRxiv https://doi.org/10.1101/2023.03.27.23287713 (2023).
doi: 10.1101/2023.03.27.23287713
pubmed: 37034728
pmcid: 10055465
Kember, R. L. et al. Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction. Nat. Neurosci. 25, 1279–1287. https://doi.org/10.1038/s41593-022-01160-z (2022).
doi: 10.1038/s41593-022-01160-z
pubmed: 36171425
pmcid: 9682545
Kember, R. L. et al. Genetic underpinnings of the transition from alcohol consumption to alcohol use disorder: Shared and unique genetic architectures in a cross-ancestry sample. Am. J. Psychiatry 180, 584–593. https://doi.org/10.1176/appi.ajp.21090892 (2023).
doi: 10.1176/appi.ajp.21090892
pubmed: 37282553
pmcid: 10731616
Märtin, A. et al. A spatiomolecular map of the striatum. Cell Rep. 29, 4320-4333.e4325. https://doi.org/10.1016/j.celrep.2019.11.096 (2019).
doi: 10.1016/j.celrep.2019.11.096
pubmed: 31875543
Saunders, A. et al. Molecular diversity and specializations among the cells of the adult mouse brain. Cell 174, 1015-1030.e1016. https://doi.org/10.1016/j.cell.2018.07.028 (2018).
doi: 10.1016/j.cell.2018.07.028
pubmed: 30096299
pmcid: 6447408
Zhang, M. J. et al. Polygenic enrichment distinguishes disease associations of individual cells in single-cell RNA-seq data. Nat. Genet. 54, 1572–1580. https://doi.org/10.1038/s41588-022-01167-z (2022).
doi: 10.1038/s41588-022-01167-z
pubmed: 36050550
pmcid: 9891382
Kranzler, H. R. et al. Genome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations. Nat. Commun. 10, 1499. https://doi.org/10.1038/s41467-019-09480-8 (2019).
doi: 10.1038/s41467-019-09480-8
pubmed: 30940813
pmcid: 6445072
Andraka, E., Phillips, R. A., Brida, K. L. & Day, J. J. Chst9 marks a spatially and transcriptionally unique population of oprm1-expressing neurons in the nucleus accumbens. bioRxiv https://doi.org/10.1101/2023.10.16.562623 (2023).
doi: 10.1101/2023.10.16.562623
pubmed: 37904940
pmcid: 10614864
Siletti, K. et al. Transcriptomic diversity of cell types across the adult human brain. Science 382, eadd7046. https://doi.org/10.1126/science.add7046 (2023).
doi: 10.1126/science.add7046
pubmed: 37824663
Zhao, Z. D. et al. A molecularly defined D1 medium spiny neuron subtype negatively regulates cocaine addiction. Sci. Adv. 8, eabn3552. https://doi.org/10.1126/sciadv.abn3552 (2022).
doi: 10.1126/sciadv.abn3552
pubmed: 35960793
pmcid: 9374336
Hong, S. et al. Predominant striatal input to the lateral Habenula in Macaques comes from striosomes. Curr. Biol. 29, 51-61.e55. https://doi.org/10.1016/j.cub.2018.11.008 (2019).
doi: 10.1016/j.cub.2018.11.008
pubmed: 30554903
Evans, R. C. et al. Functional dissection of basal ganglia inhibitory inputs onto Substantia nigra dopaminergic neurons. Cell Rep. 32, 108156. https://doi.org/10.1016/j.celrep.2020.108156 (2020).
doi: 10.1016/j.celrep.2020.108156
pubmed: 32937133
pmcid: 9887718
Watabe-Uchida, M., Zhu, L., Ogawa, S. K., Vamanrao, A. & Uchida, N. Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron 74, 858–873. https://doi.org/10.1016/j.neuron.2012.03.017 (2012).
doi: 10.1016/j.neuron.2012.03.017
pubmed: 22681690
Friedman, A. et al. A corticostriatal path targeting striosomes controls decision-making under conflict. Cell 161, 1320–1333. https://doi.org/10.1016/j.cell.2015.04.049 (2015).
doi: 10.1016/j.cell.2015.04.049
pubmed: 26027737
pmcid: 4477966
Zheng, G. X. et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun. 8, 14049. https://doi.org/10.1038/ncomms14049 (2017).
doi: 10.1038/ncomms14049
pubmed: 28091601
pmcid: 5241818
Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573-3587.e3529. https://doi.org/10.1016/j.cell.2021.04.048 (2021).
doi: 10.1016/j.cell.2021.04.048
pubmed: 34062119
pmcid: 8238499
Young, M. D. & Behjati, S. SoupX removes ambient RNA contamination from droplet-based single-cell RNA sequencing data. Gigascience https://doi.org/10.1093/gigascience/giaa151 (2020).
doi: 10.1093/gigascience/giaa151
pubmed: 33367645
pmcid: 7763177
Germain, P. L., Lun, A., Garcia Meixide, C., Macnair, W. & Robinson, M. D. Doublet identification in single-cell sequencing data using. F1000Research 10, 979. https://doi.org/10.12688/f1000research.73600.2 (2021).
doi: 10.12688/f1000research.73600.2
pubmed: 35814628
Bhaduri, A. et al. An atlas of cortical arealization identifies dynamic molecular signatures. Nature 598, 200–204. https://doi.org/10.1038/s41586-021-03910-8 (2021).
doi: 10.1038/s41586-021-03910-8
pubmed: 34616070
pmcid: 8494648
Browaeys, R., Saelens, W. & Saeys, Y. NicheNet: Modeling intercellular communication by linking ligands to target genes. Nat. Methods 17, 159–162. https://doi.org/10.1038/s41592-019-0667-5 (2020).
doi: 10.1038/s41592-019-0667-5
pubmed: 31819264
Watanabe, K., Taskesen, E., van Bochoven, A. & Posthuma, D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826. https://doi.org/10.1038/s41467-017-01261-5 (2017).
doi: 10.1038/s41467-017-01261-5
pubmed: 29184056
pmcid: 5705698
de Leeuw, C. A., Mooij, J. M., Heskes, T. & Posthuma, D. MAGMA: Generalized gene-set analysis of GWAS data. PLoS Comput. Biol. 11, e1004219. https://doi.org/10.1371/journal.pcbi.1004219 (2015).
doi: 10.1371/journal.pcbi.1004219
pubmed: 25885710
pmcid: 4401657
Arlotta, P., Molyneaux, B. J., Jabaudon, D., Yoshida, Y. & Macklis, J. D. Ctip2 controls the differentiation of medium spiny neurons and the establishment of the cellular architecture of the striatum. J. Neurosci. 28, 622–632. https://doi.org/10.1523/JNEUROSCI.2986-07.2008 (2008).
doi: 10.1523/JNEUROSCI.2986-07.2008
pubmed: 18199763
pmcid: 6670353
Fu, R. et al. clustifyr: An R package for automated single-cell RNA sequencing cluster classification. F1000Research 9, 223. https://doi.org/10.12688/f1000research.22969.2 (2020).
doi: 10.12688/f1000research.22969.2
pubmed: 32765839
pmcid: 7383722
Alquicira-Hernandez, J. & Powell, J. E. Nebulosa recovers single-cell gene expression signals by kernel density estimation. Bioinformatics 37, 2485–2487. https://doi.org/10.1093/bioinformatics/btab003 (2021).
doi: 10.1093/bioinformatics/btab003
pubmed: 33459785