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A single-cell genomic atlas for the effects of chronic ethanol exposure in the mouse dorsal striatum

Molecular Psychiatry volume 30, pages 4320–4333 (2025)Cite this article

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Abstract

Alcohol use disorder (AUD) is characterized by compulsive drinking, which is thought to be mediated by effects of chronic intermittent ethanol exposure on the dorsal striatum, the input nucleus of the basal ganglia. Despite significant efforts to understand the impact of ethanol on the dorsal striatum, the rich diversity of striatal cell types and multitude of ethanol targets expressed by them necessitates an unbiased, discovery-based approach. In this study, we used single-nuclei RNA-sequencing (snRNA-seq; n = 86,715 cells) to examine the impact of chronic intermittent ethanol exposure on the dorsal striatum in C57BL/6 male and female mice. We detected 462 differentially expressed genes at FDR < 0.05, the majority of which were mapped to spiny projection neurons (SPNs), the most prominent cell type in the striatum. Gene co-expression network analysis and functional annotation of differentially expressed genes revealed down-regulation of postsynaptic intracellular signaling cascades in SPNs. Inflammation-related genes were down-regulated across many neuronal and non-neuronal cell types. Gene set enrichment analyses also pointed to altered states of rare cell types, including the induction of angiogenesis-related genes in vascular cells. A gene module down-regulated specifically in canonical SPNs was enriched for calcium-signaling genes and components of glutamatergic synapses, as well as for genes associated with genetic risk for AUD. Genetic perturbations of six of this module’s hub genes – Foxp1, Bcl11b, Pde10a, Rarb, Rgs9, and Itgr1 – had causal effects on its expression in the mouse striatum and/or on the broader set of differentially expressed genes in alcohol-exposed mice. These data provide important clues as to the impact of ethanol on striatal biology and provide a key resource for future investigation.

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Fig. 1: Single-nuclei RNA sequencing of the mouse dorsal striatum in the context of chronic intermittent ethanol exposure.
Fig. 2: Discovery and replication of differentially expressed genes in dorsal striatum cell types from chronic intermittent ethanol (CIE)-exposed vs. control mice.
Fig. 3: Gene sets enriched for differential gene expression in CIE vs. control mice.
Fig. 4: Cell type-specific vs. shared effects of chronic intermittent ethanol across striatal cell types.
Fig. 5: Gene co-expression networks dysregulated in spiny projection neurons after chronic intermittent ethanol.
Fig. 6: Causal effects of module M43 hub genes on striatal gene expression.

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Data availability

Sequencing data have been uploaded to the Gene Expression Omnibus (GSE292642, GSE292791). All other data are presented in the main text and supplementary figures and tables.

Code availability

Code used in the data analysis is available at www.github.com/seth-ament/cie-snrnaseq.

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Acknowledgements

This study was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (R01 AA024845, BNM, PI) and the National Institute on Drug Abuse (U01 DA051947, SAA and MKL, PIs). This research is based in part on data from the Million Veteran Program (MVP), Office of Research and Development, Veterans Health Administration, and was supported by award #I01 BX004820 and the Veterans Integrated Service Network 4 Mental Illness Research, Education and Clinical Center. This publication does not represent the views of the Department of Veteran Affairs or the United States Government.

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Authors and Affiliations

  1. Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA

    Erin Wildermuth, Marcia Cortes-Gutierrez, Benjamin H. Grissom & Seth A. Ament

  2. Medical Scientist Training Program, University of Maryland School of Medicine, Baltimore, MD, USA

    Erin Wildermuth

  3. Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA

    Michael S. Patton

  4. Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Michael S. Patton & Brian N. Mathur

  5. Center for Studies of Addiction, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Zeal Jinwala & Henry R. Kranzler

  6. Mental Illness Research, Education and Clinical Center, Crescenz VAMC, Philadelphia, PA, USA

    Zeal Jinwala & Henry R. Kranzler

  7. Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Benjamin H. Grissom

  8. Department of Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Rianne R. Campbell & Mary Kay Lobo

  9. Kahlert Institute for Addiction Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Mary Kay Lobo, Seth A. Ament & Brian N. Mathur

  10. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

    Seth A. Ament

Authors
  1. Erin Wildermuth
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  2. Michael S. Patton
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  3. Marcia Cortes-Gutierrez
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  4. Zeal Jinwala
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  5. Benjamin H. Grissom
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  6. Rianne R. Campbell
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  7. Henry R. Kranzler
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  8. Mary Kay Lobo
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  9. Seth A. Ament
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  10. Brian N. Mathur
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Contributions

BNM and SAA conceptualized the study. MSP, MC-G, and RRC performed experiments. EW, ZJ, BHG, and SAA performed formal analyses of the data. HRK, MKL, SAA, and BNM supervised the study and acquired funding. EW, SAA, and BNM wrote the original draft. All authors reviewed and edited the manuscript.

Corresponding authors

Correspondence to Seth A. Ament or Brian N. Mathur.

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Competing interests

Dr. Kranzler is a member of advisory boards for Altimmune, Clearmind Medicine, Dicerna Pharmaceuticals, Enthion Pharmaceuticals, and Sophrosyne Pharmaceuticals; a consultant to Sobrera Pharmaceuticals and Altimmune; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the last three years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics; and a holder of U.S. patent 10,900,082 titled: “Genotype-guided dosing of opioid agonists,” issued 26 January 2021. All other authors declare they have nothing to disclose.

Ethics approval and consent to participate

Animal studies were performed in accordance with NIH guidelines and were approved by the Institutional Animal Care and Use Committee of the University of Maryland Baltimore (Protocol # 0522009). The central Veterans Affairs (VA) institutional review board (IRB) approved the Million Veteran Program study. All relevant ethical regulations for work with human subjects were followed in the conduct of the study and informed consent was obtained from all participants.

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Wildermuth, E., Patton, M.S., Cortes-Gutierrez, M. et al. A single-cell genomic atlas for the effects of chronic ethanol exposure in the mouse dorsal striatum. Mol Psychiatry 30, 4320–4333 (2025). https://doi.org/10.1038/s41380-025-03014-z

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