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Cell type-specific multi-omics analysis of cocaine use disorder in the human caudate nucleus

Author

Listed:
  • Lea Zillich

    (Heidelberg University
    Heidelberg University
    HITBR Hector Institute for Translational Brain Research gGmbH
    German Cancer Research Center (DKFZ))

  • Annasara Artioli

    (Heidelberg University
    HITBR Hector Institute for Translational Brain Research gGmbH
    German Cancer Research Center (DKFZ))

  • Veronika Pohořalá

    (Heidelberg University)

  • Eric Zillich

    (Heidelberg University)

  • Laura Stertz

    (University of Texas Health Science Center at Houston)

  • Hanna Belschner

    (Heidelberg University)

  • Ammar Jabali

    (Heidelberg University
    HITBR Hector Institute for Translational Brain Research gGmbH
    German Cancer Research Center (DKFZ))

  • Josef Frank

    (Heidelberg University)

  • Fabian Streit

    (Heidelberg University
    partner site Mannheim/Heidelberg/Ulm)

  • Diana Avetyan

    (Heidelberg University)

  • Maja P. Völker

    (Heidelberg University)

  • Svenja Müller

    (Heidelberg University
    partner site Mannheim/Heidelberg/Ulm)

  • Anita C. Hansson

    (Heidelberg University)

  • Thomas D. Meyer

    (University of Texas Health Science Center at Houston)

  • Marcella Rietschel

    (Heidelberg University)

  • Julia Ladewig

    (Heidelberg University
    HITBR Hector Institute for Translational Brain Research gGmbH
    German Cancer Research Center (DKFZ))

  • Rainer Spanagel

    (partner site Mannheim/Heidelberg/Ulm
    Heidelberg University)

  • Ana M. M. Oliveira

    (partner site Mannheim/Heidelberg/Ulm
    Heidelberg University)

  • Consuelo Walss-Bass

    (University of Texas Health Science Center at Houston)

  • Rick E. Bernardi

    (Heidelberg University)

  • Philipp Koch

    (Heidelberg University
    HITBR Hector Institute for Translational Brain Research gGmbH
    German Cancer Research Center (DKFZ)
    partner site Mannheim/Heidelberg/Ulm)

  • Stephanie H. Witt

    (Heidelberg University
    partner site Mannheim/Heidelberg/Ulm
    Heidelberg University)

Abstract

Structural and functional alterations in the brain’s reward circuitry are present in cocaine use disorder (CocUD), but their molecular underpinnings remain unclear. To investigate these mechanisms, we performed single-nuclei multiome profiling on postmortem caudate nucleus tissue from six individuals with CocUD and eight controls. We profiled 30,030 nuclei, identifying 13 cell types including D1- and D2-medium spiny neurons (MSNs) and glial cells. We observed 1485 differentially regulated genes and 10,342 differentially accessible peaks, with alterations in MSNs and astrocytes related to neurotransmitter activity and synapse organization. Gene regulatory network analysis identified transcription factors including ZEB1 as exhibiting distinct CocUD-specific subclusters, activating downstream expression of ion- and calcium-channels in MSNs. Further, PDE10A emerged as a potential drug target, showing conserved effects in a rat model. This study highlights cell type-specific molecular alterations in CocUD and provides targets for further investigation, demonstrating the value of multi-omics approaches in addiction research.

Suggested Citation

  • Lea Zillich & Annasara Artioli & Veronika Pohořalá & Eric Zillich & Laura Stertz & Hanna Belschner & Ammar Jabali & Josef Frank & Fabian Streit & Diana Avetyan & Maja P. Völker & Svenja Müller & Anita, 2025. "Cell type-specific multi-omics analysis of cocaine use disorder in the human caudate nucleus," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57339-y
    DOI: 10.1038/s41467-025-57339-y
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