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A multi-omics and cell type-specific characterization of the ventral striatum in human cocaine use disorder.

Cell reports

Authors: Eric Zillich, Annasara Artioli, Andrea C Rossetti, Diana Avetyan, Hanna Belschner, Josef Frank, Frank Stein, Jennifer J Schwarz, Naguib Mechawar, Gustavo Turecki, Markus M Nöthen, Anita C Hansson, Christian C Witt, Marcella Rietschel, Philipp Koch, Rainer Spanagel, Lea Zillich, Stephanie H Witt

Epigenome, transcriptome, and proteome analyses of postmortem brains have revealed initial molecular insights into cocaine use disorder (CUD). However, the inter-relationship between these omics and the contribution of individual cell types remains largely unknown. We present an in-depth analysis of molecular changes in the ventral striatum in CUD at multi-omics and single-cell resolution. Integrative multi-omics analyses of microRNA sequencing (microRNA-seq), RNA sequencing (RNA-seq), and proteomics datasets in 41 individuals and single-nuclei RNA-seq in a subset of 16 individuals revealed conserved deregulation of metabolic pathways, oxidative phosphorylation, and glutamatergic signaling. Cell type-specific analyses identified inverse metabolic pathway deregulation patterns in glial and neuronal cells, notably in astrocytes and medium-spiny neurons (MSNs). Characterizing astrocyte-neuron crosstalk revealed altered glutamatergic and cell-cell adhesion signaling in CUD. By applying a comprehensive multi-omics analytical framework, our study provides novel insights into CUD-associated molecular changes in the ventral striatum highlighting the perturbation of astrocytes, MSNs, and their crosstalk in CUD.

Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.

PMID: 39954253

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