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

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.