Faculty, Staff and Student Publications
Publication Date
4-9-2025
Journal
Nature Communications
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.
Keywords
Humans, Cocaine-Related Disorders, Caudate Nucleus, Male, Animals, Rats, Adult, Female, Gene Regulatory Networks, Neurons, Middle Aged, Astrocytes, Gene Expression Profiling, Transcriptome, Multiomics, Molecular neuroscience, Genetics of the nervous system, Addiction
DOI
10.1038/s41467-025-57339-y
PMID
40204703
PMCID
PMC11982542
PubMedCentral® Posted Date
4-9-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Medical Sciences Commons, Mental and Social Health Commons, Psychiatry Commons, Psychiatry and Psychology Commons