DESCRIPTION:

We performed single-nuclei multiome profiling on postmortem caudate nucleus (CN) tissue from six individuals with cocaine use disorder (CocUD) and eight controls, all of African American ancestry. CocUD cases and controls were balanced according to age and sex. We performed single-nuclei ATAC-seq and RNA-seq using the 10x Genomics Multiome platform. Weighted nearest neighbor analysis resulted in an integrated UMAP depicting 13 clearly delineated cell types, including astrocytes, microglia, oligodendrocytes, oligodendrocyte precursor cells (OPC), endothelial cells and lymphocytes, as well as different GABAergic neurons, such as D1 and D2 medium spiny neurons (MSNs) and a small population of cholinergic neurons.

LABEL:

DEG human CN microglia CocUD vs control_pvalue

SCORE TYPE:

P-Value

DATE ADDED:

2024-08-28

DATE UPDATED:

2024-09-04

SPECIES:

AUTHORS:

Lea Zillich, Annasara Artioli, Veronika Pohořalá, Eric Zillich, Laura Stertz, Hanna Belschner, Ammar Jabali, Josef Frank, Fabian Streit, Diana Avetyan, Maja Völker, Svenja Müller, Anita Hansson, Thomas Meyer, Marcella Rietschel, Rainer Spanagel, Ana Oliveira, Consuelo Walss-Bass, Rick Bernardi, Philipp Koch, Stephanie Witt

TITLE:

Cell type-specific Multi-Omics Analysis of Cocaine Use Disorder in the Human Caudate Nucleus.

JOURNAL:

Research square Aug 2024, Vol , pp.

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 31,178 nuclei, identifying 13 cell types including D1- and D2-medium spiny neurons (MSNs) and glial cells. We observed 1,383 differentially regulated genes and 10,235 differentially accessible peaks, with alterations in MSNs and astrocytes related to neurotransmitter activity and synapse organization. Gene regulatory network analysis identified the transcription factor 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. PUBMED: 39184101
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