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Res Sq
ResearchSquare
Research Square
2693-5015
American Journal Experts

39184101
10.21203/rs.3.rs-4834308/v1
10.21203/rs.3.rs-4834308
preprint
1
Article
Cell type-specific Multi-Omics Analysis of Cocaine Use Disorder in the Human Caudate Nucleus
Zillich Lea https://orcid.org/0000-0001-7457-374X

Artioli Annasara
Pohořalá Veronika
Zillich Eric
Stertz Laura
Belschner Hanna
Jabali Ammar
Frank Josef
Streit Fabian https://orcid.org/0000-0003-1080-4339

Avetyan Diana
Völker Maja
Müller Svenja
Hansson Anita
Meyer Thomas
Rietschel Marcella
Spanagel Rainer
Oliveira Ana
Walss-Bass Consuelo
Bernardi Rick
Koch Philipp
Witt Stephanie
15 8 2024
rs.3.rs-4834308https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
https://www.researchsquare.com/article/rs-4834308/v1
nihpp-rs4834308v1.pdf
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.
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