{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T19:11:36Z","timestamp":1779390696433,"version":"3.53.1"},"posted":{"date-parts":[[2026,5,19]]},"group-title":"Addiction Medicine","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Alcohol use disorder (AUD) is associated with altered gene expression across diverse cell types in reward-related brain regions, including the ventral tegmental area (VTA), which is rich in dopaminergic neurons. The VTA plays a central role in reward processing, learning, and memory; however, cell type-specific gene expression changes within the VTA remain uncharacterized.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We applied single-nucleus RNA sequencing (snRNA-seq) to profile transcriptomic alterations associated with AUD in the VTA. Postmortem VTA samples from four individuals of European ancestry [two with AUD (one male, one female) and two matched controls (one male, one female)] were analyzed using the 10X Genomics Chromium Fixed RNA Profiling protocol. Differentially expressed genes (DEGs) were identified using Seurat, and enriched KEGG pathways was assessed by gene set enrichment analysis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Nuclei were classified into six major cell types: astrocytes, endothelial cells, mature neurons, microglia, oligodendrocytes, and oligodendrocyte precursor cells (OPCs). At thresholds of\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.05 and |fold change| &gt; 2.0, we identified 547 DEGs in astrocytes, 727 DEGs in endothelial cells, 715 DEGs in mature neurons, 421 DEGs in microglia, 263 DEGs in oligodendrocytes, and 432 DEGs in OPCs. DEGs across VTA cell types were enriched for pathways related to mitochondrial function, neurodegeneration, and synaptic signaling. Notably, DEGs in mature neurons were enriched for addiction-related pathways. Further subdivision of mature neurons into dopaminergic, GABAergic, glutamatergic, and unclassified subtypes revealed 526, 930, 896, and 569 DEGs, respectively. Neuronal DEGs indicate a convergence on mitochondrial\/oxidative phosphorylation and neurodegeneration-related pathways across subtypes, whereas addiction- and synapse-related pathways show dopaminergic neuron-specific enrichment.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study provides the first cell type-resolved transcriptomic profiling of the human VTA, revealing AUD-associated gene expression alterations across neuronal, glial, and endothelial cells. The observed cell type-specific changes in synaptic plasticity and addiction-related genes offer new insights into molecular mechanisms underlying AUD pathophysiology.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.15.26353305","type":"posted-content","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T23:45:13Z","timestamp":1779234313000},"source":"Crossref","is-referenced-by-count":0,"title":["Single-nucleus RNA sequencing identifies transcriptomic signatures of alcohol use disorder in the human ventral tegmental area"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8516-0868","authenticated-orcid":false,"given":"Sofiya","family":"Patra","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Boston University Chobanian and Avedisian School of Medicine, Boston MA02118, USA"},{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian and Avedisian School of Medicine, Boston MA02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1776-8735","authenticated-orcid":false,"given":"Ji Sun","family":"Koo","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Boston University Chobanian and Avedisian School of Medicine, Boston MA02118, USA"},{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian and Avedisian School of Medicine, Boston MA02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4228-7754","authenticated-orcid":false,"given":"Abhyuday Singh","family":"Parihar","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Boston University Chobanian and Avedisian School of Medicine, Boston MA02118, USA"},{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian and Avedisian School of Medicine, Boston MA02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8019-7998","authenticated-orcid":false,"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine (Computational Biomedicine), Boston University Chobanian and Avedisian School of Medicine, Boston MA02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4902-0104","authenticated-orcid":false,"given":"Huiping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Boston University Chobanian and Avedisian School of Medicine, Boston MA02118, USA"},{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian and Avedisian School of Medicine, Boston MA02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052111151009000_2026.05.15.26353305v1.1","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.brainres.2016.02.016","article-title":"Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress","volume":"1637","year":"2016","journal-title":"Brain research"},{"key":"2026052111151009000_2026.05.15.26353305v1.2","unstructured":"American Psychiatric Association (1994) American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 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