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Retained introns can potentially form double-stranded RNA, activating innate immune sensors and inflammation. This mechanism has been implicated in cancer but has not been studied in neuropsychiatric diseases like alcohol use disorder. We systematically analysed transcriptome-wide intron retention events in post-mortem brain tissue from 142 individuals (66 with alcohol use disorder and 76 controls), encompassing 320 region-specific samples from the superior frontal cortex, nucleus accumbens, central nucleus and basolateral amygdala. Analyses were adjusted for demographic, technical and biological covariates. Validation was performed in alcohol-preferring (P) rats using long-read sequencing. In complementary experiments, immunofluorescent staining was used to detect double-stranded RNA in rat brain tissue, while single-cell RNA-sequencing was performed to test activation of double-stranded RNA-sensing pathways in human brains. Brains from individuals with alcohol use disorder showed significantly higher total intron retention compared with controls, independent of age, with females showing greater increases than males. A total of 368 introns were positively associated with alcohol use disorder, and these introns were significantly longer and had weaker splice acceptor sites compared with non-associated introns. Genes harbouring these intron retention events were enriched in Purkinje neurons, visual cortex neurons and oligodendrocytes. Computational predictions indicated these long introns could form duplex RNA structures. Increased double-stranded RNA was confirmed experimentally in multiple brain regions of alcohol-consuming rats, where it co-localized primarily with neuronal nuclei and dendrites. In individuals with alcohol use disorder, we found that multiple pathways including double-stranded RNA responses, neuroinflammation, interferon and NF-\u03baB signalling, adaptive immunity and apoptosis were activated. In addition, NeuN-positive neuronal counts significantly decreased in both the prefrontal and visual cortices. Furthermore, single-cell analysis demonstrated upregulation of TICAM1, the target of double-stranded RNA sensor TLR3, in oligodendrocytes, as well as widespread activation of downstream inflammatory pathways across glial and neuronal cell types. These findings provide the first evidence that chronic alcohol consumption promotes an overall increase of intron retention in the brain and is associated with the presence of double-stranded RNA. Furthermore, the double-stranded RNA may contribute to neuronal loss and brain pathology by activating a neuroinflammatory response.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag264","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T12:53:13Z","timestamp":1785243193000},"source":"Crossref","is-referenced-by-count":0,"title":["Elevated intron retention implicates neuroinflammation in brains of individuals with alcohol use disorder"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2389-1737","authenticated-orcid":false,"given":"Rudong","family":"Li","sequence":"first","affiliation":[{"name":"Center for Computational Biology and Bioinformatics (CCBB), Indiana University (IU) School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]},{"name":"Department of Medical and Molecular Genetics (MMGE), IU School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill L","family":"Reiter","sequence":"additional","affiliation":[{"name":"Center for Computational Biology and Bioinformatics (CCBB), Indiana University (IU) School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]},{"name":"Department of Medical and Molecular Genetics (MMGE), IU School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Season K","family":"Wyatt-Johnson","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, IU School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]},{"name":"Stark Neurosciences Research Institute, IU School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanpeng","family":"Dong","sequence":"additional","affiliation":[{"name":"Center for Computational Biology and Bioinformatics (CCBB), Indiana University (IU) School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]},{"name":"Department of Medical and Molecular Genetics (MMGE), IU School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caine S","family":"Smith","sequence":"additional","affiliation":[{"name":"New South Wales (NSW) Brain Tissue Research Centre, University of Sydney , Sydney, NSW 2006 ,","place":["Australia"]},{"name":"Charles Perkins Centre and School of Medical Sciences, University of Sydney , Sydney, NSW 2006 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Green","sequence":"additional","affiliation":[{"name":"Center for Computational Biology and Bioinformatics (CCBB), Indiana University (IU) School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]},{"name":"Department of Medical and Molecular Genetics (MMGE), IU School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Gao","sequence":"additional","affiliation":[{"name":"Center for Computational Biology and Bioinformatics (CCBB), Indiana University (IU) School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]},{"name":"Department of Medical and Molecular Genetics (MMGE), IU School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheketha R","family":"Hauser","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute, IU School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]},{"name":"Department of Psychiatry, IU School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manav","family":"Kapoor","sequence":"additional","affiliation":[{"name":"Ronald M. Loeb Center for Alzheimer\u2019s Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai , New York, NY 10029 ,","place":["USA"]},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10029 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Stevens","sequence":"additional","affiliation":[{"name":"New South Wales (NSW) Brain Tissue Research Centre, University of Sydney , Sydney, NSW 2006 ,","place":["Australia"]},{"name":"Charles Perkins Centre and School of Medical Sciences, University of Sydney , Sydney, NSW 2006 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R Dayne","family":"Mayfield","sequence":"additional","affiliation":[{"name":"Waggoner Center for Alcohol and Addiction Research (WCAAR), University of Texas at Austin , Austin, TX 78712 ,","place":["USA"]},{"name":"Department of Neuroscience, University of Texas at Austin , Austin, TX 78712 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Goate","sequence":"additional","affiliation":[{"name":"Ronald M. Loeb Center for Alzheimer\u2019s Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai , New York, NY 10029 ,","place":["USA"]},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10029 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics (MMGE), IU School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard J","family":"Edenberg","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics (MMGE), IU School of Medicine , Indianapolis, IN 46202 ,","place":["USA"]},{"name":"Department of Biochemistry, Molecular Biology, and Pharmacology, IU School of Medicine , Indianapolis, IN 4620 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