Journal article
Hippocampal Cofilin and CFL1 gene variants are linked to Alcohol Use Disorder phenotypes
Molecular psychiatry, Vol.31(3), pp.1216-1230
03/2026
DOI: 10.1038/s41380-025-03226-3
PMCID: PMC12916304
PMID: 40931167
Abstract
Alcohol use disorder (AUD) is characterized by pathological motivation to consume alcohol and cognitive inflexibility, leading to excessive alcohol seeking and use. In this study, we investigated the molecular correlates of impaired extinction of alcohol seeking during forced abstinence using a mouse model of AUD in the automated IntelliCage social system. This model distinguished AUD-prone and AUD-resistant animals based on the presence of ≥2 or <2 criteria of AUD, respectively. We used RNA sequencing to identify genes differentially expressed in the hippocampus, a brain region implicated in alcohol motivation, seeking during abstinence, and cognitive inflexibility. Our findings revealed differences in the hippocampal genes linked to the actin cytoskeleton and synaptic function, including cofilin (Cfl), and impaired synaptic transmission in the molecular layer of the hippocampal dentate gyrus (ML-DG) in ≥2 criteria mice as compared to <2 crit animals. To complement this data, we conducted local genetic manipulations in DG. Overexpression of Cfl in the polymorphic layer of the hippocampal dentate gyrus (PoDG) inhibited ML-DG synapses, increased motivation to seek alcohol and sucrose rewards, impaired extinction of seeking, and decreased reward consumption during relapse. Reducing Cfl levels had opposite effects. We also identified three SNPs in the human CFL1 gene (rs369270402, rs2376005, rs36124259) associated with increased AUD risk and found CFL1 mRNA blood levels correlated with alcohol-related hospital admissions. Overall, our study uncovers a novel mechanism linking hippocampal Cfl expression with AUD phenotypes and identifies CFL1 polymorphisms as AUD risk factor in humans.
Details
- Title: Subtitle
- Hippocampal Cofilin and CFL1 gene variants are linked to Alcohol Use Disorder phenotypes
- Creators
- Ahmad Salamian - Polish Academy of SciencesRoberto Pagano - International Institute of Molecular and Cell BiologyEdyta Skonieczna - Polish Academy of SciencesLiubov S Kalinichenko - Friedrich-Alexander-Universität Erlangen-NürnbergMonika Puchalska - Polish Academy of SciencesG Yiğit Ünlü - Instytut Biologii Doświadczalnej im. Marcelego NenckiegoOlga Gajewska-Woźniak - Polish Academy of SciencesLali Kruashvili - Polish Academy of SciencesMałgorzata Grochowicz - Polish Academy of SciencesBartosz Wojtas - Instytut Biologii Doświadczalnej im. Marcelego NenckiegoBartek Gielniewski - Polish Academy of SciencesZofia Harda - Polish Academy of SciencesAnna Cały - Polish Academy of SciencesChristiane Mühle - Friedrich-Alexander-Universität Erlangen-NürnbergBernd Lenz - Central Institute of Mental HealthJohannes Kornhuber - Friedrich-Alexander-Universität Erlangen-NürnbergAnbarasu Lourdusamy - University of NottinghamRobbert Havekes - University of GroningenTed Abel - University of IowaChristian P Müller - Friedrich-Alexander-Universität Erlangen-NürnbergKasia Radwanska - Polish Academy of Sciences
- Resource Type
- Journal article
- Publication Details
- Molecular psychiatry, Vol.31(3), pp.1216-1230
- DOI
- 10.1038/s41380-025-03226-3
- PMID
- 40931167
- PMCID
- PMC12916304
- NLM abbreviation
- Mol Psychiatry
- ISSN
- 1476-5578
- eISSN
- 1476-5578
- Publisher
- SPRINGERNATURE
- Grant note
- R01 MH 087463 / U.S. Department of Health & Human Services | NIH | NICHD | National Center for Medical Rehabilitation Research (NCMRR)
- Language
- English
- Electronic publication date
- 09/11/2025
- Date published
- 03/2026
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984962643102771
Metrics
8 Record Views