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Molecular fingerprints in the hippocampus of alcohol seeking during withdrawal
Preprint   Open access

Molecular fingerprints in the hippocampus of alcohol seeking during withdrawal

Roberto Pagano, Ahmad Salamian, Edyta Skonieczna, Bartosz Wojtas, Bartek Gielniewski, Zofia Harda, Anna Cały, Robbert Havekes, Ted Abel and Kasia Radwanska
bioRxiv : the preprint server for biology
08/26/2023
DOI: 10.1101/2023.08.24.554622
PMCID: PMC10473700
PMID: 37662388
url
https://doi.org/10.1101/2023.08.24.554622View
Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Alcohol use disorder (AUD) is characterized by excessive alcohol seeking and use. Here, we investigated the molecular correlates of impaired extinction of alcohol seeking using a multidimentional mouse model of AUD. We distinguished AUD-prone and AUD-resistant mice, based on the presence of ≥ 2 or < 2 criteria of AUD and utilized RNA sequencing to identify genes that were differentially expressed in the hippocampus and amygdala of mice meeting ≥ 2 or < 2 criteria, as these brain regions are implicated in alcohol motivation, seeking, consumption and the cognitive inflexibility characteristic of AUD. Our findings revealed dysregulation of the genes associated with the actin cytoskeleton, including actin binding molecule cofilin, and impaired synaptic transmission in the hippocampi of mice meeting ≥ 2 criteria. Overexpression of cofilin in the polymorphic layer of the dentate gyrus (PoDG) inhibited ML-DG synapses, increased motivation to seek alcohol and impaired extinction of alcohol seeking, resembling the phenotype observed in mice meeting ≥ 2 criteria. Overall, our study uncovers a novel mechanism linking increased hippocampal cofilin expression with the AUD phenotype. Abstract Figure

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