2024/12/09 by Gabor Egervári, Greg Donahue, Natalia A. Quijano Cardé +7 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Peroxisome Proliferator-Activated Receptors #Adipose Tissue and Metabolism #Epigenetics and DNA Methylation
paper · doi:10.1016/j.neuropharm.2024.110258
openalex publication_date 2024/12/09 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/22
Metabolic-epigenetic interactions are emerging as key pathways in regulating alcohol-related transcriptional changes in the brain. Recently, we have shown that this is mediated by the metabolic enzyme Acetyl-CoA synthetase 2 (Acss2), which is nuclear and chromatin-bound in neurons. Mice lacking ACSS2 fail to deposit alcohol-derived acetate onto histones in the brain and show no conditioned place preference for ethanol reward. Here, we further explored the role of this pathway during voluntary alcohol intake. We found that Acss2 KO mice consume significantly less alcohol in a model of binge drinking, an effect primarily driven by males. Genome-wide transcriptional profiling of 7 key brain regions implicated in alcohol and drug use revealed that, following drinking, Acss2 KO mice exhibit blunted gene expression in the ventral striatum. Similarly to the behavioral differences, transcriptional dysregulation was more pronounced in male mice. Further, we found that the gene expression changes were associated with depletion of ventral striatal histone acetylation (H3K27ac) in Acss2 KO mice compared to WT. Taken together, our data suggest that ACSS2 plays an important role in orchestrating ventral striatal epigenetic and transcriptional changes during voluntary alcohol drinking, especially in males. Consequently, targeting this pathway could be a promising new therapeutic avenue. • Acss2 KO mice consume less alcohol during drinking-in-the-dark • Loss of Acss2 affects drinking more strongly in males compared to females • Transcriptional profiling indicates the role of ventral striatal gene expression • Decreased histone acetylation in the ventral striatum of male Acss2 KO mice