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NOvel research discovers hows alcohol byproducts travel to the brain to promote addiction memory, providing insight into potential therapeutics
Emerging evidence implicates epigenetic regulation to neural functions that drive behavior. Epigenetics is the study of heritable changes in gene expression that do not involve changes to the underlying DNA sequence — a change in phenotype without a change in genotype — which in turn affects how cells read the genes. There are at least three types of epigenetic modifications – DNA methylation, histone modification, and non-coding RNA-associated gene silencing – that act to initiate and sustain epigenetic change (Elnitski). Histones are the proteins that allow the DNA to condense into chromatin, but variations in histones can influence gene expression.
Long-term alcohol abuse teaches the brain to connect social, environmental, or emotional cues to instances that remind recovering addicts of their former alcohol use, often leading to relapse (Ghiţă et al. 2019). What drives the neurobiology behind these cravings that can be targeted by therapeutics has remained largely unknown.
In order for alcohol to metabolize and effect neural functions, alcohol must breakdown alcohol in the liver and produces rapid increases in blood acetate levels. Acetate helps make acetyl-CoA, a metabolite used by cells to help build up the cell membrane. Alcohol, therefore, is a major source of acetate in the body. Acetate in the body is used in the epigenetic process of histone acetylation, where an acetyl group is transferred from one molecule (in this case, acetyl-CoA) to another (histone). This variation in the histone allows the condensed DNA in chromatin to transform into a more relaxed state that allows for greater levels of gene transcription. Suspecting that there may be a connection between epigenetic metabolites and their influences on histones and its potential role in alcohol-induced associative learning, Mews et al. (2019) investigated whether acetate that is produced from the breakdown of alcohol contributes to dynamic acetylation of histones in the brain.
To determine if alcohol metabolites such as acetate contribute to histone acetylation, the authors provided cells with alcohol and measured the presence of acetylated histones by protein mass spectrometry. Mass spectrometry identifies proteins, their post-translational modifications, and localization in various organelles, on top of other characteristics (Wang and Wilson 2013). Acetyl groups from alcohol metabolism were rapidly utilized for histone acetylation by the brain, both in the hippocampus and the prefrontal cortex, but also in the liver, where alcohol metabolism occurs. The authors additionally altered a portion of the hippocampus so that it could not incorporate acetate from the liver to the brain’s histones and saw no histone acetylation, suggesting that acetate derived from the metabolism of alcohol in the liver is transported to the brain and readily incorporated into histone acetylation. To confirm their suspicions, Mews et al. also examined mice hippocampus tissue and determined that alcohol-derived acetate that contributes to the acetylation of histones in the hippocampus is converted to acetyl-CoA. This indicates that the increased levels of blood acetate from alcohol metabolism promotes acetylation of histones in the brain.
The authors next wanted to investigate how external acetate effects gene expression in the neurons of the hippocampus. They mimicked the entry of acetate during alcohol intake and then used bioinformatic tools to determine which genes displayed increased or decreased transcription. Exposure to acetate induced the expression of 3,613 genes involved in nervous system processes, including signal transduction, learning, and memory, and decreased the expression of genes involved in immune responses. When acetate was removed, most of the induced genes displayed decreased expression levels, mostly those related to nervous system processes, behavior, learning, and memory, suggesting that acetate is critical for these genes to be transcribed. Furthermore, some of the genes influenced included those involved in addiction and alcohol use as well as fetal alcohol disorder. Together, these findings suggest that coordination of histone acetylation and subsequent gene expression may have a role in alcohol-related cues common in those suffering from alcohol addiction.
Recognizing the role these histone modifications can play for genes involved in learning, memory, and addiction, the authors next used mice to examine the potential behavioral effects that come from acetate. They observed that mice exposed to acetate levels similar to levels seen during alcohol intake showed alcohol-induced associative learning, leading the mice to prefer environmental conditions that reminded them of the exposure to acetate from alcohol. The data suggests a mechanism for alcohol-related memory formation.
Mews et al. concluded that exposure to alcohol gives rise to the acetylation of histones in the brain through the direct absorption of alcohol-derived acetate. These finding further our understanding of alcohol-induced epigenetic regulation in the brain, suggesting that acetate produced by alcohol metabolism and associated enzymes could be a possible intervention target in alcohol use disorder. Additionally, this suggests an unanticipated potential mechanism for the etiology of fetal alcohol disorder, especially if deposition of alcohol-derived acetyl-groups onto histones in fetal brains can influence early neural development.
This research sheds light on a neuroepigenetic aspect of alcohol use that can aid therapeutics and treatments for people who suffer from alcohol use disorder. While further studies will be required to determine the relative contributions of alcohol-induced histone acetylation to environmental cues and fetal alcohol disorder, the direct pathway identified here finally connects the metabolism of alcohol to alcohol-related cues that drive alcohol craving, seeking, and consumption. Translational treatment strategies that target this relationship may pave the way for therapeutic interventions for alcohol use and other neuropsychiatric disorders.
Rachel Hendricks is a senior at Davidson College expected to graduate with a Bachelor’s degree in Biology in May 2021. Contact her at rahendricks@davidson.edu
Resources
Elnitski L., Epigenetics. National Human Genome Research Institute.
Ghiţă A., L. Teixidor, M. Monras, L. Ortega, S. Mondon, et al., 2019 Identifying Triggers of Alcohol Craving to Develop Effective Virtual Environments for Cue Exposure Therapy. Front Psychol 10.
Mews P., G. Egervari, R. Nativio, S. Sidoli, G. Donahue, et al., 2019 Alcohol metabolism contributes to brain histone acetylation. Nature 574: 717–721.
Wang P., and S. R. Wilson, 2013 Mass spectrometry-based protein identification by integrating de novo sequencing with database searching. BMC Bioinformatics 14: S24.
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