Summary: Even low doses of alcohol can trigger transcriptomic and epigenomic changes in brain areas associated with addiction.
Source: University of Illinois
A new rodent study shows that even small amounts of alcohol can trigger epigenomic and transciptomic changes in brain circuitry in an area crucial to the development of addiction.
Additionally, the University of Illinois at Chicago researchers who conducted the study say the pathways involved in priming the brain for addiction are the same ones associated with spikes in alcohol consumption, such as euphoria and anxiolysis, the clinical term denoting a level of sedation. in which a person is relaxed but awake.
“This suggests that when the brain experiences the anti-anxiety and mood-enhancing effects of alcohol – the relaxation and the buzz – it is also primed for alcohol use disorders,” said the study’s lead author, Subhash Pandey, Joseph A. Flaherty. endowed professor of psychiatry and director of the Center for Alcohol Research in Epigenetics at the UIC School of Medicine.
While Pandey says the study doesn’t suggest, for example, that one drink is addictive in humans, it does provide clues as to why some people are more vulnerable to alcohol use disorders. .
“We find that addictive behaviors are not always due to long-term, high-volume habits, but result from rapid epigenetic changes in the brain, which we show in this study can start to occur even at low doses. “said Pandey, who is also a senior research scientist at the Jesse Brown Veterans Affairs Medical Center.
An article published in Molecular psychiatry details Pandey’s experiments, which studied rats under control conditions and alcohol exposure.
In the experiments, rodents were exposed to low concentrations of alcohol and their behaviors were observed as they explored a maze. Next, the researchers analyzed brain tissue samples, collected after euthanasia, with RNA sequencing and looked for gene expression patterns.
When they analyzed the samples, the researchers found that a gene called hypoxia-inducible factor 3 alpha subunit – Hif3a, for short – was associated with changes in the brain after exposure to alcohol. and behaviors, such as how long the rats remained in areas of the maze with (high anxiety) or with open arms (low anxiety).
Alcohol increased Hif3a expression, even after low doses of exposure, and reduced anxiety. And, although many of the effects of alcohol are different in men and women, there was no difference between the two in this study.
“We saw that low doses, what we consider ‘social consumption’, alter gene expression in the amygdala, a region of the brain that regulates anxiety. In other words, it creates an epigenetic pathway for addiction,” Pandey said.
Pandey and his colleagues also set up additional experiments in which they blocked the gene in the amygdala of rats with or without alcohol exposure to validate its role as an anxiety mediator. When Hif3a was blocked, anxiety increased in control rats, mimicking withdrawal from chronic alcohol exposure. On the other hand, it also prevented the anti-anxiety effects of alcohol.
The researchers also showed why. The chromatin of Hif3a – bundles of DNA and RNA – is loosely packed, meaning the genes are easily accessible for transcriptional changes.
One thing the study doesn’t suggest, however, is what level of alcohol exposure was safe for rodents. Instead, Pandey said, it’s important to know that low doses created a primer for addiction. For people, he thinks takeout is simple — don’t assume social drinking or even “pandemic drinking” is risk-free.
“Alcohol use disorder is complex and difficult to overcome. The insights we gained from this study help us better understand what is going on in the brain and, one day, could be leveraged to develop better treatments and pharmaceuticals,” Pandey said.
Co-authors of the study, titled “Unraveling Epigenomic and Transcriptomic Interaction During Alcohol-Induced Anxiolysis”, are Harish Krishnan, Huaibo Zhang, Ying Chen, John Peyton Bohnsack, Annie Shieh, Handojo Kusumo, Jenny Drnevich, Chunyu Liu, Dennis Grayson, and Mark Maienschein-Cline.
Funding: The research was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (P50AA-022538, U01AA-019971, U24AA-024605, RO1AA-010005) and the US Department of Veterans Affairs (I01BX004517, IK6BX006020).
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About this neuroscience and addiction research news
Author: Jacqueline Carey
Source: University of Illinois
Contact: Jacqueline Carey – University of Illinois
Image: Image is in public domain
Original research: Free access.
“Unraveling the epigenomic and transcriptomic interaction during alcohol-induced anxiolysis” by Harish Krishnan et al. Molecular psychiatry
Summary
Untangling epigenomic and transcriptomic interplay during alcohol-induced anxiolysis
The positive effects of alcohol consumption such as anxiolysis and euphoria appear to be a crucial factor in the initiation and maintenance of alcohol use disorder (AUD). However, the mechanisms that drive chromatin reorganization to transcriptomic changes after acute ethanol exposure remain unknown.
Here, we used Assay for Transposase-Accessible Chromatin followed by high-throughput sequencing (ATAC-seq) and RNA-seq to investigate the epigenomic and transcriptomic changes that underlie the anxiolytic effects of acute ethanol at using an animal model. Analysis of ATAC-seq data revealed an open or permissive global chromatin state associated with transcriptomic changes in the amygdala after acute ethanol exposure.
We have identified a candidate gene, Hif3a (hypoxia-inducible factor 3, alpha subunit), which had “open” chromatin regions (ATAC-seq peaks), associated with a significant increase in active epigenetic histone acetylation marks and a decrease in DNA methylation in these regions.
The mRNA levels of Hif3a were increased by acute ethanol exposure, but decreased in the amygdala during withdrawal after chronic ethanol exposure. Reversal of Hif3a expression in the amygdala central nucleus attenuated acute ethanol-induced increases Hif3a mRNA levels and blockade of anxiolysis in rats.
These data indicate that chromatin accessibility and transcriptomic signatures in the amygdala after acute ethanol exposure underlie anxiolysis and may prime chromatin for AUD development.
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