The physiological effects of alcohol on the brain and motor function have been studied extensively for decades. In low doses, alcohol causes euphoria and reduces anxiety, while in higher doses it impairs cognition and balance, and increases response time. Long-term consumption of alcohol is associated with changes in memory and alcohol-related learning, which play important roles in the development of alcohol use disorder. Dr. Philipp Mews, a CAMB graduate from the Genetics and Gene Regulation (now Genetics and Epigenetics) sub-program, explored the link between alcohol metabolism, gene expression, and alcohol-related learning behaviors, and recently published his findings in Nature.
Alcohol metabolism begins in the liver when ethanol is broken down into acetate, leading to a rapid increase in blood acetate levels. In a previous study, Mews demonstrated that acetyl-CoA synthase 2 (ACSS2), the metabolic enzyme which converts acetate to acetyl-CoA, is highly expressed in the learning center of the brain- the hippocampus, and is bound to neuronal chromatin to ‘fuel’ the modification of histone proteins with acetyl groups (Mews et al., Nature 2017). The hippocampus is a small, yet complex structure embedded deep in the brain and is associated with memory and learning. Therefore, histone modification changes in this region could affect alcohol-related learning. In their most recent study, Mews and colleagues explored how the rapid rise in blood acetate after ethanol consumption is translated into an immediate increase in acetylation of histones in the hippocampal region of the brain. Using a mouse model, they discovered that this epigenetic modification is facilitated by ACSS2 and affects alcohol-associated learning behaviors.
A. The liver metabolizes the ethanol in alcohol to acetate. B. Acetyl CoA synthase 2 (ACSS2) transfers the acetate unto histones in neurons in the hippocampus and prefrontal cortex. C. These histone modifications lead to changes in ethanol-associated memories in mice.
Dr. Mews, who did his thesis work in Dr. Shelley Berger’s lab, conceived the idea for this project in 2013 when he started working on ACSS2. It developed incrementally over the years as a side-project with help from other co-authors and collaborators. By the time the writing and review process began, Dr. Mews had already taken-up his current position as a postdoctoral fellow at the Icahn School of Medicine at Mount Sinai in Dr. Eric Nestler’s lab. With regular commutes between Philly and New York on the weekends, thus began a year-long long-distance ‘relationship’.
One of the primary techniques utilized by Mews in the study was in vivo stable-isotope labeling followed by mass spectrometry. Intraperitoneal injections of labeled ethanol in mice led to the incorporation of the label in the acetyl groups on histones in the hippocampus and prefrontal cortex of the brain. This process was extremely dynamic and detected within just minutes. A knockdown of Acss2 in the dorsal hippocampus prevented this incorporation, leading Mews and colleagues to conclude that ACSS2 mediated this acetylation of histones in the brain, exploiting the increased levels of blood acetate. A set of in vivo and ex vivo RNA-seq experiments showed that gene targets for ACSS2 belonged to pathways in neuronal plasticity, as well as ribosomal and mitochondrial functions.
Another exciting experiment done by the group was an ethanol-mediated behavioral study utilizing a method known as conditioned place preference, on Acss2 wild type and knockdown mice. After prior conditioning to ethanol, wild-type mice showed a higher preference for the spatial compartment with ethanol in comparison to Acss2-knockdown mice. These results showed how ACSS2, a metabolic enzyme, opens up the epigenetic landscape for alcohol addiction in the brain.
Lastly, the authors briefly explored how maternal alcohol use affects fetal development during pregnancy. Mass spectrometry on fetal brains at E18.5 revealed that exposure to binge-like drinking in mothers resulted in the deposition of ethanol-derived acetyl groups in the fetal mid and forebrain. This finding potentiates the inheritance of alcohol-related memory and learning behavior.
Dr. Philipp Mews’s work helps bridge the knowledge gap between alcohol metabolism and alcohol-related learning behavior, and it unveils the metabolic enzyme ACSS2 as a potential therapeutic candidate for alcohol abuse and addiction disorders. His current work at Mount Sinai examines how drugs of abuse cause long-lasting changes in chromatin in a key brain region of reward learning. He wants to eventually have his independent research lab and work on epigenetics dysregulated in psychiatric and substance use disorders.
Scientists in the field of neuro-epigenetics want to understand the role epigenetic regulation plays in brain function in mental health and related disorders. According to Dr. Mews, “the hope is to modulate brain chromatin in modern psychiatry, where psychosocial therapy in combination with pharmacological treatment may facilitate epigenetic reprogramming to alleviate symptoms and support disease recovery”. His latest work has brought us a step closer to understanding addiction, and finding more precise and druggable targets to combat it.
Reference: Mews, P. et al. (2019), Alcohol metabolism contributes to brain histone acetylation, Nature, 574(7780):717-721