I attended a talk about Brain Region Specific Memory Enhancement by Acetate via Epigenetic and Transcriptional Regulation, by Gabor Egervari, an assistant professor at WashU. He discussed the importance of metabolism in regulating the epigenetics of gene expression in the brain, eg the process that changes gene expression via the alteration of chromatin wrapping around histones. For example, ACSS2 is a metabolic cofacotr required in the nucleus to fuel histone modification enzymes, and its binding across the genome correlates with increased histone acetylation at certain genes. ACSS2 is a byproduct of a metabolic pathway, specifically, acetate creates ACSS2 which can be used to create acetyl-COA. Acetate itself comes from diet, or acetylated histones and acetylcholine, a common neurotransmitter.

One of the experiments run involved the application of these studies onto alcohol use disorder. The researchers put a mouse in one compartment of a box and exposed it to alcohol, and a second compartment in the box with exposure to saline on alternate days. After training, the mice were found to spend more time in the chamber they received alcohol due to the rewarding effects. However, ACSS2 knockdown got rid of the learned desire for alcohol, and the ACSS2 KO mice consumed less alcohol voluntarily. This is because ACSS2 helps mediate memory and learning in the hippocampus of the brain. There were also wider reaching impacts in associated areas such as the amygdala, the ventral tegmental area, and the dorsal striatum, which are responsible for negative emotions, reward, and habit formation respectively.

After this, they decided to explore whether the effect of acetate can be uncoupled from alcohol and drug exposure, since without knockdown, alcohol derived acetate is fueling histone acetylation in the brain in an ACSS2 dependent manner and driving the learned memory of alcohol. Even with cocaine, acetate facilitates associated memory formation—with only one training session with cocaine, wildtype mice did not exhibit a preference, but with an injection of cocaine and acetate together, they immediately developed a strong conditioned preference.

Acetate further only has effects on particular parts of learning. In a third experiment, the researchers compared the effects of acetate between novel object recognition (NOR) and novel object location (NOL). They found that acetate has no effect on NOR, but induces hippocampus dependent learning for NOL. When imaging the brain, they found rapid incorporation of acetate into brain histone acetylation in the dorsal hippocampus. Specifically, acetate induces acetylation of the H2A.Z gene in the hippocampus, and H2A.Z mutant mice have enhanced memory while acetyl deficient H2A.Z mutant mice have inhibited spatial memory. 

I found the talk overall incredibly fascinating, especially since addiction is such an important area of research. In the future, Dr. Egervari wants to do more research into facilitating metabolic epigenetic interactions to rescue brain learning, not just inhibit it, which could assist people with neurodegenerative diseases such as Alzheimer’s. They also want to study other metabolites and their effect on the epigenome.