Alcohol metabolism contributes to brain histone acetylation.

Emerging evidence suggests that epigenetic regulation is dependent on metabolic state, and implicates specific metabolic factors in neural functions that drive behaviour1. In neurons, acetylation of histones relies on the metabolite acetyl-CoA, which is produced from acetate by chromatin-bound acetyl-CoA synthetase 2 (ACSS2)2. Notably, the breakdown of alcohol in the liver leads to a rapid increase in levels of blood acetate3, and alcohol is therefore a major source of acetate in the body. Histone acetylation in neurons may thus be under the influence of acetate that is derived from alcohol4, with potential effects on alcohol-induced gene expression in the brain, and on behaviour5. Here, using in vivo stable-isotope labelling in mice, we show that the metabolism of alcohol contributes to rapid acetylation of histones in the brain, and that this occurs in part through the direct deposition of acetyl groups that are derived from alcohol onto histones in an ACSS2-dependent manner. A similar direct deposition was observed when mice were injected with heavy-labelled acetate in vivo. In a pregnant mouse, exposure to labelled alcohol resulted in the incorporation of labelled acetyl groups into gestating fetal brains. In isolated primary hippocampal neurons ex vivo, extracellular acetate induced transcriptional programs related to learning and memory, which were sensitive to ACSS2 inhibition. We show that alcohol-related associative learning requires ACSS2 in vivo. These findings suggest that there is a direct link between alcohol metabolism and gene regulation, through the ACSS2-dependent acetylation of histones in the brain.

Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability.

Impulsivity, a multifaceted behavioral hallmark of attention-deficit/hyperactivity disorder (ADHD), strongly influences addiction vulnerability and other psychiatric disorders that incur enormous medical and societal burdens yet the neurobiological underpinnings linking impulsivity to disease remain poorly understood. Here we report the critical role of ventral striatal cAMP-response element modulator (CREM) in mediating impulsivity relevant to drug abuse vulnerability. Using an ADHD rat model, we demonstrate that impulsive animals are neurochemically and behaviorally more sensitive to heroin and exhibit reduced Crem expression in the nucleus accumbens core. Virally increasing Crem levels decreased impulsive action, thus establishing a causal relationship. Genetic studies in seven independent human populations illustrate that a CREM promoter variant at rs12765063 is associated with impulsivity, hyperactivity and addiction-related phenotypes. We also reveal a role of Crem in regulating striatal structural plasticity. Together, these results highlight that ventral striatal CREM mediates impulsivity related to substance abuse and suggest that CREM and its regulated network may be promising therapeutic targets.