Acetate enhances long-term memory in female mice by sex-, context-, and brain region-specific epigenetic and transcriptional remodeling

Metabolic control of chromatin and gene expression is emerging as a key mechanism influencing critical neuronal functions. Here, we found that the intermediary metabolite acetate enhanced long-term memory in female mice, which was associated with epigenetic and transcriptional remodeling in the dorsal hippocampus. Acetate-enhanced memory was driven by increased acetylation of the histone variant H2A.Z and increased expression of genes implicated in learning in the female dorsal hippocampus. The effect of acetate on dorsal hippocampal histone modifications and gene expression differed markedly between the sexes during critical windows of memory consolidation and recall, and home cage exposure to acetate without the learning and recall tasks did not recapitulate these effects. These findings elucidate the ways in which acetate exposure enhances memory.