Learning and memory rely on synaptic communication in which intracellular signals are transported to the nucleus to stimulate transcriptional activation. Memory induced transcriptional increases are accompanied by alterations to the epigenetic landscape and can be pharmacologically mimicked to ameliorate memory in both healthy and cognitively impaired animals. Of particular interest in this regard is histone acetylation, as this epigenetic modification is enriched during memory formation and is readily amenable to pharmacological manipulation by means of histone deacetylase inhibitors (HDACis). Although multiple studies have shown that systemic HDACi administration can improve memory formation, their mode of action is not yet fully understood.

In this study, we tested whether HDACis â given systemically â augment epigenetic, transcriptional and electrophysiological responses that are induced by learning, thus amplifying naturally occurring responses via cognitive epigenetic priming. To do this, we combined a system-wide HDACi treatment with a sub-threshold contextual fear conditioning (CFC) paradigm, a weakened Pavlovian modal that, alone, does not lead to long term memory formation.

We found that, in combination, HDACi and CFC improve recent contextual memory that is accompanied by enhanced long-term potentiation in the hippocampus. Conversely, combined HDACi-CFC treatment induced no such synaptic strengthening in the striatum, a brain region that is not directly activated by fear conditioning. We then used bulk and single nuclear RNA-sequencing to show that HDACi activates unique transcriptional pathways, both between the two brain regions and between cell types within the hippocampus, indicating that HDACi does not act indiscriminatingly, but instead supports cellular processes that are already occurring in response to the conditioning. Finally, we show that HDACi treatment paired with contextual fear conditioning enriches H3K27ac at enhancers of known memory-related genes within the hippocampus but that not all these genes are necessarily more transcriptionally active at the same time point.

These results indicate that systemic HDACi administration acts as a cognitive enhancer by amplifying brain-region specific processes that are naturally induced during memory formation but that these results may not be a direct effect of enhancer histone acetylation. These findings shed light on the mechanisms of HDACi-mediated cognitive epigenetic priming and help to pave the way for potential new therapies for memory-related disorders.