Increasing Histone Acetylation in the Hippocampus-Infralimbic Network Enhances Fear Extinction

Background: A key finding from recent studies of epigenetic mechanisms of memory is that increasing histone acetylation after a learning experience enhances memory consolidation. This has been demonstrated in several preparations, but little is known about whether excitatory and inhibitory memories are equally sensitive to drugs that promote histone acetylation and how transcriptional changes in the hippocampal-medial prefrontal cortex network contribute to these drug effects. Methods: We compare the long-term behavioral consequences of systemic, intrahippocampal and intra-medial prefrontal cortex administration of the histone deacetylase inhibitor sodium butyrate (NaB) after contextual fear conditioning and extinction 1 and/or 14 days later in male c57BL/6J mice (n = 302). Levels of histone acetylation and expression of the product of the immediate-early gene c-Fos were assessed by immunohistochemistry following infusion of NaB into the hippocampus (n = 26). Results: Across a variety of conditions, the effects of NaB on extinction were larger and more persistent compared to the effects on initial memory formation. NaB administered following weak extinction induced behavioral extinction, infralimbic histone acetylation and c-Fos expression consistent with strong extinction. No similar effect was seen in the prelimbic cortex. The involvement of the infralimbic cortex was confirmed as infusions of NaB into the infralimbic, but not prelimbic cortex, induced extinction enhancements. Conclusions: These studies show that the memory modulating ability of drugs that enhance acetylation is sensitive to a variety of behavioral and molecular conditions. We further identify transcriptional changes in the hippocampal-infralimbic circuit associated with extinction enhancements induced by the histone deacetylase inhibitor NaB.