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Chromatin Modulation Underlies Multiple Routes to Enhanced Learning and Memory

Modulation of epigenetic targets has been shown to enhance learning and memory in rodents and humans. However, the downstream chromatin and gene expression changes responsible for these cognitive improvements are unclear. Here, we present evidence that altered expression of histone modification and neuronal plasticity genes plays a prominent role in enhanced learning and memory. We have recently shown that vagus nerve stimulation (VNS) epigenetically modulates learning and memory (SfN 2018). In this study, we compare rats that received 30 minutes of intermittent VNS bursts on 4 consecutive days to rats that received a single intracranial injection of histone deacetylase (HDAC) inhibitor. Both cohorts showed improved learning and memory, along with changes in cortical, hippocampal, and blood transcription profiles and epigenetic marks. Many of the significantly changed transcripts correlated with behavioral performance in a novel object recognition task. Interestingly, the downstream chromatin and gene expression changes differed dramatically between cohorts that received HDAC inhibitor injections versus those that received VNS. We also observed numerous within‐cohort differences between the two brain regions examined. VNS‐induced cortical changes included increased histone deacetylation, neural‐remodeling (ARC) and translation elongation (DPH1) transcripts, while significant hippocampal changes included reduced HDAC activity and calcium signaling changes (CAMK2B, CAMK2N2). Despite differences in the overall transcriptome landscape between the VNS‐stimulated cortex and hippocampus, tissue from both regions showed reductions in stress response signaling (including NF‐κB), and changes in immediate early gene (IEG) and histone‐related transcripts. Reduced NF‐κB signaling during VNS has been assumed to be a downstream effect of reduced inflammatory cytokines. However, in our study, we observed few changes in inflammatory cytokines, yet identified significant effects of epigenetic modulation and stress response signaling that correlated with behavioral performance. Our results indicate that VNS‐enhanced learning and memory may be mediated through reductions in alternative NF‐κB signaling pathways and associated effects such as double strand break (DSB) repair at phosphorylated histone 2A.X (γH2A.X)‐marked sites. This is consistent with our transcriptional profiling evidence and chromatin‐immunoprecipitation assays showing decreased γH2A.X in the cortex of stimulated rats. On the other hand, HDAC‐inhibitor‐injected rats did not display reduced stress‐response signaling, but rather showed strong decreases in cortical and hippocampal HDACs and concomitant increases in neuronal receptor gene expression. Surprisingly, VNS rats showed only small changes in HDAC2 along with increased cortical HDAC3. Although both rat cohorts showed improved novel object recognition and significant changes in neuronal plasticity transcription, the observed neuronal receptor alterations were distinct. In conclusion, our results demonstrate evidence that widely divergent chromatin modulation profiles underlie multiple paths to enhanced learning and memory.