SRA

Vagus nerve stimulation (VNS) has been shown to enhance learning and memory, yet the mechanisms behind these enhancements are unknown. We show that VNS altered the hippocampal, cortical, and blood epigenetic transcriptomes in male Sprague Dawley rats whether or not the rats performed a novelty preference behavioral task. In the hippocampus, novelty preference correlated with decreased histone deacetylase 11 (HDAC11), a transcriptional repressor enriched in CA1 cells important for memory consolidation. In the cortex, the immediate early gene (IEG) ARC was increased in VNS rats and correlated with transcription of plasticity genes and epigenetic regulators, including HDAC3. For rats performing the novelty preference task, ARC correlated with performance. Surprisingly, VNS did not significantly reduce transcription of cortical or hippocampal proinflammatory cytokines. However, TNFRSF11B (osteoprotegerin) correlated with novelty preference as well as plasticity, stress–response signaling, and epigenetic regulation in both hippocampus and cortex. Together, our findings provide the first evidence that VNS induces widespread changes in the cognitive epigenetic landscape and specifically affects epigenetic modulators associated with novelty preference, stress–response signaling, memory consolidation, and cortical neural remodeling. Overall design: Rats were stimulated with implanted vagus nerve stimulation devices for 30 minutes on 4 consecutive days. A subset of rats performed a 10 minute novelty preference task on days 2-4. For all experiment conditions, matched control rats were implanted with a sham stimulation device. Rats were decapitated immediately following the day 4 stimulation and brains dissected. Hippocampal (for rats performing the novelty preference task) and Cortical RNA was extracted and sequenced.