Cognition-Enhancing Vagus Nerve Stimulation Alters the Epigenetic Landscape

Vagus nerve stimulation (VNS) has been shown to enhance learning and memory, yet the mechanisms behind these enhancements are unknown. Here, we present evidence that epigenetic modulation underlies VNS-induced improvements in cognition. We show that VNS enhances novelty preference (NP); alters the hippocampal, cortical, and blood epigenetic transcriptomes; and epigenetically modulates neuronal plasticity and stress-response signal ing genes in male Sprague Dawley rats. Brain-behavior analysis revealed structure-specific relationships between NP test performance (NPTP) and epigenetic alterations. In the hippocampus, NPTP 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 engaged in NPTP, ARC correlated with performance. Interestingly, blood ARC transcripts decreased in VNS rats performing NPTP, but increased in VNS-only rats. Because DNA double-strand breaks (DSBs) facilitate transcription of IEGs, we investigated phosphorylated H2A.X ( gamma H2A.X), a histone modification known to colocalize with DSBs. In agreement with reduced cortical stress-response transcription factor NF-kappa B1, chromatin immunoprecipitation revealed reduced gamma H2A.X in the ARC promoter. Surprisingly, VNS did not significantly reduce transcription of cortical or hippocampal proinflammatory cytokines. However, TNFRSF11B (osteoprotegerin) correlated with NPTP as well as plasticity, stress-response signaling, and epigenetic regulation transcripts 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 NPTP, stress-response signaling, memory consolidation, and cortical neural remodeling.