Environmental enrichment (EE) enhances hippocampal plasticity. However, the individual components of EE, such as voluntary running and object exploration, provide fundamentally different sensory, motor, and cognitive forms of stimulation. Motor-based enrichment primarily recruits proprioceptive and neuromuscular pathways, whereas object-based enrichment activates sensory novelty and hippocampus-dependent spatial processing circuits. Our previous findings also demonstrated that object-only enrichment improves cognition without increasing physical activity (PA), which suggests that different enrichment conditions may engage distinct neurobiological mechanisms. Despite these observations, it remains unclear whether the behavioral differences across enrichment conditions correspond to specific pathway of epigenomic regulation and gene expression in the hippocampus. The objective of this study was to identify epigenomic and transcriptomic signatures that are dependent on the type of enrichment provided. We hypothesized that wheel-based enrichment and object-based enrichment would generate different promoter-level and transcriptional responses, and that sensory-cognitive enrichment would enhance cognitive function independently of PA. Methods: Male Wistar rats were housed for 4 weeks under four conditions: combined wheel + objects (EE), wheel-only enrichment (EER), object-only enrichment (EEO), or standard environment (SE). PA was quantified with triaxial accelerometry. Spatial learning was assessed using the Morris water maze. Promoter DNA methylation was profiled by reduced representation bisulfite sequencing (RRBS), defining differentially methylated regions (DMRs) as ≥25% methylation divergence (p 1.5, p < 0.05). Functional enrichment analyses were performed for both datasets. Results: All enriched conditions improved spatial learning relative to SE (interaction p < 0.001). PA was markedly elevated in wheel-based conditions (EE and EER; p < 0.0001), whereas EEO produced comparable cognitive enhancement without changes in PA. DNA methylation analysis revealed substantial promoter methylation remodeling in EER and EEO, whereas combined EE showed comparatively limited epigenomic alterations. DMR-associated genes in EER were enriched for neural network remodeling and axonal structure, whereas those in EEO mapped to synaptic organization and vesicle-associated pathways. RNA-seq identified 27 DEGs common to all enriched groups, including downregulation of transthyretin. Mode-specific DEG enrichment patterns paralleled those of DMR-associated genes: in EER, both datasets highlighted network remodeling processes, and in EEO, both were enriched for synaptic structural pathways. This pathway-level coherence suggests that each enrichment mode recruits a coordinated epigenomic–transcriptional program targeting distinct aspects of hippocampal neuroplasticity. Conclusion: Environmental enrichment induces mode-dependent epigenomic and transcriptomic regulation that differentially shapes hippocampal plasticity. Sensory-cognitive enrichment enhances cognition through a diverse array of molecular mechanisms that extend beyond those induced solely by PA, demonstrating that the qualitative nature of environmental stimuli, rather than activity magnitude alone, governs enrichment-induced neurobiological adaptations. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Sudo et al. (Fri,) studied this question.