Hydroxytyrosol Mitigates Anxiety-Like Behaviors After a Traumatic Experience in Aged Mice in Parallel With Increased Neurogenesis in the Ventral and Dorsal Dentate Gyrus, and Preservation of Gut Microbiota Composition

: Hydroxytyrosol (HTyr), a phenolic compound present in olive oil, exhibits antioxidant, anti-inflammatory, and neuroprotective properties, benefiting several age-related diseases. Our previous research demonstrated that oral HTyr administration counteracts age-associated neurogenesis decline in the dentate gyrus of the hippocampus by promoting the production of stem/progenitor cells and new neurons. Since new neurons generated in the dorsal dentate gyrus support contextual memory discrimination, while those generated in the ventral region modulate anxiety, we investigated whether pure HTyr, synthesized in our laboratories, selectively stimulates neurogenesis in these regions in aging mice and evaluated its effects on contextual memory and stress response. Furthermore, we examined its influence on gut microbiota composition, given the well-established role of the microbiota-gut-brain axis in memory and stress regulation. We found that HTyr induced the production of new neurons and neuroblasts in both dentate gyrus regions, with a prevalent effect in the ventral region. Consistently, we observed that HTyr treatment did not improve the contextual memory discrimination but reduced fear sensitization and anxiety-like behavior after a traumatic experience. Furthermore, we observed a reduction of neuroinflammation in HTyr-treated dentate gyri. In parallel, treatment with HTyr preserved the stability of key microbial families linked to intestinal well-being, counteracting the unhealthy effects of stress on gut microbial structure. Our results suggest that HTyr treatment in aging mice enhances resilience to posttraumatic stress by increasing neurogenesis and modulating the microbiota-gut-brain axis. Future studies should explore its potential as a therapeutic intervention for individuals experiencing posttraumatic stress disorder symptoms.