Preconditioning with Menaquinone-7 and Environmental Enrichment Produces Distinct Osteocalcin and Neuroplasticity Responses Following Chronic Social Defeat Stress

Background and Objectives: Depression is a growing global health burden, underscoring the need for preventive strategies that complement existing treatments. Environmental enrichment (EE), incorporating physical, cognitive, sensory, and social stimulation, enhances neuroplasticity and stress resilience. Menaquinone-7 (MK-7), a form of vitamin K2, may also support brain health through osteocalcin, a bone-derived hormone involved in cognition and neuroplasticity. This study examined the protective effects of EE and MK-7 preconditioning, alone and combined, against chronic social defeat stress (CSDS), focusing on the osteocalcin-mediated bone–brain axis and structural plasticity. Materials and Methods: Male C57BL/6N mice received MK-7 (100 µg), EE, or both for four weeks before a 10-day CSDS protocol. Depressive-like behavior was assessed using the forced swim and tail suspension tests, while cognition was evaluated using novel object recognition and Y-maze tests. Serum osteocalcin, brain undercarboxylated osteocalcin (ucOC), brain gene expression of Bdnf, Gpr158, and Rbbp4, and protein levels of BDNF, MAP2, and GAP43 were measured. Results: CSDS induced depressive-like behavior and cognitive impairment, accompanied by reductions in serum and brain ucOC, Bdnf expression, BDNF, GAP43, and MAP2. Both MK-7 and EE showed significant main effects on behavioral and cognitive outcomes, while MK-7 exerted broader effects on osteocalcin- and neuroplasticity-related molecular markers. Significant MK-7 × EE interactions were limited to selected outcomes, including FST and brain ucOC, indicating outcome-specific rather than generalized synergy. Conclusions: CSDS disrupts the osteocalcin-mediated bone–brain axis and neuroplasticity-related pathways. MK-7 and EE both improved behavioral and cognitive outcomes, but MK-7 exerted broader effects on ucOC- and BDNF-related molecular markers, whereas their combination produced selective interactions rather than generalized synergy.