Osteocalcin modulates hippocampal activities and influences glycophagy within astrocytes in a chronic unpredictable mild stress mouse model.

Osteocalcin (OCN), an active substance produced by bone tissue, has demonstrated potential in alleviating depressive symptoms and exerting extensive regulatory effects on glial cells in animals by participating in the communication between bone and brain, while its precise mechanisms within the central nervous system (CNS) still not fully understood. In this study, we validated the antidepressant effects of OCN in depressive mice induced by chronic unpredictable mild stress (CUMS), and conducted a comprehensive assessment of the functional impacts of OCN in hippocampus using proteomic analysis. Additionally, the effects of OCN on astrocytes were investigated. Behavioral tests suggested that OCN significantly ameliorated the depressive - like behaviors of mice exposed to CUMS, manifesting by the reduced immobility time in the tail suspension test and forced swimming test. Results from the proteomic analysis showed that 117 differentially expressed proteins were found between the CUMS group and the CUMS + OCN group. The subcellular localization of these proteins was mostly enriched in the cytoplasm and cell membrane, involving in various cellular physiological processes. Importantly, we found that OCN influenced glycophagy in astrocytes in the hippocampus. These findings uncover the antidepressant efficacy of OCN, along with its target and mechanisms of action, providing a theoretical foundation for the in - depth exploration of the crucial physiological functions of OCN in the brain.