Osteocalcin is a compensatory hormone to protect the nervous system in ovariectomized mice.

Undercarboxylated osteocalcin (ucOCN), a bone-derived hormone, modulates neurocognition and emotional regulation. Its concentration declines with aging but rises secondarily in females with estrogen deficiency caused by ovarian decline. Using an ovariectomized (OVX) mouse model, we found serum ucOCN sharply increased in early OVX stages with normal behavioral performance, whereas prolonged estrogen loss decreased ucOCN and induced cognitive and emotional impairments. Ocn knockout mice failed to exhibit OVX-triggered ucOCN elevation and displayed severe synaptic damage and behavioral deficits at the early stage, which were rescued by exogenous ucOCN supplementation. Furthermore, long-term ucOCN administration ameliorated behavioral impairments induced by sustained estrogen deficiency, upregulated the expression of synaptic proteins, and restored hippocampal synaptic plasticity. Collectively, dynamic alterations in ucOCN are correlated with neurobehavioral changes under estrogen deficiency. As a time-dependent neurocompensatory mediator, ucOCN maintains hippocampal synaptic integrity. Long-term ucOCN intervention may provide a promising therapeutic strategy for estrogen deficiency-related cognitive and emotional disorders.