The powerful regulation of bone mass exerted by the brain suggests the existence of bone-derived signals modulating this regulation or other functions of the brain. We show here that the osteoblast-derived hormone osteocalcin crosses the blood-brain barrier, binds to neurons of the brainstem, midbrain and hippocampus, enhances the synthesis of monoamine neurotransmitters, inhibits GABA synthesis, prevents anxiety and depression and favors learning and memory independently of its metabolic functions. In addition to these post-natal functions, maternal osteocalcin crosses the placenta during pregnancy and prevents neuronal apoptosis before embryos synthesize this hormone. As a result the severity of the neuro-anatomical defects and learning and memory deficits of Osteocalcin−/− mice is determined by the maternal genotype, and delivering osteocalcin to pregnant Osteocalcin−/− mothers rescues these abnormalities in their Osteocalcin−/− progeny. This study reveals that the skeleton via osteocalcin influences cognition and contributes to the maternal influence on fetal brain development.

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