Title: The Role of Osteocalcin in the Regulation of Brain Development and Functions
Description: The central nervous system controls many physiological processes including energy metabolism, immune response, reproduction, and development. In turn, hormones synthesized in and secreted by peripheral organs can be transported across the blood-brain barrier to modulate the development of the brain, the formation of new neurons, neural activity, behavior, and the secretion of brain-derived hormones. The central control of bone mass, mediated by the adipocyte-derived hormone leptin, has raised questions of whether the skeleton may signal back to the brain. In recent years, the Karsenty laboratory has uncovered the endocrine role of the bone-derived hormone osteocalcin. Through the use of a vast array of genetic tools, the Karsenty lab has discovered that osteocalcin is a potent regulator of glucose homeostasis, adaptation to exercise, energy metabolism, and male fertility. The multifunctional role of osteocalcin led us to hypothesize that it may act as a molecular means of communication between the skeleton and the brain.

We asked whether osteocalcin could regulate brain development during embryogenesis and behavioral functions in adulthood. In addressing these questions, we observed that bone-derived osteocalcin crosses the blood-brain barrier, accumulates in discrete parts of the brain including the hippocampus, and binds to several neuronal populations to favor the synthesis of monoamine neurotransmitters (serotonin, dopamine, and norepinephrine), and to impede the synthesis of the inhibitory neurotransmitter, GABA. Osteocalcin-/- mice have increased anxiety and depression and impaired learning and memory when compared to WT littermates. We also uncovered that the absence of maternal osteocalcin during embryogenesis hinders brain development and causes defects in spatial learning and memory in the adult offspring. Upon characterizing the necessity of osteocalcin for brain development and cognitive function, we investigated whether bone health is a determinant of cognition, and whether osteocalcin may be sufficient to reverse age-related cognitive decline.

In addressing the first question, we found that impairment in either bone formation or bone resorption negatively impacts both anxiety and memory. In addressing the second question, we found that osteocalcin is also necessary for the beneficial effect of young blood on cognitive functions. Finally, we observed reduced anxiety and improved memory in aged mice receiving osteocalcin peripherally. This action appears to require an increase in brain-derived neurotrophic factor levels in the hippocampus. Against the backdrop of our progressively aging population, it is important for future studies to determine whether osteocalcin may act therapeutically in humans to treat age-related cognitive decline. Additionally, to identify potential drug targets, it is important to fully characterize the molecular mechanism by which osteocalcin acts on neurons.