2026 Theses Doctoral

A Brain-Bone Axis Orchestrates Motor Coordination Throughout Life

Canal Delgado, Isabella

Bone is densely innervated by a complex network of sensory and sympathetic nerves that influence its structural functions such as bone mass accrual and bone repair after fractures. However, it remains unknown whether this innervation influences the recently described endocrine functions of bone. Here, I identify a neural circuit whereby neuron-derived glutamate stimulates the release of osteocalcin (Ocn), a bone-derived hormone made by osteoblasts. This occurs through the presence of “neuro-bone” junctions between axons and osteoblasts with enrichment of the vesicular glutamate transporter 2 (VGLUT2) on the neural side and the glutamate transporter GLAST, Psd-95, Shank-2 and members of the SNARE protein family on the osteoblast side.

To assess the physiological significance of this circuit, I modeled in mice symptoms observed in patients with loss-of-function mutations in EAAT1 (the human homologue of Glast), which cause episodic ataxia type 6 (EA6). I show that mice lacking Glast in osteoblasts exhibit the motor incoordination observed in EA6 patients. This is because Ocn signals through the G protein-coupled receptor GPR158 in Purkinje cells of the cerebellum to increase their basal firing frequency, contributing to proper motor coordination. In agreement with the fact that circulating Ocn levels decline with age as does motor coordination, restoring circulating Ocn in aged mice to what is seen in young mice, prevents the appearance of and can even reverse an existing age-related motor deficit by increasing the firing rate of Purkinje neurons.

Together, our findings reveal a bone-brain axis in which neuron-derived glutamate signals in osteoblasts to modulate motor coordination by promoting the release of Ocn. I propose that this pathway may be harnessed to treat age-related decline in motor coordination.