Bidirectional control of parathyroid hormone and bone mass by subfornical organ

Parathyroid hormone (PTH) is one of the most important hormones for bone turnover and calcium homeostasis. It is unclear how the central nervous system regulates PTH. The subfornical organ (SFO) lies above the third ventricle and modulates body fluid homeostasis. Through retrograde tracing, electrophysiology, and in vivo calcium imaging, we identified the SFO as an important brain nucleus that responds to serum PTH changes in mice. Chemogenetic stimulation of GABAergic neurons in SFO induces decreased serum PTH followed by a decrease in trabecular bone mass. Conversely, stimulation of glutamatergic neurons in the SFO promoted serum PTH and bone mass. Moreover, we found that the blockage of different PTH receptors in the SFO affects peripheral PTH levels and the PTH's response to calcium stimulation. Furthermore, we identified a GABAergic projection from the SFO to the paraventricular nucleus, which modulates PTH and bone mass. These findings advance our understanding of the central neural regulation of PTH at cellular and circuit level.