A GABAergic neural circuit in the ventromedial hypothalamus mediates chronic stress–induced bone loss
Fan Yang, Yunhui Liu, Shanping Chen, Zhongquan Dai, Dazhi Yang, Dashuang Gao, Jie Shao, Yuyao Wang, Ting Wang, Zhijian Zhang, Lu Zhang, William W. Lu, Yinghui Li, Liping Wang
Fan Yang, Yunhui Liu, Shanping Chen, Zhongquan Dai, Dazhi Yang, Dashuang Gao, Jie Shao, Yuyao Wang, Ting Wang, Zhijian Zhang, Lu Zhang, William W. Lu, Yinghui Li, Liping Wang
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Research Article Bone biology Neuroscience

A GABAergic neural circuit in the ventromedial hypothalamus mediates chronic stress–induced bone loss

Abstract

Homeostasis of bone metabolism is regulated by the central nervous system, and mood disorders such as anxiety are associated with bone metabolism abnormalities, yet our understanding of the central neural circuits regulating bone metabolism is limited. Here, we demonstrate that chronic stress in crewmembers resulted in decreased bone density and elevated anxiety in an isolated habitat mimicking a space station. We then used a mouse model to demonstrate that GABAergic neural circuitry in the ventromedial hypothalamus (VMH) mediates chronic stress–induced bone loss. We show that GABAergic inputs in the dorsomedial VMH arise from a specific group of somatostatin neurons in the posterior region of the bed nucleus of the stria terminalis, which is indispensable for stress-induced bone loss and is able to trigger bone loss in the absence of stressors. In addition, the sympathetic system and glutamatergic neurons in the nucleus tractus solitarius were employed to regulate stress-induced bone loss. Our study has therefore identified the central neural mechanism by which chronic stress–induced mood disorders, such as anxiety, influence bone metabolism.

Authors

Fan Yang, Yunhui Liu, Shanping Chen, Zhongquan Dai, Dazhi Yang, Dashuang Gao, Jie Shao, Yuyao Wang, Ting Wang, Zhijian Zhang, Lu Zhang, William W. Lu, Yinghui Li, Liping Wang

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Figure 1

A mouse model of chronic stress–induced anxiety-like behavior and bone loss.

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A mouse model of chronic stress–induced anxiety-like behavior and bone l...
(A) Schematic showing generation of the unpredictable chronic mild stress–induced anxiety mouse model. (B) Open-field (OF) test comparing the stress and control groups. Mice in the stress group exhibited significantly fewer entries to the central area and spent less time exploring the central area. Values represent mean ± SD (n = 8 per group; **P < 0.01; Student’s t test). (C) Elevated plus maze (EPM) test comparing stress and control groups. Mice in the stress group exhibited significantly fewer entries to the open arms and spent less time there. Values represent mean ± SD (n = 8 per group; *P < 0.05, **P < 0.01; Student’s t test). (D) Representative coronal (top) and sagittal (bottom) plane images of proximal tibia. Mice in the stress group displayed a low–bone mass phenotype. (E) Micro-CT analysis of trabecular bone volume/tissue volume (BV/TV), trabecular number (TbN), trabecular separation (Tb.Sp), and connectivity density (Conn.D) in the stress and control groups. Values represent mean ± SD (n = 8 per group; *P < 0.05, **P < 0.01; Student’s t test). (F) Correlation analysis of BV/TV and time spent in central area/open arms (n = 16). (G) Immunostaining of SF1 neurons in the VMH. Scale bar: 150 μm. (H) Immunostaining of vesicular glutamate transporter (Vglut2) in the VMHdm. Scale bar: 75 μm. dm/c, dorsomedial and central parts of the VMH; vl, ventrolateral part of the VMH (I) Immunostaining of GAD65-positive GABAergic projections in the VMHdm. Scale bar: 75 μm. (J) Quantification of GABA levels in the VMHdm region in stress and control groups. Values represent mean ± SD (n = 6 per group; **P < 0.01; Student’s t test). (K) Representative inhibitory postsynaptic currents (IPSCs) of SF1 neurons in the VMHdm in the stress and control groups. (L) Quantification of the frequency and amplitude of IPSCs from SF1 neurons in the stress and control groups. Values represent mean ± SD (n = 6 per group; **P < 0.01; Student’s t test).