A GABAergic neural circuit in the ventromedial hypothalamus mediates chronic stress–induced bone loss
Fan Yang, … , Yinghui Li, Liping Wang
Fan Yang, … , Yinghui Li, Liping Wang
Published September 10, 2020
Citation Information: J Clin Invest. 2020;130(12):6539-6554. https://doi.org/10.1172/JCI136105.
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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 2

Activation of GABAergic projections in the VMHdm induces anxiety-like behaviors and bone loss.

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Activation of GABAergic projections in the VMHdm induces anxiety-like be...
(A) Optical fibers were implanted into the VMHdm of VGAT-ChR2 mice, and the region was illuminated with blue light. (B) Electrophysiological recording of a typical IPSC from SF1 neurons during blue-light stimulation. (C) Schematic showing the schedule of blue-light stimulation and bone analysis with intermittent micro-CT scanning. (D) OF test of VGAT and control mice before and during blue-light stimulation. VGAT mice displayed obvious anxiety-like behavior. (E) EPM test of VGAT and control mice before and during blue-light stimulation. VGAT mice displayed obvious anxiety-like behavior. (F) Quantification of entries to, and time spent in, the central area before and during blue-light stimulation in the VGAT and control groups. Values represent mean ± SD (n = 8 per group; *P < 0.05; 1-way ANOVA with Bonferroni’s correction for comparisons). (G) Quantification of entries to, and time spent in, the open arms in the VGAT and control groups before and during blue-light stimulation. Values represent mean ± SD (n = 8 per group; *P < 0.05; 1-way ANOVA with Bonferroni’s correction for multiple comparisons). (H) Micro-CT analysis of VGAT and control group bone structure before, during, and after blue-light stimulation. A significantly low–bone mass phenotype was observed in the VGAT group 4 and 8 weeks after light stimulation began. (I) H&E staining of the proximal tibia in the VGAT and control groups at 8 weeks after stimulation. Scale bars: 200 μm. (J) Micro-CT analysis of BV/TV, TbN, Tb.Sp, and Conn.D in the VGAT and control groups. Values represent mean ± SD (n = 8 per group; *P < 0.05, **P < 0.01; 1-way ANOVA with Bonferroni’s correction for multiple comparisons).