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 Article has an altmetric score of 80

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 6

The NTS and the sympathetic system are downstream of SOM neuron–mediated stress-induced bone loss.

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The NTS and the sympathetic system are downstream of SOM neuron–mediated...
(A) Representative images of the VMH region with the virus expressing mCherry. Scale bar: 100 μm. (B) Representative image of neural projections in the SolM, a subregion of the NTS, receiving projections from SF1 neurons in the VMH. Scale bars: 100 μm (left), 50 μm (right). (C) Immunostaining of Vglut2 in the SolM region of the NTS. Scale bar: 50 μm. (D) Schematic showing viral genetic tracing of the connection of the BNST-VMH-NTS pathway using the TRIO method. AAV2-DIO-EGFP-TVA+DIO-RVG virus was injected into the VMH region, and RV-EnvA-ΔG-dsRed virus into the NTS, of SF1-Cre mice. (E) Representative images showing the labeled SF1 neurons in the VMH, SF1-projecting neural terminals in the NTS (arrowheads), and input neurons in the BSTLP region (arrows). (F) Schematic showing silencing of Vglut2 neurons innervated by SF1 neurons using the DREADD technique. AAV1-DIO-FLP virus was injected into the VMH region, and AAV-fDIO-hM4Di-eYFP virus into the NTS, of Vglut2-Cre mice. (G) Micro-CT analysis of bone structure of the eYFP and eYFP-hM4Di groups after inhibition of the Vglut2 neurons. A significant low–bone mass phenotype was observed in the hM4Di group. (H) Micro-CT analysis of BV/TV, TbN, Tb.Sp, and Conn.D in eYFP and hM4Di groups. Values represent mean ± SD (n = 5 per group; *P < 0.05; Student’s t test). (I) Immunostaining of tyrosine hydroxylase (TH) in bone and bone marrow. Positive signals were observed in both bone and bone marrow (arrows). Scale bars: 100 μm. (J) Expression of hM4Di-mCherry on TH-positive nerve fibers in bone marrow of TH-Cre mice. Scale bar: 10 μm. (K) Micro-CT analysis of BV/TV, TbN, Tb.Sp, and Conn.D in TH-Cre and TH-Cre+hM4Di groups. Values represent mean ± SD (n = 5 per group; *P < 0.05; Student’s t test).