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.
View: Text | PDF
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

×

Figure 3

Somatostatin neurons in the posterior BNST send GABAergic projections to the VMHdm region.

Options: View larger image (or click on image) Download as PowerPoint
Somatostatin neurons in the posterior BNST send GABAergic projections to...
(A) Schematic showing rabies virus–based (RV-based) monosynaptic retrograde tracing in the SF1-Cre mice. (B) Representative images of the VMH region with the helper AAV virus expressing eYFP, and of RV-labeled cells (red) in different brain regions. PVH, paraventricular nucleus of the hypothalamus; AHC, anterior hypothalamic nucleus; BSTLD, lateral dorsal BNST; BSTLP, lateral posterior BNST. Scale bars: 100 μm. (C) Schematic mapping of neural circuits from different brain regions to the VMH through monosynaptic neural connection. AHA, anterior hypothalamic area; LH, lateral hypothalamic area. (D) c-fos staining of the BSTLD and BSTLP regions in the anxiety and control groups. Scale bars: 100 μm. (E) Quantification of c-fos–positive cells in the anxiety and control groups. Values represent mean ± SD (n = 3 mice per group; **P < 0.01; 1-way ANOVA with Bonferroni’s correction for multiple comparisons). (F) Immunostaining of neural projections in VMH. PV, parvalbumin; CCK, cholecystokinin; SOM, somatostatin. Scale bars: 100 μm. (G) Double staining of SF1 neurons and SOM-positive projections in VMHdm. Scale bars: 50 μm. (H) RV was injected unilaterally into the dmVMH in SF1-Cre mice, and in situ hybridization of somatostatin mRNA in the posterior region of the BNST (BNSTLP) is shown. (I) Schematic showing AAV9 expressing mCherry and ChR2 under the EF1α promoter. (J) Schematic showing virus injection into the BNSTLP of SOM-Cre mice. (K) Top: The RV was injected unilaterally into the VMHdm in SF1-Cre mice. Bottom: In situ hybridization of somatostatin mRNA in the BSTLP region. RV signals and somatostatin mRNA were colocalized in the BSTLP region. Scale bars: 100 μm. (L) Representative image of SOM-positive neurons in the BSTLP (top) and SOM-positive neural projections in the VMHdm (bottom) after injection into the BSTLP region. Scale bars: 100 μm.