下丘脑腹内侧核胶质细胞调控焦虑引发骨丢失的神经机制研究

Plenty of evidence suggest that anxiety is closely related with bone loss, but the underlying neural mechanism is still unclear. Our previous research have shown that GABAergic neurons in VMH could regulate micro-neural-circuit in VMH modulating anxiety and associated bone loss. Numerous evidence demonstrated that astrocytes involved in regulating the important functions of neural circuits. The scientific question here is that whether astrocyets in VMH participate in an glial-neural-circuit to contribute anxiety and bone loss modulation remain unclear. Our preliminary data show that: selectively activate VMH-astrocyte induced significant anxiety-like behavior and bone loss, while inhibition of VMH-astrocytes have opposite effect on anxiety and bone metabolism. Considering our reported results that optogenetic activation of astrocytes promotes the secretion of ATP and FGF2, we hypothesize that VMH-astrocytes regulate anxiety and bone loss by maniputaing VMH neurons’ activity through an receptor based mechanism. In this study, we propose to combine transgenic mice, opto-/Chemogenetic, electrophysiology, behavioral tests and bone metabolism analysis to investigate mechanism underlying VMH-astrocytes regulating anxiety and bone loss. The implementation of this project will in-depth clarify the regulatory functional roles and mechanisms of VMH astrocytes, which also provides potential therapeutic targets for treating anxiety-induced bone loss.

诸多证据表明焦虑应激等负性情绪同骨丢失密切相关，但迄今为止神经机制尚不明确。我们前期研究证明下丘脑腹侧核团VMH中GABA能神经元可通过神经微环路调控焦虑和骨丢失；胶质细胞已被证实参与神经微环路的重要功能调控；本项目的科学问题：VMH中胶质细胞是否通过与神经元形成“胶质-神经元”微环路来调控焦虑及骨丢失？作用机制是什么？我们预实验发现：选择性激活VMH胶质细胞可诱发焦虑及骨丢失，而抑制胶质细胞则出现相反表型；结合我们已报道的光基因激活胶质细胞可促使其释放ATP及FGF2，提示VMH胶质细胞可能通过分泌相关因子作用于VMH神经元受体进而调控焦虑及骨丢失。本项目拟结合转基因动物、光遗传/药物遗传学、电生理、行为学与骨代谢分析等技术深入研究VMH胶质细胞调控焦虑与骨丢失的作用机理。本项目的完成，将阐明VMH胶质细胞介导焦虑引发骨丢失的神经分子机制，为临床干预焦虑及骨丢失提供可能的细胞及分子靶点。

诸多证据表明焦虑与应激等负性情绪同骨丢失密切相关，但迄今为止神经机制尚不明确。本项目致力于探究VMH核团星型胶质细胞以及“胶质-神经元”功能单元在介导焦虑引发的骨丢失中的作用及机制。我们以转基因动物为研究对象，结合光遗传/药物遗传学、电生理、行为学与骨代谢分析等手段，解析VMH核团及其参与构成的神经环路在调控焦虑及骨代谢中的作用及机制。研究发现：1）伴有骨丢失的焦虑小鼠模型VMH核团星型胶质细胞被激活，证明VMH星型胶质细胞在焦虑与骨代谢稳态状态维持中扮演重要角色；2）药物遗传学调控VMH星型胶质细胞活动可双向调节小鼠的焦虑和骨代谢；3）VMH星型胶质细胞通过NMDA受体调节SF-1神经元活动，形成“胶质-神经元”功能单元调节焦虑和骨代谢；4）首次在正常人体被试水平验证焦虑与骨丢失的相关性；5）发现BNST-VMH-NTS神经环路通过调节外周交感神经活动及去甲肾上腺素分泌，作用于骨细胞上的β2受体来调节焦虑引发的骨丢失过程；6）发现BNST-NAc神经环路调节焦虑情绪的机制。7）探索发现PTH可能是焦虑引发骨丢失的外周效应因子。通过该项目的实施，我们发现星型胶质细胞能够同时调节动物高级情绪以及相应的代谢过程，拓展人们对胶质细胞功能的新认识；在此基础上，我们还进一步从神经环路水平解析了焦虑引发骨丢失的神经机制，为我们深入理解大脑调控外周脏器功能的神经机制提供了新思路。相关成果为理解临床与航天医学中负面情绪与骨质疏松发生的相关性提供理论依据。本项目在执行过程中发表包括Nat Commun., J Clin Invest.和Mol Psychiatry.在内的SCI论文共7篇，国际会议论文4篇（其中两篇被SCI杂志GLIA收录）。申请发明专利4项，获授权发明专利2项。协助培养博士生1名。项目负责人获2018年度广东省自然科学奖一等奖。