内分泌为调控骨骼代谢的经典形式。而申请者发现了一种全新的骨代谢调控模式：骨神经环路调控。前期解剖示踪表明，骨内神经最终特异性传入外侧下丘脑。而黑色素聚集素+（MCH+）神经元为其中支配骨骼的关键亚型。进一步研究发现，该神经元兴奋后直接引起MCH分泌入血，激活破骨前体细胞MCH受体，经PKA、MEK信号通路调节破骨前体细胞增殖分化从而调控骨代谢进程。本课题立足骨代谢与神经调控的交互性，运用神经环路解剖、光遗传学、神经电生理与转录组学等先进技术，旨在探索骨-神经环路的关键节点；揭示神经调控骨代谢的作用模式；明确MCH调控破骨分化的转导机制；最终为多种骨骼疾病的临床防治提供理论基础与可行方案。

Endocrine is a classic form regulating bone metabolism. However, the applicant has discovered a new mode of bone metabolism regulation: osteo-neural circuit regulation. The anatomical tracing showed that the intraosseous nerve specifically conducted into the lateral hypothalamus. Melanin concentrating hormone+ (MCH+) neurons are the key subtypes that dominate bones. Further research found that the neuron excited directly caused MCH secretion into the blood, activating the MCH receptor of osteoclast precursor cells. The activation of MCHR regulates the proliferation and differentiation of osteoclast precursor cells through PKA and MEK signaling pathways, and thus regulated the bone metabolism. Based on the interaction between bone metabolism and neural regulation, this project uses advanced techniques such as neural circuit anatomy, optogenetics, electrophysiology and transcriptomics to explore the key nodes of the osteo-neural circuit; revealing the neural regulation of bone metabolism. Moreover, this project aims to clarify the transduction mechanism of MCH to regulate osteoclast differentiation. Finally, this project is with high potential to provide a theoretical basis and feasible solutions for the clinical prevention and treatment of various skeletal diseases.