三叉神经-下丘脑神经传导通路在眼压调控及青光眼发病中的作用及机制

Glaucoma is the first irreversible blind cause in the world. Open-angle glaucoma is the most harmfull due to its high incidence and latent attribute.Intraocular pressure fluctuations is regarded as one of the most prominent factors for glaucoma.However,it is still vague how the IOP remains in a steady state. Hypothalamus has previously been considered to be a key node in the control of central nervous system,which may involve in maintaining the homeostasis of intraocular pressure under physiological conditions.Trigeminal nerve regarded as the only sensory innervation of eye palys a dominant role in the receptor and transmission of the IOP signal.Previous studies have demonstrated the connective relationships betwent hypothalamus and trigeminal nerve.Therefor,this project raises a presumption: trigeminal nerve-hypothalamus pathway may play a role in the control of IOP and the pathogenesis of glaucoma.The project will make use of multi- modal functional MRI techniques to explore the functional connecions,fiber connections and neurotransmitter variation in the trigeminal-hypothalamus pathway among patients with glaucoma and ocular hypertension and normal persons.While building an animal model of glaucoma in rats , respectively, through the control of intraocular pressure and electrophysiological technologies, as well as nerve tracing and immunohistochemical methods , this project will verify further the transmission way and the biochemical bases of IOP signal. We hope to clarify the IOP mechanism of central pathways regulation and to provide a knock-down evidence for the early diagnosis of glaucoma.

青光眼是世界第一位不可逆致盲眼病，尤其是开角型青光眼发病率高、发病隐匿且早期诊断困难，因此危害极大。眼压异常波动被认为是重要危险因素，但眼压稳态维持及调控机制尚不清楚。目前认为下丘脑作为中枢神经系统关键节点，参与生理条件下眼压稳态的维持。而三叉神经作为支配眼球唯一的感觉神经在感受眼压信号及眼压信号转换中发挥举足轻重的作用。既往研究亦支持三叉神经与下丘脑间存在解剖及功能连接。因此我们提出假设：三叉神经-下丘脑神经传导通路在眼压调控以及青光眼发病中起重要作用。本项目拟通过多模态功能磁共振技术探索青光眼患者三叉神经-下丘脑神经传导通路功能连接、纤维连接以及生化代谢产物改变。并通过构建青光眼动物模型，联合逆行神经示踪、电刺激毁损及电位监测技术、免疫组化、分生技术进一步验证阐述三叉神经-下丘脑神经传导通路眼压信号传递方式以及眼压调控的生化物质基础。以期为青光眼的中枢发病机制及临床治疗新靶点提供依据。

目的：青光眼是世界首位不可逆性致盲性眼病，眼压稳态维持及调控机制尚不清楚。目前认为下丘脑作为中枢神经系统关键脑区，参与生理条件下眼压稳态的维持。本项目主要研究三叉神经-下丘脑神经传导通路在眼压调控以及青光眼发病中的作用。.方法：临床研究部分，21例青光眼患者及21例年龄性别匹配的正常人，进行3T磁共振大脑静息态扫描，数据经后处理后，寻找青光眼组与正常对照组默认网络、下丘脑、蓝斑核等相关核团之间的功能连接的差异，并分析与青光眼严重程度及眼压的相关性。动物研究部分，分别使用青光眼大鼠模型及青光眼基因鼠，研究青光眼动物下丘脑弓状核及蓝斑核形态学及分子生物学功能改变。细胞研究部分，小梁网细胞体外培养，研究内皮素Endothelin对小梁网细胞移行及增殖功能等方面的作用机制。.结果：青光眼患者左侧前内侧前额叶皮质与左侧后扣带皮质间的正连接显著减弱；左侧后扣带皮质与双侧背内侧前额叶皮质间的正连接也显著减弱等。青光眼患者蓝斑核与大脑额叶、岛叶功能连接减低，与海马旁回功能连接增强。通过饮水试验刺激副交感神经兴奋，及使用冰刺激刺激交感神经兴奋，可明显改变眼压及Schlemm 管的大小。青光眼动物下丘脑弓状核GABA能神经元的GABA-A受体、GABA-B受体表达明显增加。青光眼鼠大脑蓝斑核去甲肾上腺素能神经元数目减少，TH 及 DβH 表达降低。大鼠下丘脑弓状核及蓝斑核中枢给药损伤，发现青光眼大鼠眼压升高幅度较正常组减小。细胞实验发现内皮素Endothelin能促进小梁细胞增殖，增加Fibronectin 的合成，导致房水流出阻力增加。.结论：青光眼存在下丘脑弓状核及大脑蓝斑核变性，可能通过GABA能神经元及去甲肾上腺素能神经元的功能异常参与青光眼的发病，内皮素Endothelin可能是参与调节眼局部房水排出而调控眼压的重要递质。