线粒体分裂融合异常对肝性脑病诱致运动障碍的作用和机制研究

The occurrence of hypolocomotion induced by hepatic encephalopathy (HE) indicates the deteriorated stage of severe hepatic diseases, while the there lacks of valuable clinical medication because of the poor understanding of the mechanisms of HE. It has been shown that the abnormal neurotransmission of substantia nigra pars reticulata (SNr) and its mitochondrial dysfunction contribute to the HE. We have found that targeted upregulation of the mitochondrial dynamin-related protein 1 (DRP1) could improve spontaneous activity and locomotion ability of HE mice, and restore the balance of excitatory and inhibitory neurotransmission by recovery of balance of mitochondrial fission and fusion in neurons. However, it is still unclear about the mechanisms underlying the mitochondrial dysfunction and the role of DRP1 in HE. In the present study, we will use multiple transgenic mice and TAA-induced HE model, combined with neuromorphological, electrophysical and pharmacological genetic techniques, to observe the detailed mitochondrial dysfunction and changes of neuronal plasticity within the SNr, reveal the molecular mechanisms of improvement of HE-induced movement disorder by targeted knockdown of DRP1 within SNr, and explore the relationship between restoring mitochondrial dynamics and HE associated neuronal impairment. The finding of our study will be helpful for understanding the mechanisms of the hypolocomotion induced by HE and provide a new thought for the control and treatment of HE.

肝性脑病（HE）诱致运动障碍是肝病患者病程恶化的重要指征，然而因其分子机制不清故临床缺乏有效治疗手段。研究证实黑质网状部（SNr）异常以及神经元线粒体功能障碍是HE重要机制。我们发现，靶向抑制HE小鼠SNr中线粒体分裂蛋白DRP1能显著改善动物运动障碍，且DRP1可能通过修复线粒体分裂融合异常恢复神经传递平衡；但是，HE诱致运动迟缓状态下SNr神经元线粒体分裂融合的变化规律以及DRP1在HE中的作用机制仍需深入研究。我们将利用线粒体荧光报告小鼠以及GABA Cre小鼠，综合应用形态学、电生理学以及化学遗传学等多种技术，系统研究线粒体功能紊乱致HE状态下SNr神经元突触结构功能变化特征，探讨靶向下调DRP1缓解HE诱致运动迟缓的分子机制，验证修复SNr线粒体分裂融合异常对肝性脑病相关神经异常的改善效应。本课题将揭示HE诱致运动障碍的关键病理机制，为临床控制HE提供新思路。

肝性脑病(HE)诱致运动障碍是肝病患者病程恶化的重要指征，然而因其分子机制不清故临床缺乏有效治疗手段。研究证实黑质网状部（SNr）异常以及神经元线粒体功能障碍是HE重要机制。我们发现，靶向抑制HE小鼠SNr中线粒体分裂蛋白DRP1能显著改善动物运动障碍，且DRP1可能通过修复线粒体分裂融合异常恢复神经传递平衡;但是，HE诱致运动迟缓状态下SNr神经元线粒体分裂融合的变化规律以及DRP1在HE中的作用机制仍需深入研究。我们将利用线粒体荧光报告小鼠以及GABA-Cre小鼠，综合应用形态学、电生理学以及化学遗传学等多种技术，系统研究线粒体功能紊乱致HE状态下SNr神经元突触结构功能变化特征，探讨靶向下调DRP1缓解HE诱致运动迟缓的分子机制，验证修复SNr线粒体分裂融合异常对肝性脑病相关神经异常的改善效应。.黑质网GABA能神经元张力增加（SNr）可导致轻度肝性脑病（MHE）的运动迟缓，但其机制有待进一步阐明。在本研究中，使用FosCreERT2（TRAP2）策略和由设计药物（DREADDs）策略独家激活的设计受体结果显示，轻度肝性脑病和氨激活SNrGad2表达的GABA群体和线粒体对氨失衡敏感。我们已经证明，该群细胞的化学抑制，或在该群体中靶向线粒体UCP2过表达，或系统应用线粒体靶向抗氧化药物MitoQ，可以通过缓解神经元氧化应激和改善线粒体功能障碍，有效改善轻度肝性脑病。我们的研究结果确定了Gad2神经元的激活和氧化应激诱导的线粒体异常是轻度肝性脑病诱导的运动障碍的关键决定因素，并证明了在轻度肝性脑病运动障碍中靶向该通路的潜力。