UCP2调控肝性脑病运动丘脑神经元内线粒体分裂异常的机制研究

肝性脑病（HE）是由急慢性肝衰竭引起的神经精神综合征，运动障碍是其首发的临床症状之一。运动丘脑神经元功能异常是HE运动障碍的主要原因，但其分子机制仍不清。我们前期发现解偶联蛋白（UCP2）可调节运动丘脑神经元内线粒体功能，进而影响神经元的可塑性，提示UCP2是缓解肝性脑病运动迟缓的新靶点。但UCP2如何调控线粒体形态进而影响HE运动障碍的机制仍需深入探究。本研究在丘脑腹外侧核（VL）注射过表达或敲减UCP2的AAV病毒，并利用行为学、分子生物学、形态学等多种方法系统研究HE下线粒体分裂异常致VL内神经元功能变化特征，探讨靶向调控UCP2缓解HE运动障碍的机制，阐明修复VL线粒体分裂异常对HE相关神经异常的改善效应。拟揭示UCP2通过改善VL核团GABA神经元内线粒体形态从而维持神经递质稳态平衡，为肝性脑病运动迟缓的治疗提供可能的新靶点。

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome with caused by acute or chronic liver failure. Dyskinesia is one of the initial clinical symptoms. Motor thalamic neuron dysfunction is the main cause of dyskinesia in HE, but its molecular mechanism is still unclear. Our preliminary experiments found that uncoupling protein (UCP2) can regulate mitochondrial function in motor thalamic neurons, and then affect the plasticity of neurons, suggesting that UCP2 may be a new target for alleviating hepatic encephalopathy motor retardation. Nevertheless, the mechanism that UCP2 regulates mitochondrial morphology and function, and ulteriorly affects the of bradykinesia in HE needs further exploration. In this study, we will utilize targeted stereotactic injection of the AAV virus that overexpressed or knocked down UCP2 in the ventrolateral nucleus of the thalamus (VL), and employ a variety of methods such as ethology, molecular biology, and morphology to systematically investigate the characteristics of VL neuron function changes during mitochondrial abnormal fission in HE state to explore the molecular mechanism of targeted regulation of UCP2 to alleviate HE dyskinesia, and to elucidate the improvement effect of repairing VL mitochondrial abnormal fission on HE-related neurological abnormalities. This study intends to reveal that UCP2 maintains the homeostasis of neurotransmitter by improving the mitochondrial morphology in GABA neurons of the VL nucleus, providing a possible new target for the treatment of hepatic encephalopathy.