基于光遗传学技术研究纹状体微清蛋白阳性中间神经元在亨廷顿舞蹈病早期病理生理机制中的作用

亨廷顿舞蹈病(HD)是一种常染色体显性遗传的神经变性疾病，至今无有效治疗方法。纹状体微清蛋白（PV）阳性中间神经元在HD早期可能存在功能异常，但尚缺乏直接的实验证据。我们前期研究发现YAC128小鼠在3个月时表现为活动增加，与HD早期症状相似，这为我们进一步研究纹状体PV阳性中间神经元在HD早期病理生理机制中的作用提供了良好的动物模型。本项目拟通过在体多通道光电极记录技术，在体记录纹状体PV阳性中间神经元在HD小鼠疾病早期（3个月时）的放电情况；通过光遗传学技术研究选择性改变正常小鼠纹状体PV阳性中间神经元活性对运动行为的影响；探索在HD小鼠疾病早期纠正纹状体PV阳性中间神经元活性对症状的改善作用。研究结果将有助了解纹状体PV阳性中间神经元在HD早期的功能变化，及纹状体PV阳性中间神经元活性改变与HD早期症状之间的因果关系，为纹状体PV阳性中间神经元作为HD治疗可能的新靶点提供实验依据。

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. Currently, there is no effective treatment to prevent its progression. Parvalbumin-positive striatal interneurons dysfunction may be involved in the early stage of HD. However, there is a lack of direct evidence of the causal relationship between parvalbumin-positive interneurons and the symptoms of early HD. Our previous study found that the HD transgenic mice (YAC128 mice) exhibit initial hyperactivity (3 months old). This is similar to the symptom in the early stage of HD. This mouse model is suitable for study of pathophysiologic mechanisms in the early stage of HD. In this study, we plan to use a channelrhodopsin assisted recording method allowing the efficient in vivo recording of parvalbumin-positive striatal interneurons in young YAC128 mice. We will use optogenetic tools to study the relationship between the activity of parvalbumin-positive striatal interneurons and the symptom in the early stage of HD. Moreover, we plan to explore the potential therapeutic strategies for HD by modulating the activities of parvalbumin-positive striatal interneurons. The obtained results will validate the dysfunction of parvalbumin-positive striatal interneurons in early HD and provide the new therapeutic target for HD.