Optogenetic Stimulation of Striatal Output Neurons in Mouse Models of Huntingtons Disease

 描述（由申请人提供）：亨廷顿病（HD）是一种遗传性神经系统疾病，其特征为舞蹈病、认知缺陷和精神症状。在HD中，纹状体中型多刺神经元（MSN）大量丢失。根据其投射到的输出核团，MSNs可分为直接和间接纹状体输出通路的神经元。还可以基于分子标记物例如直接途径MSN上的多巴胺D1受体（D1）和间接途径MSN上的腺苷受体（A2A）的表达来分离每种途径的MSN。间接输出通路的MSN主要投射到苍白球（GPe）的外部段，与直接通路MSN相比，间接输出通路的MSN被认为在HD进展中更早受到影响。HD的大多数研究集中在纹状体，但很少有人研究直接通路（黑质网状部（SNr））或间接通路（GPe）的纹状体输出核中发生的变化。我建议研究如何直接和间接通路纹状体输出核改变HD通过研究发生在小鼠模型的HD的变化。我将使用光遗传学技术来调节直接或间接途径MSN的发射，以确定潜在的输入改变。最后，我将从直接或间接途径MSN中删除突变的亨廷顿基因。然后，我将使用光遗传学来刺激这些通路，并检查在具有正常D1或A2A MSN的动物中发生了什么变化，而所有其他细胞都含有突变的亨廷顿蛋白。

 DESCRIPTION (provided by applicant): Huntington's disease (HD) is a hereditary neurological disorder characterized by chorea, cognitive deficits and psychiatric symptoms. In HD there is a massive loss of striatal medium-sized spiny neurons (MSNs). MSNs can be divided into neurons of the direct and indirect striatal output pathways, based on the output nuclei they project to. MSNs of each pathway can also be separated based on molecular markers such as the expression of dopamine D1 receptors (D1) on direct and adenosine receptors (A2A) on the indirect pathway MSNs. MSNs of the indirect output pathway, which project primarily to the external segment of the globus pallidus (GPe), are believed to be affected earlier in the progression of HD compared to direct pathway MSNs. Most research in HD focuses on the striatum, but little has been done on examining the alterations that occur in striatal output nuclei of the direct pathway (substantia nigra pars reticulata (SNr)) or the indiret pathway, the GPe. I propose to examine how the direct and indirect pathway striatal output nuclei are altered in HD by studying changes that occur in mouse models of HD. I will use optogenetic techniques to regulate the firing of direct or indirect pathway MSNs to determine potential input alterations. Finally I will remove the mutant huntingtin gene from either the direc or indirect pathway MSNs. Then I will use optogenetics to stimulate the pathways and examine what alterations occur in an animal that has normal D1 or A2A MSNs while all other cells contain the mutant huntingtin protein.