CHARACTERIZATION OF NEURAL NETWORK ALTERATIONS IN HUNTINGTON'S DISEASE MODEL

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 亨廷顿氏病（HD）是一种无法治愈的遗传性神经退行性疾病，由于基底神经节中特定神经元的丧失，导致运动和认知功能障碍以及过早死亡。获得第一个HD转基因大鼠模型后，该项目将首次深入调查症状前和症状大鼠大脑中的神经网络变化。来自神经解剖学、遗传学和高分辨率断层成像的专业知识将被用来解决HD如何影响基底神经节神经回路的问题。我们将首先使用对比增强的体外高分辨率磁共振成像（MRI）和弥散加权成像（DWI）结合免疫细胞化学和组织学分析，定位和量化与观察到的行为改变相关的主要脑结构变化。其次，我们将采用顺行和逆行轴突追踪技术相结合的方法描述基底节神经回路发生的变化。第三，我们将评估DWI作为一种诊断工具，用于检测在这个HD大鼠模型中轴突投射的损失。为了便于比较动物和实验中的多模态数据，将构建基底神经节的局部坐标系。该坐标系将用于在一个通用框架中规范化和共配准所有数据，适用于未来在3D脑图谱环境中共享数据。该项目将为后续的HD病理生理学研究和潜在治疗干预的评价提供有价值的解剖学数据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Huntingtons Disease (HD) is an untreatable inherited neurodegenerative disease causing motor and cognitive dysfunction and premature death, due to loss of specific neurons in the basal ganglia. Having access to the first transgenic rat model of HD, this project will provide the 1st in-depth survey of neural network changes in the brains of pre-symptomatic and symptomatic rats. Expertise from neuroanatomy, genetics, and high-resolution tomographic imaging will be employed to address questions about how HD affects the neural circuitry of the basal ganglia. We will first localize and quantify major structural brain changes occurring in conjunction with observed behavioral alterations, using contrast-enhanced in vitro high-resolution magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) in combination with immunocytochemistry and histological analysis. Secondly, we will characterize alterations occurring in the basal ganglia neural circuits using combined anterograde and retrograde axonal tracing techniques. Third, we will evaluate DWI as a diagnostic tool for detecting loss of axonal projections in this HD rat model. To facilitate comparison of multi-modal data across animals and experiments, a local coordinate system for the basal ganglia will be constructed. This coordinate system will serve to normalize and co-register all data in a common framework, suitable for future sharing of data in a 3D brain atlas environment. The project will provide valuable anatomical data relevant for subsequent investigations of HD pathophysiology and evaluation of potential therapeutic interventions.