CHARACTERIZATION OF NEURAL NETWORK ALTERATIONS IN HUNTINGTON'S DISEASE MODEL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 亨廷顿病(HD)是一种无法治疗的遗传性神经退行性疾病，由于基底节中特定神经元的丢失，导致运动和认知功能障碍和过早死亡。在获得第一个HD转基因大鼠模型后，该项目将提供对症状前期和症状大鼠大脑神经网络变化的第一次深入调查。将利用神经解剖学、遗传学和高分辨率断层成像的专业知识来解决HD如何影响基底神经节的神经回路的问题。我们将首先使用体外增强的高分辨率磁共振成像(MRI)和扩散加权成像(DWI)结合免疫细胞化学和组织学分析来定位和量化伴随观察到的行为变化而发生的主要脑结构变化。其次，我们将使用顺行和逆行轴突追踪技术来描述基底神经节神经回路中发生的改变。第三，我们将评估弥散加权成像作为检测HD大鼠模型轴突投射丢失的诊断工具。为了便于比较动物和实验中的多模式数据，将构建基底节的局部坐标系。这个坐标系将在一个共同的框架内对所有数据进行标准化和共同登记，适合今后在3D脑图谱环境中共享数据。该项目将为随后的HD病理生理学研究和评估潜在的治疗干预措施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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.