Hippocampal Microstructure and Function in APP Tg Mice

我们提出了一个纵向研究的生化，微观结构，功能和行为的变化，在小鼠过度表达突变的人淀粉样前体蛋白基因，以检测早期变化，是至关重要的认知能力下降。该研究将检查预定年龄的杂合Tg2576和PDAPP小鼠，从非常年轻的年龄到整个生命周期。非转基因同窝仔将用作对照。海马子区CA1和CA3、齿状回以及海马回路的连接皮层和皮层下结构的完整性对于记忆和学习至关重要。我们推测，由于Aβ的性质改变，海马回路中神经元组装体的细胞结构发生了微妙的变化。在发展中的Aβ病理中，结构变化先于淀粉样蛋白沉积。微结构的变化，反映在水的自扩散特性，将使用在体内扩散张量磁共振成像与高空间分辨率测量。将计算感兴趣区域的分数各向异性。将进行形态学分析，以研究扩散各向异性变化的细胞学基础。将测量洗涤剂可溶性和洗涤剂不溶性Aβ，以跟踪Aβ病理过程。在对Tg2576小鼠的初步实验中，我们发现相对于对照小鼠，24周龄小鼠的齿状回和CA3子区的各向异性分数显著降低，这是APP转基因小鼠海马中观察到的最早变化之一。在12周龄时，转基因小鼠和对照小鼠表现出相似的扩散特性。我们进一步假设Aβ诱导的海马区微结构变化可能损害海马功能，进而导致行为缺陷。海马回路功能的中断将通过记录在开放场中运动期间背侧海马区域theta带的场振荡来测量。将使用Morris水迷宫任务测量小鼠执行神经依赖性任务的能力。拟议的研究将确定海马分区和相关的皮质和皮质下结构，这些结构在早期受到发展中的Aβ病理学的影响。这些信息可能有助于开发治疗AD的治疗策略。研究计划的纵向设计将最大限度地减少可能影响横断面研究的个体差异和队列效应。

We propose a longitudinal study of biochemical, microstructural, functional and behavioral changes in mice overexpressing mutant human amyloid precursor protein genes in order to detect early changes that are critical to cognitive decline. The study will examine heterozygous Tg2576 and PDAPP mice at pre-determined ages, from a very young age over their entire lifespan. Non-transgenic littermates will be used as controls. The integrity of the hippocampal subfields CA1 and CA3, dentate gyrus, and connected cortical and subcortical structures of the hippocampal circuit is crucial for memory and learning. We hypothesize subtle changes occur in the cytoarchitecture of the neuronal assemblies in the hippocampal circuit as a result of the changing nature of Aβ. Structural changes precede amyloid deposition in the developing Aβ pathology. Microstructural changes, reflected in water self-diffusion characteristics, will be measured using in vivo diffusion tensor MR imaging with high spatial resolution. Fractional anisotropy will be calculated for the regions of interest. Morphometric analysis will be carried out to investigate the cytological basis for changes in diffusion anisotropy. Detergent soluble and detergent insoluble Aβ will be measured to follow the course of Aβ pathology. In preliminary experiments on Tg2576 mice, we have found significant reduction in fractional anisotropy in dentate gyrus and CA3 subfield of 24-week old mice relative to control mice, one of the earliest changes observed in the hippocampus in APP transgenic mice. At 12 weeks of age, transgenic and control mice exhibited similar diffusion characteristics. We further hypothesize that Aβ induced microstructural changes to the hippocampal regions are likely to compromise hippocampal function and in turn lead to deficits in behavior. Disruption in the function of the hippocampal circuit will be measured by recording field oscillations at the theta band in the area over the dorsal hippocampus during locomotion in an open field. The ability of the mice to perform hippocampally-dependent tasks will be measured using the Morris water maze task. The proposed study will identify the hippocampal subdivisions and related cortical and subcortical structures that are affected early by the developing Aβ pathology. Such information could be useful for developing therapeutic strategies for the treatment of AD. The longitudinal design of the research plan will minimize individual differences and cohort effects that may affect cross-sectional studies.