Parietal-hippocampal network in the triple transgenic mouse model of Alzheimers

 描述（由申请人提供）：阿尔茨海默氏病对个人和社会都是毁灭性的。空间导航和记忆障碍是其主要症状之一。同样，阿尔茨海默病的啮齿动物模型也表现出空间导航的障碍。新出现的证据表明，阿尔茨海默氏症患者的后顶叶皮层（PPC）和海马体之间存在异常通讯。拟议的研究的目的是探索在淀粉样变性的动物模型中的海马-PPC网络的功能，以开发一个模型来评估改变的皮质-海马功能对阿尔茨海默病的潜在贡献。为了做到这一点，我将利用三重转基因小鼠模型阿尔茨海默氏症，其中三个主要基因与家族性阿尔茨海默氏症的表达。这种小鼠模型模拟了该疾病的斑块和缠结病理学特征，其分布模式与人类患者相似，包括边缘系统中的突触变化。具体地说，在三个不同的实验中，我将：a）评估海马群体的活动和行为，以测量三重转基因小鼠利用外部刺激的能力。B）评估三重转基因小鼠中海马和后顶叶皮质内和跨海马和后顶叶皮质的静息相关记忆重放和功能性突触连接; c）利用一种新的药物遗传学方法来测试暂时和特异性海马失活将产生记忆重放损伤的理论，其模拟在动物模型中观察到的那些。最后，三重转基因模型中的发现将在一种更类似于人类散发性阿尔茨海默病的新的阿尔茨海默病模型中得到证实。因此，该项目将提供对阿尔茨海默病中功能失调的电路的正常功能的深入了解，并允许我在阿尔茨海默病的小鼠模型中探测该电路，以便我们可以开始了解该网络中的变化，这些变化可能是阿尔茨海默病患者中观察到的损伤的基础。

 DESCRIPTION (provided by applicant): Alzheimer's disease is devastating for both individuals and society. Impaired spatial navigation and memory is one of its major symptoms. Similarly, rodent models of Alzheimer's disease also exhibit impairments in spatial navigation. Emerging evidence suggests abnormal communication between the posterior parietal cortex (PPC) and hippocampus in humans with Alzheimer's. The objective of the proposed research is to explore the functionality of the hippocampal-PPC network in an animal model of amyloidosis, in order to develop a model for assessing potential contributions of altered cortico-hippocampal function to Alzheimer's disease. To do this, I will utilize a triple transgenic mouse model of Alzheimer's where three major genes associated with familial Alzheimer's disease are expressed. This mouse model mimics both plaque and tangle pathological hallmarks of the disease with a distribution pattern similar to human patients, including synaptic changes in the limbic system. Specifically, in three different experiments I will: a) assess hippocampal population activity and behavior to measure the ability of triple transgenic mice to utilize an external (room based) reference frame when their internal position reference frame is disrupted; b) assess both rest related memory replay and functional synaptic connectivity within and across the hippocampus and posterior parietal cortex in the triple transgenic mouse; c) utilize a novel pharmacogenetic approach to test the theory that temporary and specific hippocampal inactivation will produce impairments in memory replay that mimic those seen in animal models. Finally, findings in the triple transgenic model will be confirmed in a newer model of Alzheimer's that is more similar to sporadic Alzheimer's in humans. Therefore, this project will provide insight into the normal function of a circuit that is dysfunctional in Alzheimer's disease and allo me to probe this circuit in a mouse model of Alzheimer's, so that we can begin to understand changes in this network that may underlie impairments observed in individuals with Alzheimer's disease.