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

 描述(申请人提供)：阿尔茨海默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显示出空间导航障碍。越来越多的证据表明，阿尔茨海默病患者顶叶后皮质(PPC)和海马区之间的通讯异常。本研究的目的是探索淀粉样变性动物模型中海马-PPC网络的功能，以开发一种评估皮质-海马区功能改变对阿尔茨海默病的潜在贡献的模型。要做到这一点，我将利用阿尔茨海默氏症的三重转基因小鼠模型，其中表达与家族性阿尔茨海默病相关的三个主要基因。这个小鼠模型模仿了这种疾病的斑块和缠结病理特征，其分布模式类似于人类患者，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)评估海马区群体的活动和行为，以衡量三重转基因小鼠在其内部位置参考系被破坏时，其利用外部(基于房间)参考系的能力；b)评估三重转基因小鼠中与休息相关的记忆重放以及海马区和顶后皮质内及之间的功能性突触连接；c)利用一种新的药物遗传学方法来测试以下理论，即暂时和特定的海马区失活将导致记忆重播中的损伤，类似于在动物模型中看到的那些。最后，三重转基因模型中的发现将在一种新的阿尔茨海默氏症模型中得到证实，该模型更类似于人类的散发性阿尔茨海默氏症。因此，这个项目将提供对阿尔茨海默病中功能失调的回路的正常功能的洞察，并帮助我在阿尔茨海默氏症的小鼠模型中探索这一回路，以便我们能够开始了解这一网络中的变化，这些变化可能是阿尔茨海默病患者观察到的损害的基础。

 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.