Age-Related Changes in Neural Network Activity and Tau in a rat model of Alzheimer's Disease

摘要： 阿尔茨海默病（AD）从早期前驱期到晚期的毁灭性进展， 刺激了对药物的研究，以防止这种进展，并寻求药物，可以治疗的症状 记忆力减退，以提高生活质量，即使在面对下降。我们假设， AD进展对啮齿动物海马中重要局部回路的动态活动的影响， 已知的空间记忆的基础电路，将产生更相关的大脑功能障碍的早期指标， 对于发现将在人类中工作的药物，特别是考虑到在所有哺乳动物中保护这一电路。 海马体内的CA 3和CA 1锥体细胞（或“定位细胞”）的放电模式响应并编码 空间表征我们先前对老年受损大鼠进行的体内电生理研究， 遗忘性认知障碍（aMCI），表明我们能够量化年龄和新奇性的具体影响， 药物对CA 3和CA 1位置细胞动力学和空间记忆的影响（Robitsek 2015）。在本申请中，我们 建议使用一种令人兴奋的新的AD大鼠模型（TgF 344-AD），该模型显示淀粉样蛋白斑块，重要的是， 神经元缠结，以确定在人类患者中观察到的病理学进展如何与 海马位置细胞动力学随时间的变化。此外，我们将探讨GABA的急性影响- 一种对含有紧张活性α 5亚基的受体具有选择性的受体负变构调节剂， 一种记忆增强剂我们将使用高密度体内电生理学进行监测 在这个新的大鼠转基因模型中，“位置细胞”功能随着年龄的增长而变化，以提出以下问题： 突触回路受到干扰P-tau蛋白和神经元缠结是否与早期紊乱有关 是独立的，还是独立的？海马三突触回路中是否有一个明显的部分， 在疾病发展过程中易受伤害？最后，我们是否可以开始解释一个消极的 活性抑制性受体的变构调节剂导致空间记忆增强。我们预计 这些研究的完成将确定AD大鼠中CA 3和CA 1位置细胞的活性谱， 导致记忆丧失和神经病变的扩散。这些研究将是阐明 在人APP 695和PS 1上，作为空间记忆下降基础的神经回路功能障碍的发作 显示进行性神经系统缠结和认知障碍的背景， 为改善AD管理中记忆增强剂急性给药的评估奠定了基础。

Abstract: The devastating progression of Alzheimer's disease (AD) from the early prodromal to late stages has stimulated a search for drugs that prevent this progression and a quest for drugs that can treat the symptoms of memory loss to improve the quality of life even in the face of decline. We hypothesize that determining the effect of AD progression on the dynamic activity of important local circuits in the rodent hippocampus, the tri-synaptic circuit known to underlie spatial memory, will produce an early indicator of brain dysfunction that is more relevant for the discovery of drugs that will work in humans, especially given the conservation of this circuit in all mammals. The firing patterns of CA3 & CA1 pyramidal cells (or “place cells”) within the hippocampus respond to and encode spatial representations. Our previous in vivo electrophysiological study of aged impaired rats, a model for amnestic cognitive impairment (aMCI), demonstrated that we are able to quantify age and novelty specific effects of drugs on CA3 & CA1 place cell dynamics and on spatial memory (Robitsek 2015). In this application, we propose to use an exciting new rat model for AD (TgF344-AD) that displays amyloid plaques and, importantly, neurofibrillary tangles to determine how the progression of pathology seen in human patients is associated with alterations in hippocampal place cell dynamics over time. In addition, we will probe the acute effects of a GABA- A receptor negative allosteric modulator selective for tonically active alpha5 subunit containing receptors that is a memory enhancer on place cell dynamics. We will use high density in vivo electrophysiology for monitoring “place cell” function with age in this novel rat transgenic model to ask the following questions: When does the tri- synaptic circuit become disturbed? Is early disturbance associated with P-tau and neurofibrillary tangle formation, or is it independent? Is there a distinct part of the hippocampal tri-synaptic circuitry that is most vulnerable during disease progression? And finally, can we begin to explain the mechanism by which a negative allosteric modulator of active inhibitory receptors results in spatial memory enhancement. We anticipate that completion of these studies will identify the activity profile of CA3 & CA1 place cells in AD rats that eventually leads to a loss in memory and spread of neuropathology. These studies will be a first step toward elucidating the onset of neural circuitry dysfunction underlying spatial memory decline over a human APP695 and PS1 background that exhibits progressive neurofibrillary tangles and cognitive impairment and will provide a foundation for improved assessment for acute administration of memory enhancers in AD management.