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)从早期的前驱症状到晚期的毁灭性进展 刺激了对阻止这种进展的药物的研究，以及对可以治疗糖尿病症状的药物的追求 在记忆力丧失的情况下，即使面对衰退也要提高生活质量。我们假设决定效应的是 阿尔茨海默病进展对啮齿动物海马三型突触重要局部回路动态活动的影响 已知的作为空间记忆基础的回路，将产生更相关的大脑功能障碍的早期指标 发现对人类有效的药物，特别是考虑到所有哺乳动物的这一回路的保守性。 海马区CA3和CA1锥体细胞(或“定位细胞”)的放电模式响应并编码 空间表示法。我们先前对衰老受损大鼠的在体电生理研究，建立了一种 遗忘性认知障碍(AMCI)，表明我们能够量化年龄和新奇的特定影响 药物对CA3和CA1细胞动力学和空间记忆的影响(Robitsek，2015)。在此应用程序中，我们 建议使用一种令人兴奋的AD大鼠模型(TgF344-AD)，该模型显示淀粉样斑块，重要的是， 神经原纤维缠结以确定人类患者的病理进展如何与 随着时间的推移，海马区细胞动力学的改变。此外，我们还将探讨GABA的急性影响- 一种受体负性变构调节剂，选择性作用于具有调理活性的α5亚基，其包含的受体是 关于Place细胞动力学的记忆增强剂。我们将使用高密度的活体电生理来监测 在这种新型的大鼠转基因模型中，“放置细胞”的功能随年龄增长而发挥作用，以提出以下问题：三种细胞在什么时候被激活？ 突触回路受到干扰？早期精神障碍是否与P-tau和神经纤维缠绕有关？ 队形，还是独立的？在海马区的三突触回路中，有没有一个明显的部分 在疾病发展过程中易受攻击吗？最后，我们能不能开始解释一种消极的 活性抑制受体的变构调节剂具有增强空间记忆的作用。我们预料到 这些研究的完成将确定AD大鼠CA3和CA1定位细胞的活性分布，最终 会导致记忆力丧失和神经病理的传播。这些研究将是澄清的第一步 基于人类APP695和PS1的空间记忆下降的神经回路功能障碍的开始 背景表现为进行性神经原纤维缠绕和认知障碍，并将提供 为改善AD管理中记忆增强剂急性给药的评估奠定基础。

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.