Cortical-hippocampal brain dynamics during sleep following spatial learning in rodents modeling Tau and AB aggregation feature of Alzheimer's disease

啮齿类动物空间学习后睡眠期间皮质-海马脑动态，模拟阿尔茨海默病的 Tau 和 AB 聚集特征

• 批准号: 10337209
• 负责人: Aaron A Wilber
• 金额: $ 52.38万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337209
• 关键词: 3xTg-AD mouse; Abeta clearance; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid deposition; Animal Model; Animals; Behavior; Brain; Cells; Clinical; Code; Communication; Coupling; Detection; Disease; Disease Progression; Dissection; Early treatment; Episodic memory; Exhibits; Functional disorder; Genes; Hippocampal Formation; Hippocampus (Brain); Histology; Human; Impaired cognition; Impairment; Individual; Interneurons; Knowledge; Learning; Light; Limbic System; Link; Memory; Memory impairment; Mission; Mus; Neurofibrillary Tangles; Parietal Lobe; Parvalbumins; Pathologic; Pathology; Patients; Pattern; Performance; Phase; Photic Stimulation; Process; Public Health; Pyramidal Cells; Rattus; Research; Rest; Rodent; Rodent Model; Role; Senile Plaques; Series; Sleep; Sleep disturbances; Slow-Wave Sleep; Societies; Symptoms; Synapses; Technology; Testing; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Visual; Visual Cortex; abeta accumulation; abeta deposition; brain abnormalities; brain dysfunction; cognitive change; early detection biomarkers; efficacy testing; experience; extracellular; familial Alzheimer disease; forgetting; hyperphosphorylated tau; improved; insight; juvenile animal; knowledge base; memory consolidation; mouse model; novel; optogenetics; potential biomarker; pre-clinical; prevent; protein aggregation; relating to nervous system; spatial memory; spatiotemporal; tau Proteins; tau aggregation; tau-1; theories; way finding

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease is devastating for individuals and society. Impaired learning and memory, particularly in the context of spatial navigation, is one of its early and major symptoms. Similarly, rodents recapitulating aspects of Alzheimer’s disease also exhibit early impairments in spatial navigation. A preponderance of evidence suggests abnormal cortical-hippocampal communication in humans with Alzheimer’s disease. Hippocampal-cortical interactions during sleep are thought to be critical for consolidation of newly acquired memories. However, no studies have assessed these brain dynamics during sleep in rodents modeling Tau and amyloid beta (Aβ) aggregation aspects of Alzheimer’s disease. Thus, the proposed research will explore the functionality of brain dynamics during sleep in the hippocampal-PC network in animal models of Tau and Aβ aggregation (TAβA). To do this, we will use a triple transgenic mouse where three major genes associated with familial Alzheimer’s disease are expressed leading to TAβA. This mouse model mimics plaque and tangle pathological hallmarks of the disease, with a distribution pattern similar to human patients, including synaptic changes in the limbic system. In addition, all findings will be confirmed in a transgenic rat with Aβ accumulation, plaque formation, tau accumulation, cell loss, and spatial memory impairments. Specifically, we will: 1) assess the relationship between spatial learning and memory, as well as brain dynamics during sleep, both within and across the hippocampus and cortex; 2) use a novel targeted optogenetic approach to functionally dissect the relative contributions of TAβA in the hippocampus to impaired hippocampal-cortical coupling during sleep and impaired spatial learning. 3) test the efficacy of a non-invasive visual stimulation approach, known for clearing cortical TAβA, to relieve impaired hippocampal-cortical coupling during sleep and impaired spatial learning. This project will provide insight into the normal function of a circuit that is dysfunctional in Alzheimer’s disease and allow us to probe dysfunction in this circuit that emerges in very early stages of disease progression in rodents modeling TAβA aspects of Alzheimer’s disease. This research will allow us to begin understanding changes in this network which may underlie the emergence of cognitive impairments observed in Alzheimer’s disease and begin testing the efficacy of a non-invasive treatment for reversing the functional brain abnormalities and impaired cognition.

项目摘要/摘要 阿尔茨海默氏病对个人和社会造成破坏性。学习和记忆受损，尤其是 空间导航的背景是其早期和主要症状之一。同样，啮齿动物概括了 阿尔茨海默氏病也暴露了空间导航的早期障碍。大量证据表明 人类与阿尔茨海默氏病的异常皮质海马交流。海马皮层 睡眠期间的相互作用被认为对于巩固新获得的记忆至关重要。但是，没有研究 在啮齿动物中，在啮齿动物中评估了这些大脑动力学，以建模tau和淀粉样β（Aβ）聚集方面 阿尔茨海默氏病。这是拟议的研究将探索睡眠期间大脑动态的功能 在TAU和Aβ聚集动物模型（TAβA）的海马PC网络中。为此，我们将使用 三重转基因小鼠，其中三个与阿尔茨海默氏病有关的主要基因被表达 导致taβa。该小鼠模型模仿斑块和纠缠疾病的病理标志， 分布模式与人类患者类似，包括边缘系统的突触变化。另外，所有人 结果将在具有Aβ积累，斑块形成，tau积累，细胞损失的转基因大鼠中得到证实 和空间记忆障碍。具体来说，我们将：1）评估空间学习与 记忆以及睡眠期间的大脑动态，包括海马和皮质的内部和脑部动力。 2）使用 新型的靶向光遗传学方法可以在功能上剖析taβa的相对贡献 海马在睡眠和空间学习障碍过程中损害海马 - 皮层耦合。 3）测试 非侵入性视觉刺激方法的功效，以清除皮质TAβA而闻名，可以挽救受损 睡眠期间的海马皮层耦合和空间学习受损。该项目将提供有关 在阿尔茨海默氏病中功能失调的电路的正常功能，使我们能够探测功能障碍 该电路是在啮齿动物进展的早期阶段出现 阿尔茨海默氏病。这项研究将使我们能够开始理解该网络中的变化 是在阿尔茨海默氏病中观察到的认知障碍的出现并开始测试效率的基础 用于逆转功能性脑异常和认知受损的非侵入性治疗方法。