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: 10551309
• 负责人: Aaron A Wilber
• 金额: $ 42.95万
• 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/10551309
• 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; Code; Communication; Coupling; Detection; Disease; Disease Progression; Dissection; Early treatment; Episodic memory; Exhibits; Functional disorder; Genes; Head; Hippocampal Formation; Hippocampus; 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; Rat Transgene; Research; Rest; Rodent; Rodent Model; Role; Series; Sleep; Sleep disturbances; Slow-Wave Sleep; Societies; Symptoms; Synapses; Technology; Testing; Transgenic Mice; United States National Institutes of Health; Visual; Visual Cortex; abeta accumulation; abeta deposition; brain abnormalities; brain dysfunction; cellular pathology; cognitive change; early detection biomarkers; efficacy testing; experience; extracellular; familial Alzheimer disease; forgetting; hyperphosphorylated tau; improved; insight; juvenile animal; knowledge base; memory acquisition; memory consolidation; mouse model; neural; novel; optogenetics; potential biomarker; pre-clinical; prevent; protein aggregation; 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.

项目概要/摘要 阿尔茨海默病对个人和社会来说都是毁灭性的。学习和记忆受损，尤其是在 空间导航的背景，是其早期和主要症状之一。同样，啮齿类动物也概括了 阿尔茨海默病还表现出空间导航的早期障碍。大量证据表明 患有阿尔茨海默病的人的皮质-海马通讯异常。海马皮质 睡眠期间的互动被认为对于巩固新获得的记忆至关重要。然而，没有研究 评估了啮齿类动物睡眠期间的这些大脑动态，对 Tau 蛋白和淀粉样蛋白 β (Aβ) 聚集方面进行建模 阿尔茨海默病。因此，拟议的研究将探索睡眠期间大脑动力学的功能 Tau 和 Aβ 聚集 (TAβA) 动物模型的海马-PC 网络中。为此，我们将使用 三重转基因小鼠，表达与家族性阿尔茨海默病相关的三个主要基因 导致 TAβA。该小鼠模型模拟了该疾病的斑块和缠结病理特征，具有 分布模式与人类患者相似，包括边缘系统的突触变化。此外，所有 研究结果将在转基因大鼠中得到证实：Aβ 积累、斑块形成、tau 积累、细胞损失、 和空间记忆障碍。具体来说，我们将：1）评估空间学习与 记忆力，以及睡眠期间海马体和皮层内部和之间的大脑动态； 2）使用 新颖的靶向光遗传学方法可从功能上剖析 TAβA 在 海马体在睡眠期间海马体-皮质耦合受损以及空间学习受损。 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，可缓解受损的症状 睡眠期间的海马-皮质耦合和空间学习受损。该项目将提供深入了解 阿尔茨海默病中功能失调的电路的正常功能，使我们能够探究 这个回路出现在啮齿类动物疾病进展的早期阶段，对 TAβA 方面进行建模 阿尔茨海默病。这项研究将使我们能够开始了解该网络的变化，这可能 是阿尔茨海默病中观察到的认知障碍出现的基础，并开始测试其功效 一种用于逆转功能性大脑异常和认知受损的非侵入性治疗方法。