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.

项目总结/摘要 阿尔茨海默病对个人和社会都是毁灭性的。学习和记忆受损，尤其是在 空间导航的背景下，是其早期和主要症状之一。同样，啮齿类动物重演了 阿尔茨海默病也表现出空间导航的早期损伤。大量证据表明 阿尔茨海默病患者大脑皮层-海马体通讯异常海马皮质 睡眠期间的相互作用被认为是巩固新获得的记忆的关键。然而，没有研究 我评估了啮齿动物睡眠期间的这些脑动力学，模拟Tau和淀粉样蛋白β（Aβ）聚集方面 老年痴呆症因此，拟议的研究将探索睡眠期间大脑动力学的功能 在Tau和Aβ聚集（TAβA）的动物模型中，为此，我们将使用 表达与家族性阿尔茨海默病相关的三个主要基因的三重转基因小鼠 导致TAβA。该小鼠模型模拟了该疾病的斑块和缠结病理学标志， 分布模式与人类患者相似，包括边缘系统的突触变化。酒店客房经过精心 这些发现将在转基因大鼠中得到证实，转基因大鼠具有Aβ积累、斑块形成、tau积累、细胞损失， 和空间记忆障碍。具体而言，我们将：1）评估空间学习与 记忆，以及睡眠期间的大脑动力学，包括海马体和皮层内部和整个海马体和皮层; 2）使用 一种新的靶向光遗传学方法，在功能上剖析了TAβA在肿瘤细胞中的相对贡献。 睡眠时海马-皮层耦合受损和空间学习受损。3)测试 已知用于清除皮质TAβA的非侵入性视觉刺激方法缓解受损的 睡眠时大脑皮层-皮层耦合与空间学习障碍。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，并允许我们探测 在啮齿动物模型中，这种回路出现在疾病进展的非常早期阶段， 老年痴呆症这项研究将使我们开始了解这个网络的变化， 在阿尔茨海默氏症中观察到的认知障碍的出现，并开始测试疗效 一种非侵入性的治疗方法，用于逆转功能性大脑异常和受损的认知。