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 阿尔茨海默病对个人和社会都是毁灭性的。学习和记忆受损，尤其是在 语境空间导航，是其早期和主要症状之一。同样，啮齿类动物概括了 阿尔茨海默病也表现出空间导航的早期障碍。大量证据表明 阿尔茨海默病患者大脑皮质-海马区通讯异常。海马区皮质 睡眠中的相互作用被认为是巩固新获得的记忆的关键。然而，没有研究表明 在模拟牛磺酸和淀粉样β蛋白(Aβ)聚集方面的啮齿动物中，我评估了睡眠期间的这些脑动力学 阿尔茨海默氏症。因此，这项拟议的研究将探索睡眠期间大脑动力学的功能 在海马-PC网络的动物模型中，Tau和Aβ聚集(TA，β，A)。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。这种小鼠模型模拟了这种疾病的斑块和缠绕的病理特征，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 结果将在转基因大鼠中得到证实，Aβ积聚，斑块形成，tau积聚，细胞丢失， 和空间记忆障碍。具体地说，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，无论是在海马体和皮质内还是跨海马体和皮质；2)使用 一种新的靶向光遗传学方法功能分析TAβA在脑内的相对贡献 海马区与睡眠期间海马区-皮质耦合受损和空间学习受损有关。3)测试 一种非侵入性视觉刺激方法的有效性，已知的清除皮质TAβA，以缓解受损 睡眠中的海马区-皮质耦合和空间学习障碍。该项目将提供对 阿尔茨海默病中功能失调的回路的正常功能，使我们能够探测阿尔茨海默病的功能障碍。 在啮齿动物疾病进展的非常早期阶段出现的这个回路，模拟TAβA方面 阿尔茨海默氏症。这项研究将使我们能够开始了解这个网络的变化，这些变化可能 在阿尔茨海默病中观察到的认知障碍的出现并开始测试其有效性 一种非侵入性治疗，逆转功能性大脑异常和认知受损。