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: 10097080
• 负责人: Aaron A Wilber
• 金额: $ 49.64万
• 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/10097080
• 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; 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/文摘