Sleep and affective disturbances in the etiology of Alzheimer's disease

阿尔茨海默病病因中的睡眠和情感障碍

• 批准号: 10491668
• 负责人: Catherine Anne Marcinkiewcz
• 金额: $ 52.08万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491668
• 关键词: Affective; Age; Agreement; Alzheimer' s Disease; American; Appearance; Automobile Driving; Behavior; Behavior Disorders; Behavioral; Behavioral Symptoms; Biological Assay; Brain; Brain region; Chronic; Clinical Data; Cognitive; Cognitive deficits; Data; Denervation; Deterioration; Disease; Disinhibition; Early Diagnosis; Electroencephalography; Electrophysiology (science); Etiology; Exhibits; Expectancy; Fiber; Goals; Hippocampus (Brain); Human; Hyperactivity; Impaired cognition; Intervention; Investigation; Lead; Measures; Mediating; Memory; Memory impairment; Mental Depression; Microinjections; Monitor; Mus; Nerve Degeneration; Neurobehavioral Manifestations; Neurofibrillary Tangles; Neurons; Onset of illness; Pathology; Periodicity; Photometry; Quality of life; Receptor Signaling; Research; Risk; Role; Scanning; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Receptor 5-HT2A; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Slice; Symptoms; Tauopathies; Testing; Three-Dimensional Imaging; affective disturbance; age related neurodegeneration; attenuation; cognitive development; depressive behavior; depressive symptoms; dorsal raphe nucleus; early detection biomarkers; entorhinal cortex; hTau Mice; in vivo; mild cognitive impairment; mouse model; mutant; neural circuit; neurofibrillary tangle formation; neuromechanism; neuron loss; neuronal excitability; optogenetics; prevent; relating to nervous system; sleep quality; tau Proteins; tau aggregation; tau-1; transmission process

Project Summary / Abstract Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease that can severely curtail life quality and expectancy. Depression and sleep disorders manifest decades before disease onset and may serve as an important early biomarker. Serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) exhibit neurofibrillary changes in the early stages of AD, which may contribute to some of these early non-cognitive symptoms. The goal of this application is to determine whether tau accumulation in 5-HT DRN neurons induces depressive-like behaviors and disordered sleep, leading to chronic sleep disruption. These sleep deficits, in turn, may promote hyperexcitability of 5-HT neurons and lead to neurodegeneration. The increased activity in 5-HT neurons due to sleep deprivation also facilitates the spread of tau pathology to the entorhinal cortex (EC), another region that is impacted early in the course of AD. Loss of 5-HT inputs from the DRN to the EC will disinhibit neurons that project to the hippocampus, precipitating tau spread and the onset of cognitive and memory problems. In Aim 1, we will use in vivo fiber photometry to measure neural activity in 5-HT neurons during tests of depressive-like behavior in mouse models of tauopathy to see if the normal function of these neurons is negatively impacted. We will also monitor 5-HT activity during sleep to see if that is altered by tau pathology. In Aim 2, we will examine the effect of sleep deprivation on 5-HT neuronal excitability and the progression of tau pathology in the brain using electrophysiology and 3D imaging. The role of increased neural activity in 5-HT neurons on the spread of tau pathology will also be examined using chemogenetic manipulations of neural activity. In Aim 3, we will determine whether tau-induced loss of 5-HT inputs to the EC alters 5-HT signaling in principal neurons that project to the hippocampus. We will also establish a role for 5-HT/5-HT2A receptor signaling in the spread of tau pathology to the hippocampus and the onset of cognitive deficits. In total, the proposed research will provide essential information concerning the impact of tau pathology on early behavioral symptoms of AD and the later development of cognitive and memory deficits.

项目摘要 /摘要 阿尔茨海默氏病（AD）是一种毁灭性的与年龄相关的神经退行性疾病，可严重缩短生命 质量和期望。抑郁症和睡眠障碍在疾病发作前几十年表现出来，并可能服务 作为重要的早期生物标志物。背侧raphe核（DRN）中的5-羟色胺（5-HT）神经元展示 AD早期阶段的神经原纤维变化，这可能有助于这些早期非认知 症状。该应用的目的是确定tau在5-HT DRN神经元中的积累是否诱导 抑郁症的行为和睡眠不足，导致慢性睡眠中断。这些睡眠不足反过来 可能促进5-HT神经元的过度兴奋性并导致神经退行性。 5-HT的活动增加 由于睡眠剥夺而导致的神经元还促进了tau病理学到内嗅皮层（EC）的传播，另一种 在AD过程中受到影响的地区。从DRN到EC的5-HT输入损失将抑制 将投射到海马的神经元，促进tau的散布以及认知和记忆的发作 问题。在AIM 1中，我们将在测试过程中使用体内纤维光度法测量5-HT神经元的神经活动 在tauopathy的小鼠模型中，抑郁样行为的行为，以查看这些神经元的正常功能是否为 负面影响。我们还将监测睡眠期间的5-HT活动，以查看tau病理学是否改变了。在 AIM 2，我们将检查睡眠剥夺对5-HT神经元兴奋性和TAU的进展的影响 使用电生理学和3D成像中的大脑病理学。神经活动增加在5-HT中的作用 还将使用神经的化学作用操纵来检查有关TAU病理传播的神经元 活动。在AIM 3中，我们将确定tau诱导的5-HT输入输入是否会改变5-HT信号传导 投射到海马的主要神经元。我们还将建立5-HT/5-HT2A受体信号的作用 在tau病理学到海马和认知缺陷的发作中。总共提议 研究将提供有关TAU病理对早期行为症状的影响的重要信息 AD以及后来的认知和记忆缺陷的发展。