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.

项目概要/摘要 阿尔茨海默病 (AD) 是一种破坏性的与年龄相关的神经退行性疾病，可严重缩短寿命 质量和期望。抑郁症和睡眠障碍在疾病发作前数十年就已显现，可能会起到作用 作为重要的早期生物标志物。中缝背核 (DRN) 中的血清素 (5-HT) 神经元表现出 AD 早期阶段的神经原纤维变化，这可能导致其中一些早期非认知障碍 症状。本应用的目标是确定 5-HT DRN 神经元中 tau 蛋白的积累是否会诱导 抑郁样行为和睡眠紊乱，导致慢性睡眠中断。这些睡眠不足反过来， 可能会促进 5-HT 神经元过度兴奋并导致神经退行性变。 5-HT活性增加 睡眠不足导致的神经元损伤也会促进 tau 蛋白病理学向内嗅皮层 (EC) 的传播，这是另一个 AD 早期受影响的区域。从 DRN 到 EC 的 5-HT 输入丢失将解除抑制 投射到海马体的神经元，促进 tau 蛋白扩散以及认知和记忆的发生 问题。在目标 1 中，我们将在测试过程中使用体内光纤光度法测量 5-HT 神经元的神经活动 在 tau 蛋白病小鼠模型中观察抑郁样行为，看看这些神经元的正常功能是否正常 受到负面影响。我们还将监测睡眠期间的 5-HT 活性，看看它是否会因 tau 病理学而改变。在 目标 2，我们将检查睡眠剥夺对 5-HT 神经元兴奋性和 tau 进展的影响 使用电生理学和 3D 成像研究大脑病理学。 5-HT 中神经活动增加的作用 神经元对 tau 病理学传播的影响也将通过神经化学遗传学操作进行检查 活动。在目标 3 中，我们将确定 tau 诱导的 EC 5-HT 输入丢失是否会改变 5-HT 信号传导 投射到海马体的主要神经元。我们还将确定 5-HT/5-HT2A 受体信号传导的作用 tau 蛋白病理学向海马体的扩散和认知缺陷的发生。总共，建议 研究将提供有关 tau 病理学对早期行为症状影响的重要信息 AD 以及随后出现的认知和记忆缺陷。