Electrophysiological Evaluation of Brain Regions Vulnerable to Alzheimers Disease

易患阿尔茨海默病的大脑区域的电生理学评估

• 批准号: 9973904
• 负责人: Syed Abid Hussaini
• 金额: $ 64.59万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9973904
• 关键词: 20 year old; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Amyloid beta-Protein; Animal Testing; Animals; Arousal; Behavior; Behavioral; Biological Markers; Brain; Brain Stem; Brain region; Cognitive; Cognitive deficits; Computing Methodologies; Confusion; Data; Disorientation; Electrophysiology (science); Environment; Evaluation; Functional disorder; Halorhodopsins; Head; Hippocampus (Brain); Home environment; Human; Hyperactive behavior; Immunohistochemistry; Impaired cognition; Impairment; Knock-in; Knock-in Mouse; Lead; Learning; Life; Location; Measures; Medial; Memory; Memory impairment; Mus; Neurobehavioral Manifestations; Neuronal Dysfunction; Neurons; Neurosciences; Pathologic; Pathology; Performance; Physiological; Positioning Attribute; Property; Quick Test for Liver Function; Role; Seeds; Silicon; Sleep; Sleep Disorders; Sleep Stages; Sleep disturbances; Slow-Wave Sleep; Symptoms; Tauopathies; Techniques; Testing; Wild Type Mouse; Work; behavior measurement; cognitive ability; cognitive testing; computational neuroscience; entorhinal cortex; locus ceruleus structure; machine learning algorithm; mouse model; neuron loss; non rapid eye movement; optogenetics; predictive test; rapid eye movement; relating to nervous system; sleep behavior; sleep regulation; spatial memory; targeted treatment; tau Proteins; tau aggregation; tool; virtual environment; virtual reality; virtual reality environment; way finding

The entorhinal cortex (EC) is long known to be the region affected first in Alzheimer’s disease (AD) with symptoms such as disorientation, confusion and inability to navigate appearing early in life. But more recently, a region in the brainstem- locus coeruleus (LC) was found to have tau accumulation in young healthy adults, making it the first region in the brain with AD pathology. The LC is known to be important for arousal and controls the sleep/wake switch. The neurons of LC project to several regions including EC and hippocampus which are known to be important for spatial memory. Unsurprisingly, one of the earliest symptoms of AD is spatial difficulties and it is possible that early pathology in LC affects sleep leading to spatial memory deficits. With both LC and EC important for memory, we aim to identify which of them is more vulnerable to tau and Aβ pathology. To explore this possibility, we will first inject LC and EC regions of wildtype mouse with pathological tau derived from human AD brains to make them dysfunctional, and evaluate their neuronal function. We will also assess sleep and test memory performance in relevant behavior tasks. To understand how aβ affects tau pathology, we will inject human tau in the APP Knock-In mice which has physiological amounts of APP expressed in them. We will determine if Aβ together with tau worsens the neuronal function of LC and EC neurons and it sleep and memory is impaired further. We will use multi-region silicon probes to simultaneously record activity from LC or medial EC and hippocampal neurons. The MEC and hippocampal neurons are well characterized with properties that can be easily measured using spatial navigation tasks. We will make use of virtual reality head-fixed setup for the animals to navigate in, and allowing us to quickly test animal’s memory in any context and environment. The animals will be tested for object-location memory and context-dependent memory in virtual environment. We will use machine learning algorithms to decode animal’s position in the LC, MEC and HPC neural data and determine if it is affected by tau or Aβ or both. We will also assess sleep parameters and correlate with memory. We hypothesize that tau in LC and EC will make its neurons dysfunctional and directly affect sleep and memory, and this in concert with Aβ will exacerbate neuronal dysfunction leading to increased sleep problems and spatial memory impairment as seen in early AD. With this we aim to identify electrophysiological biomarker of neuronal dysfunction before the onset of behavioral troubles. We will test if increasing the neuronal firing in hypoactive neurons and reducing the firing in hyperactive neurons will restore downstream neuronal dysfunction and reverse sleep problems and cognitive impairment. The proposal brings together diverse fields (neuroscience, pathology and computational neuroscience) applying large-scale recording techniques simultaneously across multiple brain regions to develop analytical and predictive tests to interrogate function in vulnerable brain regions that are dysfunctional in AD.

众所周知，肠道皮质（EC）是在阿尔茨海默氏病（AD）中首先受到影响的地区 在生活中出现了症状，诸如对导航的迷惑，混乱和无效的症状。 发现脑干 - 核心层中的一个区域（LC）在年轻的健康成年人中积累了tau tau 使其成为AD病理学的大脑中的第一个区域。 控制睡眠/唤醒开关。 对于毫不奇怪的是，广告的最早症状之一是 空间差异，LC中的早期病理可能会影响睡眠导致空间记忆缺陷。 对于LC和EC对记忆很重要，我们旨在确定哪些容易受到TAU和Aβ的影响 病理学。 tau源自人类的大脑，使其功能失调，并评估其神经元功能 还评估相关行为任务中的睡眠和测试记忆表现。 病理学，我们将在具有生理量的APP的APP敲入小鼠中注入人类Tau 在它们中表示。 神经元和睡眠和记忆进一步损害。 从LC或内侧EC和海马神经元的记录活性。 用空间导航任务可以轻松测量的属性。 虚拟现实固定供动物导航的设置 任何上下文和环境都将测试对象位置记忆和上下文 在虚拟环境中，我们将使用机器学习算法来解码动物在LC中的位置 MEC和HPC神经数据受到TAU或Aβ的影响，我们还将评估睡眠。 参数并与内存相关。 功能障碍并直接影响睡眠和记忆，并且与Aβ协同作用会加剧神经元 功能障碍导致睡眠问题增加，空间记忆力障碍 我们旨在鉴定行为发作之前的神经元功能障碍的电生物学生物标志物 麻烦。 多动神经元将恢复下游神经元功能障碍和反向睡眠问题和认知 损害。 该提案汇集了各种领域（神经科学，病理和计算神经科学） 跨多脑大脑区域同时应用大规模记录技术来发展分析 以及在AD中功能失调的脆弱大脑区域中询问功能的预测测试。