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

基本信息

批准号：
10383675
负责人：
Syed Abid Hussaini
金额：
$ 62.53万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/10383675
关键词：
20 year old Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos 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 Human Hyperactivity 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 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

项目摘要

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，内嗅皮层（EC）是在阿尔茨海默氏病（AD）中首先受到影响的地区诸如迷失方向，混乱和无法导航的症状在生命的早期出现。但是最近，发现脑干 - 基因座（LC）中的一个区域在年轻健康的成年人中积累了tau，使其成为大脑中第一个具有AD病理学的区域。 LC对于唤醒和控制睡眠/唤醒开关。 LC项目的神经元针对包括EC和海马在内的多个地区已知对于空间记忆很重要。毫不奇怪，广告的最早症状之一是空间困难，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都对记忆很重要，我们旨在确定其中哪些更容易受到TAU和Aβ的影响病理。为了探索这种可能性，我们将首先注射wildtype小鼠的LC和EC区域 tau源自人的大脑，使其功能失调，并评估其神经元功能。我们将还要评估相关行为任务中的睡眠和测试记忆表现。了解Aβ如何影响tau 病理学，我们将在App敲入鼠标中注入人tau，该型具有物理数量的应用在他们中表达。我们将确定Aβ与Tau是否会使LC和EC的神经元功能恶化神经元和睡眠和记忆进一步损害。我们将使用多区域硅问题轻松记录LC或内侧EC和海马神经元的活性。 MEC和海马神经元很好具有可以使用空间导航任务轻松测量的属性表征。我们将利用虚拟现实固定设置，供动物导航，并允许我们快速测试动物的记忆任何上下文和环境。将测试动物的对象位置记忆和上下文依赖性虚拟环境中的内存。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神经数据并确定它是否受TAU或Aβ或两者的影响。我们还将评估睡眠参数并与内存相关。我们假设LC和EC中的Tau会成为其神经元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如AD早期所见，功能障碍导致睡眠问题增加和空间记忆障碍。与此我们旨在鉴定行为发作之前的神经元功能障碍的电生理生物标志物麻烦。我们将测试是否增加了性神经元中的神经元发射并减少发射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。该提案汇集了潜水领域（神经科学，病理和计算神经科学）在多个大脑区域同时应用大规模记录技术以发展分析以及在AD中功能失调的脆弱大脑区域中询问功能的预测测试。