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：
10615686
负责人：
Syed Abid Hussaini
金额：
$ 62.94万
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/10615686
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 Home Human Hyperactivity Immunohistochemistry Impaired cognition Impairment Knock-in Mouse Learning Life Location Measures Medial Memory Memory impairment Mus Neurobehavioral Manifestations Neuronal Dysfunction Neurons Neurosciences Pathologic Pathology Performance Physiological Positioning Attribute Property Role Shapes 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 memory consolidation mouse model neural neuron loss non rapid eye movement optogenetics predictive test rapid eye movement 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) 是阿尔茨海默病 (AD) 中最先受影响的区域诸如迷失方向、混乱和无法导航等症状在生活的早期就出现了。研究发现，年轻健康成年人的脑干蓝斑 (LC) 区域存在 tau 蛋白积聚， LC 被认为是大脑中第一个出现 AD 病理的区域，对于觉醒和觉醒非常重要。 LC 的神经元控制睡眠/觉醒开关，投射到包括 EC 和海马体在内的多个区域。众所周知，这对空间记忆很重要，AD 最早的症状之一是。空间困难，并且 LC 的早期病理可能会影响睡眠，导致空间记忆缺陷。由于 LC 和 EC 对记忆都很重要，我们的目标是确定它们中哪一个更容易受到 tau 和 Aβ 的影响为了探索这种可能性，我们首先将病理学注射到野生型小鼠的LC和EC区域。我们将从人类 AD 大脑中提取 tau 蛋白，使其发挥功能，并评估其神经功能。还评估睡眠并测试相关行为任务中的记忆表现，以了解 aβ 如何影响 tau。病理学方面，我们将人tau蛋白注射到具有生理量APP的APP Knock-In小鼠体内我们将确定 Aβ 与 tau 一起是否会恶化 LC 和 EC 的神经元功能。神经元，它的睡眠和记忆会进一步受损，我们将使用多区域硅探针来同时进行。记录 LC 或内侧 EC 和海马神经元的活动 MEC 和海马神经元状况良好。我们将利用可以使用空间导航任务轻松测量的属性。虚拟现实头部固定装置可供动物导航，并允许我们快速测试动物的记忆任何背景和环境都将测试动物的物体位置记忆和背景依赖性。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到 tau 蛋白或 Aβ 或两者的影响。我们还将评估睡眠。我们爬升了 LC 和 EC 中的 tau 蛋白将使其神经元相关。功能失调，直接影响睡眠和记忆力，这与 Aβ 协同作用会使神经元恶化功能障碍导致睡眠问题增加和空间记忆障碍，如早期 AD 所示。我们的目标是在行为发生之前识别神经功能障碍的电生理生物标志物我们将测试是否增加低活性神经元的神经元放电并减少神经元的放电。过度活跃的神经元将恢复下游神经元功能障碍并扭转睡眠问题和认知问题损害。该提案汇集了不同领域（神经科学、病理学和计算神经科学）大规模记录技术同时应用于多个大脑区域以开发分析以及预测性测试，以询问 AD 中功能失调的脆弱大脑区域的功能。