Understanding the role of gamma oscillations underlying entorhinal cortex dysfunction in Alzheimer’s disease

了解伽玛振荡在内嗅皮层功能障碍在阿尔茨海默病中的作用

• 批准号: 10404049
• 负责人: Kei M Igarashi
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404049
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein Precursor; Animal Disease Models; Animal Experiments; Animal Model; Animals; Area; Atrophic; Attenuated; Behavior; Behavioral Assay; Biological Markers; Brain; Brain region; Cells; Data; Deep Brain Stimulation; Dementia; Development; Disease Progression; Dorsal; Electric Stimulation; Electrophysiology (science); Family Caregiver; Foundations; Functional disorder; Goals; Hippocampus (Brain); Histologic; Histology; Immunohistochemistry; Impairment; Knock-in Mouse; Knowledge; Literature; Long-Term Potentiation; Medial; Membrane Potentials; Memory; Memory Loss; Memory impairment; Methods; Mission; Molecular; Mus; Neurofibrillary Tangles; Neurons; Optics; Output; Pathogenesis; Patients; Pattern; Persons; Phase; Physiological; Procedures; Protocols documentation; Public Health; Research; Retrieval; Role; Site; Societies; Sum; Synapses; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; United States National Institutes of Health; base; cell type; combat; cost; design; entorhinal cortex; excitatory neuron; fight against; histological studies; imaging study; improved; mental function; mouse model; neuron loss; neurophysiology; novel; optogenetics; potential biomarker; preservation; prevent; therapeutic target; tool

Abstract Alzheimer's disease (AD) is the most common form of dementia. It currently affects 5 million people in the US, a number that is expected to rise to a staggering 16 million by 2050. AD not only deprives patients of their basic mental functions, but severely batters families and caregivers. Its costs are currently estimated at $236 billion, and will likely increase to more than $1 trillion by 2050. As our society rapidly ages, the need for combating AD is pressing. Histological and imaging studies in AD patients and animal models have shown that the entorhinal cortex is a primary site of atrophy and activity loss in the early phases of AD. However, it is still largely unclear what type of activity is lost in the entorhinal cortex in early AD. Using in vivo neurophysiological recording methods, we recently demonstrated that gamma oscillations, a network activity reflecting summed neuronal membrane potentials, are impaired in the entorhinal cortex of an AD mouse model. Our results and recent literature suggest a possibility that entorhinal gamma oscillations can be used for both a biomarker and a therapeutic target of AD. Here we propose studies to investigate the role of gamma oscillations of entorhinal cortex in memory impairments using AD mouse models. Our approach involves in vivo recording of local field potentials (theta and gamma oscillations) and spike activity, optogenetic and chemogenetic methods, closed- loop stimulation, cell-type specific histological analyses of neuronal loss and a novel APP knock-in mouse model. There are three Specific Aims: (Aim 1) identify the extent and time course of entorhinal cortex (EC) gamma impairments; (Aim 2) determine whether the reactivation of network activity using gamma stimulation of EC attenuates or eliminates memory impairments in APP-KI mice, and (3) determine cell types that underlie the EC gamma impairment. If successful, our studies will identify in vivo network mechanisms of memory impairment in AD, and will help identify neuronal activities as therapeutic targets to prevent or slow the progression of disease. Furthermore, our study will help us develop more effective and safer procedures for deep-brain stimulation as a powerful tool to preserve or improve memory function that may eventually be used to slow the rate of memory decline in AD patients.

摘要 阿尔茨海默病（AD）是痴呆症最常见的形式。它目前影响着美国500万人， 到2050年，这一数字预计将上升到惊人的1600万。AD不仅剥夺了患者的 基本的精神功能，但严重打击家庭和照顾者。其费用目前估计为236美元 10亿美元，到2050年可能会增加到1万亿美元以上。随着我们的社会迅速老龄化， 防治AD刻不容缓。AD患者和动物模型的组织学和成像研究表明， 内嗅皮层是AD早期萎缩和活动丧失的主要部位。但是依然 在很大程度上不清楚什么类型的活动是在早期AD的内嗅皮层丢失。使用体内神经生理学 记录方法，我们最近证明，伽马振荡，一个网络活动，反映了总结 神经元膜电位在AD小鼠模型的内嗅皮层中受损。我们的结果和 最近的文献提出了一种可能性，即内嗅γ振荡可用于生物标志物， AD的治疗靶点。在这里，我们提出的研究，以调查伽玛振荡的作用，内嗅 使用AD小鼠模型研究大脑皮层的记忆障碍。我们的方法包括在体内记录局部场 电位（θ和γ振荡）和尖峰活性，光遗传学和化学遗传学方法，封闭- 环刺激，神经元丢失的细胞类型特异性组织学分析和一种新的APP基因敲入小鼠 模型具体目的有三：（目的1）确定内嗅皮层（EC）的范围和时间进程 伽马损伤;（目的2）确定是否使用伽马刺激重新激活网络活动 EC减弱或消除APP-KI小鼠的记忆障碍，和（3）确定细胞类型， EC伽马损伤如果成功，我们的研究将确定记忆的体内网络机制 这将有助于确定神经元活动作为治疗靶点，以预防或减缓AD的发生。 疾病进展。此外，我们的研究将帮助我们开发更有效和更安全的程序， 深部脑刺激作为一种强大的工具，以保持或改善记忆功能， 减缓AD患者记忆力下降的速度。