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: 10633260
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633260
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein Precursor; Animal Disease Models; Animal Experimentation; Animal Model; Animals; Area; Atrophic; Attenuated; Behavior; Behavioral Assay; Biological Markers; Brain; Brain region; Caregivers; Cells; Data; Deep Brain Stimulation; Dementia; Development; Disease Progression; Dorsal; Electric Stimulation; Electrophysiology (science); Family; Foundations; Functional disorder; Genetic; Goals; Hippocampus; 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; Protocols documentation; Public Health; Research; Retrieval; Role; Site; Societies; Sum; Synapses; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; United States National Institutes of Health; cell type; combat; cost; design; entorhinal cortex; excitatory neuron; fighting; histological studies; imaging study; improved; in vivo; mental function; mouse model; neuron loss; neurophysiology; novel; optogenetics; potential biomarker; preservation; prevent; procedure safety; 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.

抽象的 阿尔茨海默氏病（AD）是痴呆症的最常见形式。目前，它影响美国500万人， 到2050年，预计将增加1600万的数字。广告不仅剥夺了患者的 基本的心理功能，但严重击败家庭和照顾者。目前估计其成本为236美元 十亿美元，到2050年可能会增加到超过1万亿美元。随着我们的社会迅速增长，需要 打击广告正在压力。 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早期阶段萎缩和活性丧失的主要部位。但是，仍然是 在AD早期，在内部皮层中丢失了哪种类型的活动类型。使用体内神经生理学 记录方法，我们最近证明了伽马振荡，一种反映的网络活动。 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 最近的文献表明，肠γ振荡可以用于生物标志物和 AD的治疗靶标。在这里，我们提出研究旨在研究内嗅γ振荡的作用 使用AD鼠标模型的记忆障碍中的皮层。我们的方法涉及本地领域的体内记录 电势（theta和伽马振荡）以及峰值活性，光学遗传学和化学遗传学方法，闭合 循环刺激，神经元丧失的细胞类型特异性组织学分析和一种新型的APP敲入小鼠 模型。有三个特定的目的：（目标1）确定内河皮层（EC）的程度和时间过程 伽马损伤； （AIM 2）确定是否使用伽马刺激重新激活网络活动 EC的减弱或消除APP-KI小鼠的记忆障碍，（3）确定基于的细胞类型 EC伽马障碍。如果成功，我们的研究将确定内存的体内网络机制 AD损伤，将有助于确定神经元活动是预防或减慢的治疗靶点 疾病的进展。此外，我们的研究将帮助我们制定更有效，更安全的程序 深脑刺激是保存或改善记忆功能的强大工具，最终可以使用该功能 减慢AD患者的记忆率下降。