Tracking the onset of spatial memory deficits in aging and Alzheimers disease models with single neuron resolution electrophysiology

利用单神经元分辨率电生理学追踪衰老和阿尔茨海默病模型中空间记忆缺陷的发生

• 批准号: 10248502
• 负责人: Theodore Joseph Zwang
• 金额: $ 12.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248502
• 关键词: Adult; Affect; Age; Age of Onset; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; American; Animal Model; Behavioral; Biological Models; Biotechnology; Brain; Brain region; Cells; Characteristics; Chronic; Clinical; Clinical Trials; Cognition; Communities; Data; Dementia; Disease Progression; Electronics; Electrophysiology (science); Foreign Bodies; Foundations; Functional disorder; Goals; Heterogeneity; Hippocampus (Brain); Histology; Human; Immune; Impaired cognition; Impairment; Individual; Injectable; Lead; Learning; Longitudinal Studies; Medial; Medical; Memory; Memory impairment; Modeling; Monitor; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Pathologic; Pathology; Population; Process; Research; Research Personnel; Resistance; Resolution; Structure; Syringes; Techniques; Technology; Testing; Time; Training; Work; age related; aged; aging and technology; aging brain; aging hippocampus; aging population; behavioral study; career; entorhinal cortex; excitatory neuron; experience; experimental study; innovation; insight; middle age; mouse model; neural circuit; neuron loss; neuronal circuitry; normal aging; novel; pathological aging; physical science; prevent; response; skills; spatial memory; spatiotemporal; tau Proteins; tau aggregation; tau mutation; tool; virtual reality

Project Summary/Abstract Aging changes the adult brain both structurally and functionally. Something about these changes promotes cognitive decline and increases the risk of Alzheimer’s disease, a neurodegenerative disease that affects millions of Americans and is the leading cause of dementia among adults. I propose to carry out longitudinal electrophysiology and behavioral studies to understand how age-related changes in individual neurons and their circuits contribute to cognitive impairments in mouse models of aging and Alzheimer’s disease. I plan to take advantage of a novel biotechnology, mesh electronics, that will overcome many previous challenges preventing the study of aging processes of single neurons and their circuits. I will use this technology combined with behavioral tasks in virtual reality to understand how neurons and their circuits within the hippocampus and entorhinal cortex change with normal aging and lead to cognitive decline. Then I will perform similar studies to understand how spatial memory and learning deficits arise in a model of early aging in Alzheimer’s disease that expresses pathological tau, with the goal of determining if either soluble or aggregated tau leads to neuronal dysfunction and spatial memory impairment or if they arise coincidentally. These data will be extremely valuable for the medical community as aggregated tau is currently the target of several ongoing clinical trials. These experiments will also establish mesh electronics as a useful tool for the study of normal and pathological aging that could be extended to understand the onset of cognitive decline in many other model systems.

项目概要/摘要 衰老会在结构和功能上改变成年人的大脑。 促进认知能力下降并增加患阿尔茨海默病的风险，阿尔茨海默病是一种神经退行性疾病， 影响了数百万美国人，是我建议开展的成年人痴呆症的主要原因。 纵向电生理学和行为研究，以了解个体与年龄相关的变化如何 神经元及其回路会导致衰老和阿尔茨海默病小鼠模型的认知障碍。 我计划利用一种新颖的生物技术——网状电子技术，它将克服以前的许多挑战 防止单个神经元及其电路的老化过程的研究我将结合使用这项技术。 通过虚拟现实中的行为任务来了解海马体内的神经元及其回路如何 内嗅皮层随着正常衰老而变化并导致认知能力下降，然后我将进行类似的研究。 了解阿尔茨海默病早期衰老模型中空间记忆和学习缺陷是如何出现的 表达病理性 tau，目的是确定可溶性或聚集性 tau 是否会导致神经元 功能障碍和空间记忆障碍，或者如果它们同时出现，这些数据将非常有价值。 对于医学界来说，聚集的 tau 蛋白目前是多项正在进行的临床试验的目标。 实验还将建立网状电子学作为研究正常和病理性衰老的有用工具 可以扩展到理解许多其他模型系统中认知能力下降的发生。