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

项目总结/摘要 衰老改变了成年人的大脑结构和功能。这些变化 促进认知能力下降，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， 影响着数百万美国人，是成年人痴呆症的主要原因。我提议执行 纵向电生理学和行为研究，以了解如何与年龄有关的变化，在个人 神经元和它们的回路导致了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，它将克服许多以前的挑战 阻碍了对单个神经元及其回路的老化过程的研究。我会把这项技术 在虚拟现实中的行为任务，以了解神经元和他们的电路在海马体， 内嗅皮层随正常衰老而改变，并导致认知能力下降。然后我将进行类似的研究， 了解空间记忆和学习缺陷如何在阿尔茨海默病的早期衰老模型中出现， 表达病理性tau，目的是确定可溶性或聚集的tau是否导致神经元的 功能障碍和空间记忆障碍，或者它们是偶然出现的。这些数据将是极其宝贵的 对于医学界来说，聚集的tau是目前几个正在进行的临床试验的目标。这些 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 这可以扩展到理解许多其他模型系统中认知下降的开始。

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.