The role of cortical neuron and circuit function in tau induced neurodegeneration

皮质神经元和回路功能在 tau 诱导的神经变性中的作用

• 批准号: 7912300
• 负责人: TIMOTHY JOEL CHERRY
• 金额: $ 4.56万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912300
• 关键词: Affect; Alzheimer' s Disease; Brain; Cell physiology; Cerebral cortex; Defect; Disease; Event; Frontotemporal Dementia; Functional disorder; Genes; Human; Image; Impaired cognition; Lead; Life; Mediating; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Pick Disease of the Brain; Role; Signal Transduction; Synapses; System; Tauopathies; Transgenic Mice; calcium indicator; improved; in vivo; information processing; mouse model; mutant; neural circuit; public health relevance; relating to nervous system; tau Proteins; tau expression; tau mutation; tool; two-photon

DESCRIPTION (provided by applicant): Mutations in the gene encoding the microtubule associated protein tau can lead to devastating neurodegenerative diseases in humans. Previous studies in humans and mice have shown that synapse loss is one of the earliest events in tau-mediated neurodegeneration. Until recently however, it has been impossible to assess the effects of this synapse loss on the function of cells and circuits in the intact brain. The studies put forward in this proposal will: 1) determine how mutant tau expression affects the spontaneous and evoked activity of neurons within the mouse cerebral cortex, 2) characterize the consequences of mutant tau expression on cortical information processing, and 3) assess the dysfunction of local cortical circuits caused by mutant tau. These studies will use in vivo two-photon imaging with calcium indicators to determine how synaptic defects lead to cellular and system-wide dysfunction in mouse models of tau-mediated disease. I anticipate that these studies will improve the current understanding of the initiating events of neurodegeneration and how neural activity is compromised in brains expressing mutant forms of tau. PUBLIC HEALTH RELEVANCE: A tremendous gap in our understanding of neurodegenerative diseases lies between the molecular events that occur at the synapse and the cognitive decline of people suffering from these devastating diseases. The dysfunction of the neuronal protein tau is a hallmark of many neurodegenerative diseases such as Alzheimer's Disease, Pick's Disease and Frontotemporal Dementia, and is known to disrupt synaptic signaling and lead to cognitive decline. This proposal aims to bridge the gap in our understanding by determining the effects of mutant tau on neuronal activity and neural circuit function by using the powerful tools of transgenic mouse models of disease and in vivo two-photon imaging of activity within the living brain.

描述（由申请人提供）： 编码微管相关蛋白 tau 的基因突变可能导致人类毁灭性的神经退行性疾病。先前对人类和小鼠的研究表明，突触丢失是 tau 介导的神经变性中最早的事件之一。然而直到最近，我们还无法评估这种突触损失对完整大脑中细胞和回路功能的影响。本提案中提出的研究将：1）确定突变 tau 表达如何影响小鼠大脑皮层内神经元的自发和诱发活动，2）表征突变 tau 表达对皮质信息处理的影响，以及 3）评估功能障碍由突变 tau 引起的局部皮质回路。 这些研究将使用带有钙指示剂的体内双光子成像来确定突触缺陷如何导致 tau 介导疾病的小鼠模型中的细胞和系统范围的功能障碍。我预计这些研究将增进目前对神经退行性变的起始事件以及表达 tau 突变形式的大脑中神经活动如何受到损害的理解。 公共卫生相关性： 我们对神经退行性疾病的理解存在巨大差距，存在于突触发生的分子事件与患有这些毁灭性疾病的人的认知能力下降之间。神经元蛋白 tau 的功能障碍是许多神经退行性疾病的标志，例如阿尔茨海默氏病、皮克氏病和额颞叶痴呆，并且已知会破坏突触信号传导并导致认知能力下降。该提案旨在通过使用转基因小鼠疾病模型和活体大脑活动的体内双光子成像的强大工具来确定突变 tau 对神经元活动和神经回路功能的影响，从而弥合我们的理解差距。