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In vivo neurophysiological study of a neurodegenerative mouse model

神经退行性小鼠模型的体内神经生理学研究

基本信息

批准号：
8412768
负责人：
Daoyun Ji
金额：
$ 18.88万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-15 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8412768
关键词：
Address Alzheimer&apos s Disease Animal Model Animals Appearance Area Behavioral Biochemical Biological Assay Brain Cells Data Development Doxycycline Eating Environment Fire - disasters Functional disorder Goals High Frequency Oscillation Hippocampus (Brain)Human Immunohistochemistry Intervention Life Measures Mediating Memory Memory Loss Memory impairment Methods Modeling Molecular Monitor Mus Mutate Nerve Degeneration Neurobehavioral Manifestations Neurofibrillary Tangles Neurons Outcome Pathogenesis Pathological Staging Pathology Phenotype Phosphorylation Process Property Rest Retrieval Rodent Running Staging Symptoms Tauopathies Techniques Testing Time Transgenic Organisms Variant Western Blotting Work age group age related feeding hyperphosphorylated tau in vivo innovation insight memory process mouse model neural circuit neuromechanism neuron loss neurophysiology novel prevent tau Proteins tau aggregation way finding

项目摘要

ABSTRACT A hallmark of Alzheimer's disease is the progressive appearance of hyper-phosphorylated tau protein, tau neurofibrillary tangles, and neuron loss in the memory-processing circuits including the hippocampus. The functional changes and adaptations in these altered neural circuits are what ultimately give rises to the cognitive symptoms such as memory loss. However, it is unknown what functional changes occur in the hippocampus of the living brain with ongoing tau pathology and what pathological features causes these changes. The development of tauopathy mouse models and the tetrode recording technique, which can record hippocampal neurons in freely moving mice, make it possible to address this question. This proposal will apply the tetrode technique to a tauopathy mouse model, the transgenic rTau4510 mice, in which the over- expression of a mutated version of human tau leads to age-dependent memory deficits. We focus on a hypothesis that tau pathology in this model disrupts neural mechanisms for memory consolidation and the disruption results in unstable hippocampal memory representations. Hippocampal neurons and local field potentials will be recorded while mice perform spatial navigation tasks and while they rest. The tau pathology in the recorded brains will be subsequently examined by biochemical and immunohistochemical methods. We will investigate how the electrophysiological markers related to memory consolidation, including ripples, neuronal synchrony, and place field stability, are altered at various pathological stages in the rTg4510 mice, and which pathological parameters are critical for these electrophysiological alterations.

摘要阿尔茨海默氏病的一个标志是过度磷酸化的tau蛋白，tau蛋白神经元缠结，以及包括海马体在内的记忆处理回路中的神经元损失。的这些改变的神经回路中的功能变化和适应性是最终引起认知症状，如记忆丧失。然而，尚不清楚在这些细胞中发生了什么功能变化。海马体的活脑与正在进行的tau病理和什么病理特征导致这些变化Tau蛋白病小鼠模型的建立及四极记录技术海马神经元在自由活动的小鼠，使解决这个问题成为可能。这项建议将适用于 tetrode技术应用于tau蛋白病小鼠模型，即转基因rTau 4510小鼠，其中过度- 人tau的突变形式的表达导致年龄依赖性记忆缺陷。我们关注了该模型中的tau病理学破坏了记忆巩固的神经机制，破坏导致海马体记忆表征不稳定。海马神经元和局部场当小鼠执行空间导航任务时以及当它们休息时，将记录电位。Tau病理学在随后将通过生物化学和免疫组织化学方法对记录的大脑进行检查。我们将研究如何与记忆巩固相关的电生理标志物，包括波纹，神经元同步性和位置场稳定性在rTg 4510小鼠的不同病理阶段发生改变，病理参数对于这些电生理学改变是关键的。