In vivo neurophysiological study of a neurodegenerative mouse model

描述（由申请人提供）：阿尔茨海默病的标志是过度磷酸化tau蛋白、tau神经元缠结和包括海马在内的记忆处理回路中的神经元损失的进行性出现。这些改变的神经回路中的功能变化和适应最终导致了认知症状，如记忆丧失。然而，尚不清楚在具有持续tau病理的活体大脑的海马体中发生了什么功能变化以及什么病理特征导致这些变化。tau蛋白病小鼠模型和四极记录技术（可记录自由活动小鼠的海马神经元）的发展使解决这一问题成为可能。该提议将四极技术应用于tau蛋白病小鼠模型，即转基因rTau4510小鼠，其中突变形式的人tau蛋白的过表达导致年龄依赖性记忆缺陷。我们专注于一个假设，即在这个模型中的tau病理破坏记忆巩固的神经机制和破坏结果在不稳定的海马记忆表示。当小鼠执行空间导航任务时以及当它们休息时，将记录海马神经元和局部场电位。随后将通过生物化学和免疫组织化学方法检查记录的脑中的tau病理学。我们将研究如何与记忆巩固，包括波纹，神经元同步性，和放置场稳定性，相关的电生理标记物，在不同的病理阶段在rTg4510小鼠，以及这些电生理改变的病理参数是至关重要的。 公共卫生相关性：该项目研究大脑中的病理变化如何导致具有阿尔茨海默病样症状的小鼠的记忆丧失。结果将促进我们对阿尔茨海默病症状原因的理解，并产生对新干预策略的见解。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This project studies how the pathological changes in the brain give rise to the loss of memory in mice with Alzheimer's disease-like symptoms. The outcome will advance our understanding of the causes of Alzheimer's disease symptoms and generate insights into novel intervention strategies.