In vivo neurophysiological study of a neurodegenerative mouse model

描述（由申请人提供）：阿尔茨海默病的一个标志是tau蛋白过度磷酸化的进行性出现，tau神经原纤维缠结，以及包括海马体在内的记忆处理回路中的神经元丧失。这些改变的神经回路的功能改变和适应最终导致了认知症状，如记忆丧失。然而，目前尚不清楚tau病理持续的活脑海马中发生了哪些功能变化，以及哪些病理特征导致了这些变化。脑损伤小鼠模型的建立和可以记录自由运动小鼠海马神经元的四极记录技术的发展，使解决这一问题成为可能。这一建议将四极电极技术应用于tau病小鼠模型，转基因rTau4510小鼠，其中人类tau突变版本的过度表达导致年龄依赖性记忆缺陷。我们关注的假设是，该模型中的tau病理学破坏了记忆巩固的神经机制，并导致海马记忆表征不稳定。在小鼠执行空间导航任务和休息时，将记录海马神经元和局部场电位。随后将用生化和免疫组织化学方法检查记录的脑中的tau病理。我们将研究rTg4510小鼠在不同病理阶段与记忆巩固相关的电生理标记（包括波纹、神经元同步和位置场稳定性）是如何改变的，以及哪些病理参数对这些电生理改变至关重要。

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.