In vivo neurophysiological study of a neurodegenerative mouse model

描述(申请人提供)：阿尔茨海默病的一个特征是过度磷酸化的tau蛋白、tau神经原纤维缠结和包括海马体在内的记忆处理电路中的神经元丢失。这些改变的神经回路中的功能变化和适应最终会导致记忆力丧失等认知症状的增加。然而，目前还不清楚在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了这些变化。直立面疗法小鼠模型的发展和可以记录自由活动小鼠海马神经元的四极管记录技术的发展，使解决这个问题成为可能。这项建议将把Tetrode技术应用于Tetrode小鼠模型，即转基因rTau4510小鼠，在该模型中，人类tau突变版本的过度表达会导致与年龄相关的记忆缺陷。我们专注于一个假设，即在这个模型中，tau的病理破坏了记忆巩固的神经机制，这种破坏导致了不稳定的海马体记忆表征。当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。随后将通过生化和免疫组织化学方法检查记录的大脑中的tau病理。我们将研究与记忆巩固相关的电生理标记物，包括波纹、神经元同步性和位置场稳定性，在rTg4510小鼠的不同病理阶段是如何改变的，以及哪些病理参数对这些电生理改变至关重要。 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力丧失。这一结果将促进我们对阿尔茨海默病症状原因的理解，并对新的干预策略产生见解。

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.