Abnormal spatial memory processing in tau pathology and neurodegeneration

摘要 Tau病理学，包括Tau蛋白过度磷酸化、神经元缠结和随后的 神经变性在包括阿尔茨海默病在内的tau蛋白病的认知症状中起关键作用。 最近使用动物模型的研究在理解tau蛋白的发病机制及其作用机制方面取得了快速进展。 参与认知缺陷。然而，行为缺陷最终是由功能变化介导的， 体内的神经回路一个很少被研究的重要问题是神经回路功能是如何 在活脑中改变，伴有持续的tau病理学和神经变性。在这里，我们建议确定在 在神经回路中由tau病理和神经变性引起的体内功能异常 海马体（HP）和内嗅皮层，这些区域对于tau蛋白病中的记忆丧失至关重要。主要使用 四极记录技术，结合行为和药理学操作，我们将 同时记录tau蛋白病小鼠模型的自由活动动物中的大量神经元， 包括转基因rTg 4510小鼠和htau小鼠。我们将重点关注一个具体的“内部-外部 不平衡”假说：这些老鼠的记忆回路不能形成正常的记忆，因为它们是 由海马体内产生的内部活动主导，因此无法对外部感觉做出反应。 输入.为了验证这一假设，我们将旨在确定在tau蛋白病模型中HP神经元的活动是否 比对照组小鼠更倾向于由内部活动驱动，这种异常是如何发生的？ 产生的记忆神经回路，它改变了什么计算过程，以及它是如何连接到 行为记忆缺陷

Abstract Tau pathology, including tau protein hyperphosphorylation, neurofibrillary tangles and subsequent neurodegeneration, plays a key role in cognitive symptoms of tauopathies including Alzheimer’s disease. Recent studies using animal models have made rapid progress in understanding tau pathogenesis and its involvement in cognitive deficits. However, behavioral deficits are ultimately mediated by functional changes in neural circuits in vivo. An important question that has rarely been studied is how neural circuit functions are altered in the living brain with ongoing tau pathology and neurodegeneration. Here we propose to determine in vivo functional abnormalities caused by tau pathology and neurodegeneration in the neural circuits of hippocampus (HP) and entorhinal cortex, areas that are crucial for memory loss in tauopathies. Primarily using the tetrode recording technique, in combination with behavioral and pharmacological manipulations, we will simultaneously record a large number of neurons in freely moving animals of tauopathy mouse models, including the transgenic rTg4510 mouse and htau mouse. We will focus on a specific “internal-external imbalance” hypothesis: The memory circuits in these mice cannot form normal memories because they are dominated by internal activities generated within the hippocampus and thus fail to respond to external sensory input. To test the hypothesis, we will aim to determine whether activities of HP neurons in tauopathy models are preferentially driven by internal activities more than those in control mice, how this abnormality is generated by the memory neural circuits, what computational process it alters, and how it is linked to behavioral memory deficits.