Abnormal spatial memory processing in tau pathology and neurodegeneration

tau 病理学和神经变性中的异常空间记忆处理

基本信息

批准号：
10238047
负责人：
Daoyun Ji
金额：
$ 39.63万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238047
关键词：
Address Age Alzheimer&apos s Disease Animal Model Animals Area Behavioral Brain Cell physiology Cells Code Cognitive deficits Disease Disease Progression Environment Fire - disasters Hippocampus (Brain)Intervention Lead Link Medial Mediating Memory Memory Loss Memory impairment Modeling Molecular Mus Nerve Degeneration Neurobehavioral Manifestations Neurodegenerative Disorders Neurofibrillary Tangles Neurons Neurophysiology - biologic function Outcome Pathogenesis Pathologic Pathology Pattern Performance Phenotype Play Process Rattus Recurrence Symptoms Synapses Synaptic Transmission Synaptic plasticity Tauopathies Techniques Testing Tetanus Helper Peptide Transgenic Animals Transgenic Organisms Travel age related base behavioral impairment behavioral pharmacology computational basis entorhinal cortex hTau Mice in vivo in vivo Model insight memory process mouse model neural circuit normal aging novel response sensory input spatial memory tau Proteins tau aggregation tau-1

项目摘要

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.

抽象的 Tau 病理学，包括 tau 蛋白过度磷酸化、神经原纤维缠结和随后的神经退行性变在包括阿尔茨海默氏病在内的 tau蛋白病的认知症状中发挥着关键作用。最近使用动物模型的研究在了解 tau 发病机制及其作用方面取得了快速进展然而，行为缺陷最终是由功能变化介导的。体内神经回路的一个很少被研究的重要问题是神经回路如何发挥作用。活体大脑中持续的 tau 病理学和神经变性发生改变。 tau 病理学和神经回路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蛋白病的记忆丧失至关重要。四极记录技术，结合行为和药理学操作，我们将同时记录tau蛋白病小鼠模型中自由活动动物的大量神经元，包括转基因rTg4510小鼠和htau小鼠，我们将重点关注特定的“内部-外部”。 “不平衡假说”：这些小鼠的记忆回路无法形成正常记忆，因为它们受海马体内产生的内部活动支配，因此无法对外部感觉做出反应为了检验这一假设，我们的目标是确定 tau 蛋白病模型中 HP 神经元的活动是否存在。与对照小鼠相比，更倾向于由内部活动驱动，这种异常是如何发生的由记忆神经回路生成，它改变什么计算过程，以及它如何与行为记忆缺陷。