Mechanisms of pathology and neuronal hyperactivity in a memory circuit in Alzheimer's disease

阿尔茨海默病记忆回路的病理学和神经元过度活跃机制

• 批准号: 10487389
• 负责人: Edward S. Boyden
• 金额: $ 64.42万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487389
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid deposition; Area; Automobile Driving; Axon; Behavior; Behavioral; Brain; Dementia; Deposition; Efferent Neurons; Electrophysiology (science); Etiology; Exhibits; Goals; Grant; Hippocampus (Brain); Human; Hyperactivity; Image; Interneurons; Investigation; Ion Channel; Label; Lateral; Link; Location; Long-Term Effects; Mammillary body structure; Maps; Medial; Memory; Microscopy; Mus; Myelin; Nerve Degeneration; Neurons; Neurosciences; Pathology; Patients; Pattern; Performance; Pharmacology; Population; Population Analysis; Resolution; Sampling; Severities; Site; Slice; Source; Stains; Structure; Techniques; Testing; Work; Zebrafish; in situ sequencing; in vivo; mouse model; optogenetics; single-cell RNA sequencing; tool; tool development; translational potential; voltage; white matter; white matter change

Previous work from the Tsai lab (Canter et al 2019) identified the mamillary body (MB) as one of the first sites of amyloid deposition in 5XFAD model mice, a region that also correlates with dementia severity in human patients. Single cell RNA sequencing of the mouse MB identified 2 distinct neuronal populations within the MB, with segregated distribution, target projection, and unique electrophysiology. Analysis of these populations in the 5XFAD mice found that one of these populations, those found in the lateral MB (LM), are uniquely susceptible to hyperactivity and neurodegeneration, while the second population (medial MB, MM) is largely unaffected. The activity of the LM population also directly contributes to mouse performance in memory tasks. Additionally, using iterative direct-expansion microscopy (idExM) from the Boyden lab, we have identified intriguing patterns of amyloid associated with specific projections in the fornix, the white matter tract from the subiculum with axonal inputs to the MB. This grant proposes to investigate the links between amyloid and excitability changes in the MB and fornix, including development of the tools necessary to achieve this goal. The hypothesis to be tested in this application is that amyloid preferentially associates with the subiculum-LM projection and that these axons exhibit hyperexcitability. Aim 1 will map the connections between this new population of LM neurons and its upstream inputs from the hippocampus, using a newly developed in situ sequencing techniques, as well as exploring pathology in the white matter projection regions of this circuit in 5XFAD mice and human brain samples, using recently developed expansion microscopy. Aim 2 will characterize the source and location of hyperactivity found in the LM neurons through advanced voltage imaging, as well as expand this work to other mouse models of AD. Aim 3 will use optogenetics and pharmacological approaches to determine if specific aberrant circuit activity drives the pathology and behavioral changes seen in the AD model mice.

Tsai Lab的先前工作（Canter等，2019年）将Mamillary体（MB）确定为 5xFAD模型小鼠中淀粉样蛋白沉积的第一个位点，该区域也与 人类患者的痴呆严重程度。小鼠MB的单细胞RNA测序2 MB内的不同神经元种群，分布分布，目标投影和 独特的电生理学。对5xFAD小鼠中这些种群的分析发现 这些人群，在侧向MB（LM）中发现的人群非常容易受到多动症的影响 和神经变性，而第二个人群（中间MB，MM）在很大程度上不受影响。 LM种群的活性也直接导致了记忆中的鼠标性能 任务。此外，使用Boyden实验室的迭代直接曝光显微镜（IDEXM），我们 已经确定了与Fornix中特定预测相关的淀粉样蛋白的有趣模式， 白质从带有轴突输入到MB的下部的下部。这笔赠款提议 研究MB和FORNIX的淀粉样蛋白和兴奋性变化之间的联系，包括 开发实现此目标所需的工具。在此要检验的假设 应用是淀粉样蛋白优先与下型LM投影相关联，并且 这些轴突表现出过度刺激性。 AIM 1将映射此新的连接 LM神经元的种群及其来自海马的上游输入，使用新的 开发了原位测序技术，并探索白质的病理学 该电路在5xFAD小鼠和人脑样品中的投影区域，最近使用 发展的膨胀显微镜。 AIM 2将表征的来源和位置 通过高级电压成像在LM神经元中发现的多动症，并扩展 使用AD的其他鼠标模型。 AIM 3将使用光遗传学和药理学 确定特定异常电路活动是否驱动病理和行为的方法 广告模型小鼠中看到的变化。