Investigating spatial representation in hippocampal entorhinal circuit of knock in Alzheimer's model

研究阿尔茨海默病模型中海马内嗅回路敲击的空间表征

• 批准号: 10368018
• 负责人: Heechul Jun
• 金额: $ 3.22万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368018
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein Precursor; Animal Model; Animals; Atrophic; Axon; Back; Brain; Brain region; Cells; Cognitive deficits; Computer Analysis; Data; Dementia; Deterioration; Disease; Electrophysiology (science); Environment; Functional disorder; Gene Proteins; Gene Transfer; Genes; Goals; Health Care Costs; Healthcare Systems; Hippocampus (Brain); Human; Human Amyloid Precursor Protein; Impairment; Interneurons; Knock-in; Knock-in Mouse; Knowledge; Lead; Medial; Memory; Memory Loss; Memory impairment; Mental disorders; Methods; Mind; Modeling; Molecular; Mouse Protein; Mutate; Neurons; Parvalbumins; Pathologic; Patients; Pattern; Phase; Play; Positioning Attribute; Property; Proteins; Retrieval; Role; Site; Techniques; Testing; Time; Transgenes; Viral Genes; age group; cell type; clinical translation; entorhinal cortex; histological studies; imaging study; in vivo; mortality; mouse model; nervous system disorder; neural circuit; neural network; new therapeutic target; novel; novel therapeutic intervention; optogenetics; relating to nervous system; spatial memory; therapeutically effective; transgenic model of alzheimer disease

Project Summary (Abstract) Alzheimer’s disease (AD) is a progressive neurological disorder that debilitates our mind and memory. The very sense of self is lost and ability to distinguish between different environments and remember are also impaired in these patients. Currently, AD affects 5 million people in the US and it is creating significant burden on the health care system (> $100 billion). Despite significant advances made in uncovering molecular and cellular mechanisms behind AD pathology, we still lack the proper treatment. No clear studies have been performed to investigate the changes that occur in the brain circuits of AD. By understanding what type of neuronal activities are lost and demonstrating the relationship between the dysfunctional neural network and cognitive deficits, we can develop novel therapies targeted to reactivate these activities in AD patients. Our lab has been investigating the impairment of brain activity in the AD mouse model using electrophysiological recording methods. We are focusing on a brain region called the entorhinal cortex (EC). Neurons in the EC receive input from multiple cortical regions and send projections to the hippocampus. CA1 cells in the hippocampus send their axons back to the EC, thus, forming the EC-hippocampal loop circuit. This connection between the two brain regions is involved in memory formation and retrieval and damage to this circuit results in memory impairment. Histological and imaging studies in AD patients and animal models have shown that the EC is a primary site of atrophy and activity loss in the early phases of AD. However, it is still unclear what type of activity is lost in the EC of AD patients, or even in AD mouse models. Using a novel amyloid precursor protein (APP) knock-in mouse model, we found that brain network activity called gamma oscillations are impaired in the medial part of the EC (MEC). Furthermore, we acquired preliminary data showing that MEC neurons called grid cells, a cell type harboring spatial memory-related activity, are impaired in APP knock-in mice. Place cells, another memory-associated neurons in the hippocampus, are also impaired. By optogenetically manipulating the principal neurons in the medial entorhinal cortex, we will reactivate the impaired grid cell activity and test if the disrupted spatial memory of APP knock-in mice can be rescued. This will be the first study to demonstrate whether cell type specific electroceutical approach can be an effective means of treatment for AD and it will create opportunities for additional studies in a variety of AD mouse models as well as potential clinical translation to studies in patients.

项目摘要（摘要） 阿尔茨海默氏病（AD）是一种渐进的神经系统疾病，使我们的思想和记忆衰弱。那是 自我意识丢失了，区分不同环境的能力也会受到损害 这些患者。目前，广告在美国影响500万人，这对健康造成了巨大的烧伤 护理系统（> 1000亿美元）。尽管在发现分子和细胞方面取得了重大进展 AD病理学背后的机制，我们仍然缺乏适当的治疗方法。没有进行明确的研究 研究AD大脑电路中发生的变化。通过了解哪种类型的神经元活动 丢失并证明了功能失调的神经网络与认知缺陷之间的关系，我们 可以开发针对AD患者重新激活这些活性的新型疗法。 我们的实验室一直在研究使用电生理的AD小鼠模型中大脑活动的损害 记录方法。我们专注于一个称为内嗅皮层（EC）的大脑区域。 EC中的神经元 从多个皮质区域接收输入，并将项目发送到海马。 CA1细胞 海马将轴突寄回到EC，从而形成EC - 海马环路。这个连接 两个大脑区域之间涉及记忆形成和检索和对该电路的损害导致 记忆力障碍。 AD患者和动物模型的组织学和成像研究表明 EC是AD早期阶段萎缩和活性丧失的主要部位。但是，目前尚不清楚哪种类型 AD患者甚至AD小鼠模型中的EC中损失了活性。 使用新型淀粉样蛋白前体蛋白（APP）敲入小鼠模型，我们发现大脑网络活动称为 EC（MEC）的媒体部分受损γ振荡。此外，我们获得了初步数据 表明称为网格细胞的MEC神经元（一种具有空间记忆相关活性的细胞类型）受损 在App敲入小鼠中。位置细胞是海马中的另一个与记忆相关的神经元的，也受到损害。 通过光遗传学操纵内侧内hin骨皮质中的主要神经元，我们将重新激活 网格细胞活性受损，并测试是否可以挽救APP敲击小鼠的空间记忆。这会 成为第一个证明细胞类型特定电气方法的研究是否可以有效手段 AD的治疗，它将为各种AD鼠标模型提供其他研究的机会 作为患者研究的潜在临床翻译。