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.

项目概要（摘要） 阿尔茨海默病 (AD) 是一种进行性神经系统疾病，会削弱我们的思维和记忆力。 自我意识丧失，区分不同环境和记忆的能力也受到损害 目前，AD 影响着美国 500 万人，给健康造成了巨大负担。 尽管在揭示分子和细胞方面取得了重大进展，但护理系统（> 1000 亿美元）。 AD 病理背后的机制，我们仍然缺乏适当的治疗方法。 通过了解什么类型的神经活动来研究 AD 大脑回路中发生的变化。 迷失并证明功能失调的神经网络与认知缺陷之间的关系，我们 可以开发新的疗法来重新激活 AD 患者的这些活动。 我们的实验室一直在利用电生理学研究 AD 小鼠模型中大脑活动的受损情况 我们关注的是 EC 中称为内嗅皮层 (EC) 的大脑区域。 接收来自多个皮质区域的输入并将投射发送到海马体中的 CA1 细胞。 海马体将轴突送回 EC，从而形成 EC-海马环路。 两个大脑区域之间涉及记忆的形成和检索，该电路的损坏会导致 AD 患者和动物模型的记忆障碍的组织学和影像学研究表明， EC 是 AD 早期萎缩和活性丧失的主要部位，但目前尚不清楚是什么类型。 AD 患者甚至 AD 小鼠模型的 EC 中的活性丧失。 使用新型淀粉样前体蛋白（APP）敲入小鼠模型，我们发现称为 EC (MEC) 内侧部分的伽马振荡受损。此外，我们还获得了初步数据。 研究表明，称为网格细胞（一种具有空间记忆相关活动的细胞类型）的 MEC 神经元受损 在 APP 敲入小鼠中，海马体中另一种与记忆相关的神经元——Place 细胞也受到损害。 通过光遗传学操纵内侧内嗅皮层的主要神经元，我们将重新激活 受损的网格细胞活性并测试 APP 敲入小鼠受损的空间记忆是否可以被挽救。 是第一个证明细胞类型特异性电疗法是否可以成为有效手段的研究 AD 治疗的新进展，也将为各种 AD 小鼠模型的进一步研究创造机会 作为对患者研究的潜在临床转化。