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）