Circuit mechanisms underlying associative memory impairment in knock-in Alzheimer's model

敲入阿尔茨海默病模型中联想记忆损伤的回路机制

• 批准号: 10689059
• 负责人: Jason Yen Sun Lee
• 金额: $ 4.39万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2024-08-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10689059
• 关键词: Affect; Age Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein Precursor; Animal Disease Models; Animal Model; Association Learning; Atrophic; Brain; Categories; Cells; Cues; Data; Deep Brain Stimulation; Dementia; Deterioration; Dopamine; Electrophysiology (science); Epidemic; Exhibits; Fiber; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Hippocampus; Impairment; Individual; Investigation; Knock-in; Knock-in Mouse; Knowledge; Lateral; Literature; Maps; Medial; Memory; Memory Loss; Memory impairment; Methods; Molecular; Mus; Neuronal Dysfunction; Neurons; Pathogenesis; Performance; Persons; Phase; Photometry; Positioning Attribute; Rattus; Reporting; Research; Retrieval; Rewards; Sensory; Signal Transduction; Site; Substantia nigra structure; Symptoms; Techniques; Testing; Therapeutic; Time; Ventral Tegmental Area; Wild Type Mouse; abeta accumulation; abeta deposition; age group; entorhinal cortex; feeding; histological studies; improved; in vivo; mouse model; neural; neural circuit; neuroregulation; novel therapeutics; optogenetics; pars compacta; prevent; sensory input; spatial memory; therapeutic development; transmission process

Project Summary Alzheimer’s disease (AD), the most common dementia, currently affects ~6 million individuals in the U.S. and is expected to triple by 2050. A devastating hallmark symptom is the progressive loss of the ability to form memories. Treatments for rescuing memory function in AD patients are nonexistent, due in part to insufficient research characterizing the activity of neural memory circuits affected by AD. Developing memory-restoring therapeutics that modulate specific neural circuits demands investigation of which circuit-level functions are impacted, when during pathophysiological progression they show impairment, and how they relate to memory performance. Neurons in the entorhinal cortex (EC) act as a gateway for sensory inputs feeding into the hippocampus. This EC-hippocampus circuit is critical for memory formation and retrieval. The lateral entorhinal cortex (LEC) is a primary site of atrophy and activity loss in the early phases of AD. Despite its significance to AD pathophysiology, it remains unclear what type of activity is lost in the LEC of AD patients or animal models. The proposed studies center on two Specific Aims: (Aim 1) Determine the time course of memory cell impairment in APP-KI mice; and (Aim 2) Test whether reactivation of LEC dopamine inputs restores associative memory formation. This study is expected to identify neuronal dysfunction of the LEC in AD. The project is expected to yield advances towards developing therapeutics to rescue memory function via neuromodulation in the lateral entorhinal cortex.

项目摘要 阿尔茨海默氏病（AD）是最常见的痴呆症，目前在美国影响约600万人， 预计到2050年将增加三倍。一个毁灭性的标志性症状是形成能力的逐渐丧失 回忆挽救AD患者记忆功能的治疗是不存在的，部分原因是缺乏足够的治疗。 一项研究描述了受AD影响的神经记忆回路的活动。显影恢复记忆 调节特定神经回路的治疗需要研究哪些回路水平的功能是 受影响，当在病理生理学进展过程中，他们表现出损害，以及他们如何与记忆 性能内嗅皮层（EC）中的神经元充当感觉输入进入大脑皮层的通道。 海马体。这种EC-海马回路对于记忆的形成和提取至关重要。外侧内嗅 皮质（LEC）是AD早期萎缩和活动丧失的主要部位。尽管它的重要性， 虽然AD的病理生理学研究进展缓慢，但仍不清楚AD患者或动物模型的LEC中丢失了何种类型的活性。 本研究主要有两个目的：（1）确定记忆细胞损伤的时间进程 （目的2）测试LEC多巴胺输入的再激活是否恢复联想记忆 阵这项研究预计将确定神经元功能障碍的LEC在AD。该项目预计将 通过神经调节在侧支神经系统中恢复记忆功能的治疗方法的开发取得进展 内嗅皮层