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: 10538464
• 负责人: Jason Yen Sun Lee
• 金额: $ 4.22万
• 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/10538464
• 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; Atrophic; Brain; Cells; Cues; Data; Deep Brain Stimulation; Dementia; Deterioration; Dopamine; Electrophysiology (science); Epidemic; Exhibits; Fiber; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Hippocampus (Brain); Impairment; Individual; Investigation; Knock-in; Knock-in Mouse; Knowledge; Lateral; Literature; 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; base; classical conditioning; entorhinal cortex; feeding; histological studies; improved; in vivo; mouse model; neural circuit; neuroregulation; novel therapeutics; optogenetics; pars compacta; prevent; relating to nervous system; 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），最常见的痴呆症目前影响美国约600万人 预计到2050年将三倍。毁灭性的标志症状是逐渐丧失形成能力 回忆。 AD患者营救记忆功能的治疗不存在，部分原因是 表征受AD影响的神经记忆电路活性的研究。开发内存恢复 调节特定中性电路的治疗需要调查哪些电路级功能是 受影响的，当病理生理过程中，它们显示出损害，以及它们与记忆的关系 表现。内嗅皮层（EC）中的神经元充当进食的感觉输入的门户 海马。该EC-Haimpocampus电路对于记忆形成和检索至关重要。侧向内河 皮层（LEC）是AD早期阶段萎缩和活性丧失的主要部位。尽管对 AD病理生理学，目前尚不清楚AD患者或动物模型的LEC中损失了哪种类型的活性。 拟议的研究集中于两个具体目标：（目标1）确定记忆细胞障碍的时间过程 在App-ki小鼠中； （AIM 2）测试LEC多巴胺输入的重新激活是否恢复关联记忆 格式。预计这项研究将鉴定AD中LEC的神经元功能障碍。该项目有望 在以后的 内河皮质。