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.

项目概要 阿尔茨海默病 (AD) 是最常见的痴呆症，目前影响美国约 600 万人，并且 预计到 2050 年将增加两倍。一个毁灭性的标志症状是形成能力的逐渐丧失 挽救 AD 患者记忆功能的治疗方法尚不存在，部分原因是记忆力不足。 表征受 AD 影响的神经记忆回路活动的研究。 调节特定神经回路的疗法需要研究哪些回路级功能 受到影响，在病理生理进展期间它们表现出损害，以及它们与记忆的关系 内嗅皮层 (EC) 中的神经元充当感觉输入输入到大脑的网关。 该 EC-海马回路对于记忆形成和检索至关重要。 皮层 (LEC) 是 AD 早期萎缩和活动丧失的主要部位，尽管它对 AD 很重要。 AD 病理生理学方面，目前尚不清楚 AD 患者或动物模型的 LEC 中丢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）确定记忆细胞损伤的时间进程 在 APP-KI 小鼠中；以及（目标 2）测试 LEC 多巴胺输入的重新激活是否可以恢复联想记忆 这项研究预计将确定 AD 中 LEC 的神经元功能障碍。 通过侧脑神经调节来挽救记忆功能的疗法的开发取得了进展 内嗅皮层。