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

项目摘要 阿尔茨海默病(AD)是最常见的痴呆症，目前在美国影响着约600万人， 预计到2050年将增加两倍。一个毁灭性的症状是逐渐丧失形成的能力 回忆。目前尚不存在挽救AD患者记忆功能的治疗方法，部分原因是治疗不足 研究阿尔茨海默病影响的神经记忆回路的活动。发展中的记忆恢复 调节特定神经回路的治疗需要研究哪些电路水平的功能 在病理生理过程中，它们何时表现出损害，以及它们与记忆的关系 性能。内嗅觉皮质(EC)中的神经元是感觉输入输入到 海马体。这种EC-海马体回路对于记忆的形成和恢复至关重要。侧内嗅觉 大脑皮层(LEC)是AD早期萎缩和活动丧失的主要部位。尽管它对 在病理生理学方面，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。 所提出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多巴胺输入重新激活是否恢复联想记忆 队形。这项研究有望确定AD患者LEC的神经元功能障碍。该项目预计将 在开发通过外侧区神经调节挽救记忆功能的治疗方法方面取得进展 内嗅皮层。

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.