Dysfunctional Orexin-Regulated Neural Circuits in Alzheimer's Disease

阿尔茨海默病中食欲素调节的神经回路功能失调

• 批准号: 10372270
• 负责人: Paulette B. Goforth
• 金额: $ 15.6万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372270
• 关键词: Affect; Age; Age-Months; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Area; Arousal; Autopsy; Calcium; Cell physiology; Cerebrospinal Fluid; Cognitive deficits; Data; Defect; Development; Disease; Disorientation; Down-Regulation; Electrophysiology (science); Exhibits; Follow-Up Studies; Functional disorder; Health; Image; Impaired cognition; Impairment; Infusion procedures; Knowledge; Lead; Lesion; Mediating; Memory; Memory impairment; Molecular; Mus; Neuronal Dysfunction; Neurons; Neuropeptides; Pathway interactions; Periodicity; Persons; Physiological; Physiological Processes; Population; Preparation; Process; Regulation; Rodent Model; Role; Shapes; Signal Transduction; Slice; Spatial Behavior; Symptoms; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Work; antagonist; base; experience; human model; hypocretin; improved; in vivo; mouse model; network dysfunction; neural circuit; novel; optogenetics; orexin 1 receptor; preservation; prevent; receptor; relating to nervous system; repaired; response; spatial memory; targeted treatment; therapeutic target; way finding

Persons with Alzheimer's Disease (AD) experience spatial disorientation that emerges early in the disease process. In both humans and rodent models of AD, dysfunction within the retrosplenial cortex (RSC), a crucial locus for spatial navigation and memory, is observed prior to the onset of cognitive decline. Understanding the mechanisms underlying RSC dysfunction is important to develop strategies aimed at improving spatial navigation and memory in AD. We observe aberrant RSC network activity that includes reduced RSC rhythmic synchrony during spatial navigation in a mouse model of AD, yet the cellular and molecular basis for these defects are unknown. Here, using a newly developed mouse line, we identify a specific population of RSC neurons that express the orexin 1 receptor (RSCOX1R) and are activated by the neuropeptide orexin. In WT mice, direct stimulation of these RSCOX1R neurons enhances RSC synchrony, suggesting these neurons are an important population in which to examine cellular mechanisms of AD-related RSC dysfunction, and to target for therapeutic intervention. Orexin signaling affects numerous physiologic processes, including spatial memory, and abnormalities in orexin signaling are implicated in AD pathology. Studies of specific orexin-regulated memory circuits in AD is lacking, however. In this proposal, we examine whether RSCOX1R neurons are directly altered in the 5xFAD model of AD (Aim 1). We also test the hypothesis that the activation of RSCOX1R neurons or enhancement of orexin-signaling/regulation of RSC neurons can restore the AD-associated deficits in RSC rhythmic activity (Aim 2). The completion of this work will pave the way for larger-scale follow up studies across multiple models of AD, with the potential to identify novel RSC and orexin-based therapies aimed at ameliorating a range of spatial memory and cognitive deficits in persons with AD.

阿尔茨海默病（AD）患者在疾病早期出现空间定向障碍 过程在人类和啮齿动物AD模型中，压后皮质（RSC）功能障碍，一个关键的神经元， 空间导航和记忆的位点，在认知衰退开始之前观察到。了解 RSC功能障碍的潜在机制对于开发旨在改善空间分布的策略是重要的。 导航和记忆我们观察到异常的RSC网络活动，包括降低RSC节律性 在AD小鼠模型中，空间导航期间的同步性，但这些的细胞和分子基础 缺陷是未知的。在这里，使用一个新开发的小鼠系，我们确定了一个特定的人口RSC 表达食欲素1受体（RSCOX 1 R）并被神经肽食欲素激活的神经元。以WT 在小鼠中，直接刺激这些RSCOX 1 R神经元可增强RSC的同步性，这表明这些神经元是一种 研究AD相关RSC功能障碍的细胞机制，并靶向 治疗干预食欲素信号传导影响许多生理过程，包括空间记忆， 增食欲素信号传导异常与AD病理学有关。特定食欲素调控的研究 然而，AD中的存储器电路是缺乏的。在这个提议中，我们研究RSCOX 1 R神经元是否直接 在AD的5xFAD模型中改变（目的1）。我们还检验了RSCOX 1 R神经元的激活 或增强RSC神经元的食欲素信号传导/调节可以恢复RSC中AD相关的缺陷 节奏活动（目标2）。这项工作的完成将为跨区域更大规模的后续研究铺平道路。 多种AD模型，有可能确定新的RSC和基于食欲素的治疗方法， 改善AD患者的一系列空间记忆和认知缺陷。