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) 患者在疾病早期会出现空间定向障碍 过程。在人类和啮齿类动物的 AD 模型中，压后皮层 (RSC) 内的功能障碍是一个关键因素。 在认知能力下降之前观察到空间导航和记忆的轨迹。了解 RSC 功能障碍的机制对于制定旨在改善空间的策略非常重要 公元中的导航和记忆。我们观察到异常的 RSC 网络活动，包括 RSC 节律减少 AD 小鼠模型空间导航过程中的同步性，但这些的细胞和分子基础 缺陷未知。在这里，我们使用新开发的小鼠品系，鉴定了 RSC 的特定群体 表达食欲素 1 受体 (RSCOX1R) 并被神经肽食欲素激活的神经元。在WT中 小鼠中，直接刺激这些 RSCOX1R 神经元可增强 RSC 同步性，表明这些神经元是 重要人群，在其中检查 AD 相关 RSC 功能障碍的细胞机制，并针对 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、 食欲素信号传导异常与 AD 病理有关。特定食欲素调节的研究 然而，AD 缺乏记忆电路。在这个提案中，我们检查 RSCOX1R 神经元是否直接 AD 的 5xFAD 模型发生了改变（目标 1）。我们还测试了 RSCOX1R 神经元激活的假设 或增强 RSC 神经元的食欲素信号/调节可以恢复 RSC 中与 AD 相关的缺陷 有节奏的活动（目标 2）。这项工作的完成将为更大规模的后续研究铺平道路 AD 的多种模型，有可能确定新的 RSC 和基于食欲素的疗法，旨在 改善 AD 患者的一系列空间记忆和认知缺陷。