Experimental sleep fragmentation and cognition in aged marmosets

老年狨猴的实验性睡眠碎片和认知

• 批准号: 10300344
• 负责人: Agnes Lacreuse
• 金额: $ 23.93万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300344
• 关键词: Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Animal Model; Attention; Automobile Driving; Behavior; Behavioral; Brain; Callithrix; Callithrix jacchus jacchus; Chronic; Cognition; Cognitive; Cognitive deficits; Control Groups; Development; Devices; Disease Progression; Elderly; Etiology; Event; Exhibits; Experimental Designs; Exposure to; Functional disorder; Future; Home; Human; Impaired cognition; Impairment; Inflammation; Inflammatory; Learning; Link; Longevity; Longitudinal Studies; Measures; Memory; Metabolic; Metabolism; Modeling; Monkeys; Mus; Patients; Pattern; Peripheral; Phenotype; Physiological; Physiology; Play; Polysomnography; Pre-Clinical Model; Primates; Procedures; Process; Randomized; Rattus; Rodent; Role; Sleep; Sleep Disorders; Sleep Fragmentations; Sleep Wake Cycle; Sleep disturbances; Social Interaction; Testing; Therapeutic; Training; Validation; abeta deposition; actigraphy; age related; aged; aging brain; clinically relevant; cognitive function; cognitive performance; cognitive task; design; emotion regulation; executive function; experience; experimental study; hyperphosphorylated tau; hypocretin; insight; middle age; neuropathology; new therapeutic target; nonhuman primate; sleep pattern; sleep regulation; tau Proteins; therapeutic target; touchscreen; translational model

SUMMARY Elderly people frequently experience sleep disturbances, which contribute to age-related cognitive decline and are thought to be a core component of Alzheimer's disease (AD) and its pathophysiology. However, whether sleep disturbances cause cognitive impairment and neuropathology in AD remain unclear. Indeed human studies are unable to determine whether sleep disturbances precede or follow the development of AD pathology. Identifying the precise sequence of events linking sleep fragmentation and disease progression is a crucial step in better understanding the etiology of AD and identifying new therapeutic targets. Studies in animal models are needed to investigate this issue. Rodents are useful to identify basic mechanisms underlying the relationships between sleep and brain function, but also have limitations due to substantial differences from humans in sleep, cognitive and brain aging phenotypes. Using a more translational animal model with regards to sleep, cognitive function and neuropathology would likely provide critical new insights into the role of sleep disturbances in driving AD. The common marmoset (Callithrix jacchus) is ideally suited as such a model. This diurnal nonhuman primate exhibits monophasic sleep, shows age-related decline in several cognitive domains, and possesses two hallmarks of AD neuropathology, amyloid-β deposition and accumulation of hyperphosphorylated tau proteins. In addition, its short lifespan of about 10-12 years is ideal for longitudinal studies. Marmosets will be fitted with an actigraphy device to monitor sleep/wake patterns. The monkeys will be trained on a battery of cognitive tasks administered on touchscreens in their home cage. After baseline recording of sleep and cognitive performance, they will be randomly assigned to a sleep fragmentation (SF) or undisturbed sleep (control) group. The SF group will be chronically exposed to periods of disrupted sleep designed to mimic fragmented sleep in AD patients, whereas the control group will be kept undisturbed. Changes in physiology and cognitive function will be assessed throughout the experiment. The proposed study should validate the marmoset as a translational preclinical model for future studies focusing on the role of SF on AD neuropathology. The availability of such a model will be crucial for identifying preventative or therapeutic strategies that are clinically relevant.

总结 老年人经常经历睡眠障碍，这有助于与年龄相关的认知障碍。 下降，被认为是阿尔茨海默病（AD）及其病理生理学的核心组成部分。然而，在这方面， 睡眠障碍是否导致AD的认知障碍和神经病理学尚不清楚。确实 人类研究不能确定睡眠障碍是在AD发展之前还是之后 病理确定睡眠片段化和疾病进展之间的确切事件顺序是一项重要的研究。 这是更好地了解AD病因和确定新治疗靶点的关键一步。动物研究 需要模型来研究这个问题。啮齿类动物有助于确定 睡眠与大脑功能之间的关系，但由于与大脑功能的实质性差异，也存在局限性 人类在睡眠、认知和大脑老化表型中的作用。使用一个更平移的动物模型， 认知功能和神经病理学可能会为睡眠的作用提供重要的新见解 驾驶AD的障碍。普通的绒猴（Callithrix jacchus）是理想的适合作为这样的模型。这 昼夜非人灵长类动物表现出双相睡眠，在几个认知领域表现出与年龄相关的下降， 并且具有AD神经病理学的两个标志，淀粉样蛋白-β沉积和 过度磷酸化的tau蛋白。此外，其约10-12年的短寿命是纵向的理想选择。 问题研究绒猴将配备活动记录仪，以监测睡眠/觉醒模式。猴子们会 在笼子里的触摸屏上接受认知任务训练。基线记录后 睡眠和认知表现，他们将被随机分配到睡眠片段（SF）或不受干扰 睡眠对照组。SF组将长期暴露于睡眠中断期， 在AD患者中进行片段睡眠，而对照组将保持不受干扰。生理变化和 在整个实验中评估认知功能。这项拟议中的研究将验证绒猴 作为未来研究的转化临床前模型，重点关注SF对AD神经病理学的作用。的 这种模型的可用性将是至关重要的，以确定预防或治疗策略， 相关的