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: 10469570
• 负责人: Agnes Lacreuse
• 金额: $ 19.94万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469570
• 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; Persons; 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.

概括 老年人经常出现睡眠障碍，这会导致与年龄相关的认知能力下降 下降并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。 睡眠障碍是否会导致 AD 的认知障碍和神经病理学确实尚不清楚。 人类研究无法确定睡眠障碍是在 AD 发生之前还是之后发生 确定睡眠碎片和疾病进展之间的精确事件顺序是一个病理学。 更好地了解 AD 的病因学和确定新的动物治疗靶点的关键一步。 需要模型来研究这个问题，这有助于确定潜在的基本机制。 睡眠与大脑功能之间的关系，但由于与睡眠和大脑功能之间的巨大差异，也存在局限性。 人类在睡眠、认知和大脑老化表型方面使用更具转化性的动物模型。 对于睡眠，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 普通狨猴（Callithrix jacchus）非常适合作为这样的模型。 昼夜非人类灵长类动物表现出单相睡眠，在几个认知领域表现出与年龄相关的衰退， 并具有 AD 神经病理学的两个特征：淀粉样蛋白沉积和淀粉样蛋白积累 此外，其约 10-12 年的短寿命非常适合纵向。 研究中，狨猴将配备体动记录仪来监测猴子的睡眠/觉醒模式。 基线记录后，他们在家里的笼子里接受了一系列认知任务的训练。 根据睡眠和认知表现，他们将被随机分配到睡眠碎片 (SF) 或不受干扰的睡眠 睡眠（对照组）组将长期处于旨在模仿的睡眠中断时期。 AD患者的睡眠是碎片化的，而对照组则保持生理和生理变化不受干扰。 认知功能将在整个实验过程中进行评估。拟议的研究应该验证狨猴的有效性。 作为未来研究的转化临床前模型，重点关注 SF 在 AD 神经病理学中的作用。 这种模型的可用性对于确定临床上的预防或治疗策略至关重要 相关的。