Experimental sleep fragmentation and cognition in aged marmosets

摘要 老年人经常经历睡眠障碍，这会导致与年龄相关的认知 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， 睡眠障碍是否会导致阿尔茨海默病患者的认知障碍和神经病理尚不清楚。确实如此 人类研究无法确定睡眠障碍是在阿尔茨海默病发生之前还是之后发生 病理学。确定将睡眠片断和疾病进展联系起来的准确事件序列是一个 在更好地了解AD的病因和确定新的治疗靶点方面迈出了关键的一步。在动物身上的研究 需要模型来研究这个问题。啮齿类动物有助于识别潜在的 睡眠与大脑功能之间的关系，但也有局限性，因为与 人类在睡眠、认知和脑老化方面的表型。使用更具翻译性的动物模型 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关键的新见解 驾驶广告时的骚乱。常见的绒猴(Callithrix Jacchus)非常适合作为这样的模型。这 非人灵长类动物白天表现出单相睡眠，在几个认知领域显示出与年龄相关的下降， 并具有AD神经病理的两个特征，即淀粉样蛋白β沉积和 过度磷酸化的tau蛋白。此外，它的寿命短，大约10-12年，是纵向的理想选择 学习。绒猴将安装一个活动记录仪来监测睡眠/觉醒模式。猴子们将会是 在它们家笼子里的触摸屏上接受了一系列认知任务的训练。在基线记录之后 对于睡眠和认知表现，他们将被随机分配到睡眠碎片(SF)或不受干扰 睡眠(对照组)组。SF组将长期处于睡眠中断的状态，旨在模仿 AD患者睡眠碎裂，而对照组则保持不受干扰。生理和心理上的变化 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绒猴的有效性 作为翻译的临床前模型，用于未来的研究，重点是SF在AD神经病理学中的作用。这个 这种模型的可用性对于确定临床上的预防或治疗策略将是至关重要的。 切合实际。

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.