Sleep Regulation in the Genetic Mouse Model for Fatal Familial Insomnia

最近的研究结果表明，健康的睡眠对身心健康非常重要，特别是作为预防阿尔茨海默氏症等神经退行性疾病的保护因素。睡眠的重要性日益得到重视，但我们对睡眠的神经调节却知之甚少。这是由致命的家族性失眠症（FFI）。FFI是一种在中年突然发病的遗传性朊病毒病。受影响的人完全失去恢复性睡眠，并在几个月至几年内死亡。目前的睡眠调节模型无法解释这种无与伦比的睡眠能力丧失。目前可用的睡眠药物在FFI患者中基本无效。更好地了解FFI的神经病理机制有望提高我们对睡眠调节的总体理解，并且对于改善FFI患者以及可能患有更常见睡眠病理的患者的治疗是必要的。由于缺乏合适的动物模型，FFI研究的进展受到阻碍。最近，基因敲入小鼠模型被引入作为该疾病的第一个遗传动物模型。到目前为止，还不知道这只小鼠是否复制了人类患者中存在的明显的睡眠中断。该项目旨在使用脑电图/肌电图（EEG/EMG）记录彻底表征FFI小鼠的睡眠表型及其对睡眠稳态系统实验挑战的反应能力。此外，将使用Fos免疫组织化学评估FFI突变对睡眠-觉醒调节脑区域功能的影响。FFI小鼠与野生型对照以及朊病毒敲除小鼠的比较将允许区分突变的功能丧失和功能获得效应。

Recent findings imply that healthy sleep is highly important for physical and mental health, particularly as a protective factor against neurodegenerative diseases like Alzheimer´s. The growing recognition of the importance of sleep is contrasted by our insufficient knowledge of its neuronal regulation. This is illustrated by fatal familial insomnia (FFI). FFI is a hereditary prion disease with abrupt onset at midlife. Affected individuals completely lose restorative sleep and die within months to a few years. Current models of sleep regulation cannot explain this unparalleled loss of the ability to sleep. Currently available sleep medication is largely ineffective in FFI patients. A better understanding of the neuropathological mechanisms of FFI is expected to improve our general understanding of sleep regulation and is necessary to improve treatment for FFI patients and possibly also patients with more common sleep pathologies. Progress in FFI research has been hampered by the lack of appropriate animal models. Recently, a knock-in mouse model was introduced as the first genetic animal model for the disease. To date, it is not known whether this mouse replicates the pronounced sleep disruption present in human patients. This project aims to thoroughly characterize the sleep phenotype of the FFI mouse and its ability to respond to experimental challenges to the sleep-homeostatic system, using electroencephalographic/electromyographic (EEG/EMG) recordings. Further, effects of the FFI-mutation on the function of sleep-wake regulatory brain regions will be assessed using Fos immunohistochemistry. Comparison of the FFI mouse with wild type controls as well as prion knock-out mice will allow differentiating between loss-of-function and gain-of-function effects of the mutation.