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患者S等神经退行性疾病的保护因素。人们越来越多地认识到睡眠的重要性，但我们对睡眠的神经元调节知之甚少。致命的家族性失眠(FFI)就说明了这一点。FFI是一种遗传性Pron病，在中年突然发病。受影响的人完全失去恢复性睡眠，并在几个月到几年内死亡。目前的睡眠调节模型无法解释这种前所未有的睡眠能力丧失。目前可用的睡眠药物对FFI患者基本上无效。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一般理解，对于改善FFI患者的治疗是必要的，也可能是有更常见睡眠病理的患者。由于缺乏合适的动物模型，FFI研究的进展一直受到阻碍。最近，一种基因敲入的小鼠模型被引入，作为该疾病的第一个遗传动物模型。到目前为止，还不知道这种小鼠是否会复制人类患者存在的明显睡眠中断。该项目旨在利用脑电/肌电(EEG/EMG)记录，彻底表征FFI小鼠的睡眠表型，以及它对睡眠-稳态系统的实验挑战的反应能力。此外，FFI突变对睡眠-觉醒调节脑区功能的影响将通过Fos免疫组织化学进行评估。将FFI小鼠与野生型对照小鼠以及普恩基因敲除小鼠进行比较，可以区分突变的功能丧失和功能获得的影响。

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.