Abstract：
Central fatigue is a common pathological state characterized by psychological loss of drive, lack of appetite, drowsiness, and decreased psychic alertness. The mechanism underlying central fatigue is still unclear, and there is no widely accepted successful animal model that fully represents human characteristics. We aimed to construct a more clinically relevant and comprehensive animal model of central fatigue. In this study, we utilized the Modified Multiple Platform Method (MMPM) combined with alternate-day fasting (ADF) to create the animal model. The model group rats are placed on a stationary water environment platform for sleep deprivation at a fixed time each day, and they were subjected to ADF treatment. On non-fasting days, the rats were allowed unrestricted access to food. This process was sustained over a period of 21 days. We evaluated the model using behavioral assessments such as open field test, elevated plus maze test, tail suspension test, Morris water maze test, grip strength test, and forced swimming test, as well as serum biochemical laboratory indices. Additionally, we conducted pathological observations of the hippocampus and quadriceps muscle tissues, transmission electron microscope observation of mitochondrial ultrastructure, and assessment of mitochondrial energy metabolism and oxidative stress-related markers. The results revealed that the model rats displayed emotional anomalies resembling symptoms of depression and anxiety, decreased exploratory behavior, decline in learning and memory function, and signs of skeletal muscle fatigue, successfully replicating human features of negative emotions, cognitive decline, and physical fatigue. Pathological damage and mitochondrial ultrastructural alterations were observed in the hippocampus and quadriceps muscle tissues, accompanied by abnormal mitochondrial energy metabolism and oxidative stress in the form of decreased ATP and increased ROS levels. In conclusion, our ADF+MMPM model comprehensively replicated the features of human central fatigue and is a promising platform for preclinical research. Furthermore, the pivotal role of mitochondrial energy metabolism and oxidative stress damage in the occurrence of central fatigue in the hippocampus and skeletal muscle tissues was corroborated.
摘要：
中枢疲劳是一种常见的病理状态，其特征是心理失去动力，缺乏食欲,困倦,精神警觉性下降。中枢疲劳的机制尚不清楚，并且没有被广泛接受的成功动物模型完全代表人类特征。我们的目的是建立一个更具有临床相关性和综合性的中枢疲劳动物模型。在这项研究中,我们利用改良多平台法(MMPM)结合隔日禁食(ADF)建立动物模型.模型组大鼠放置在固定的水环境平台上,每天固定时间进行睡眠剥夺,他们接受了ADF治疗。在非禁食的日子里，允许大鼠不受限制地获取食物。这个过程持续了21天。我们使用行为评估方法对模型进行了评估，例如开场测试，高架加迷宫测试，尾部悬挂试验,莫里斯水迷宫测试，抓地力试验,强迫游泳测试,以及血清生化实验室指标。此外,我们对海马和股四头肌组织进行了病理观察，透射电镜观察线粒体超微结构,并评估线粒体能量代谢和氧化应激相关标志物。结果显示，模型大鼠表现出类似抑郁和焦虑症状的情绪异常，减少探索行为，学习和记忆功能下降，和骨骼肌疲劳的迹象，成功复制负面情绪的人类特征，认知能力下降,和身体疲劳。在海马和股四头肌组织中观察到病理损伤和线粒体超微结构改变，伴随着异常的线粒体能量代谢和氧化应激的形式减少ATP和增加的ROS水平。总之,我们的ADF+MMPM模型全面复制了人类中枢疲劳的特征,是一个有前景的临床前研究平台.此外，证实了线粒体能量代谢和氧化应激损伤在海马和骨骼肌组织中枢疲劳发生中的关键作用。
