Mitochondrial energy metabolism, redox state and sleep

睡眠障碍越来越普遍，多达三分之二的成年人经历过睡眠中断。睡眠障碍伴随着正常的衰老，也是多种疾病的特征，包括代谢障碍、阿尔茨海默病、帕金森病、抑郁症和焦虑症。睡眠不佳会对健康产生许多负面影响，包括白天嗜睡加剧、认知功能受损以及患糖尿病、肥胖和道路交通事故的风险增加。治疗睡眠障碍已被证明是有益的，但目前的药物受到过度镇静、健忘和成瘾等副作用的限制。该项目旨在更好地理解哺乳动物模型中睡眠是如何被控制的。通过确定控制体内平衡睡眠驱动的过程，我们希望为开发改善睡眠障碍的药物找到新的目标，这样的治疗方法将降低与睡眠剥夺相关的风险。一般认为，有两个主要的神经系统控制着睡眠：生理时钟使身体内部的日常节律与太阳的节律保持一致，使人们在黑暗的时候睡觉；并且，一个保证充足睡眠的体内平衡过程发生了。体内平衡过程应该测量所经历的睡眠剥夺的程度，一旦达到足够的阈值，就允许从清醒状态切换到睡眠状态。然后Sleep应该重置开关。在哺乳动物中，睡眠依赖变量和传感器形成的这种稳态尚未被完全描述。之前的研究已经确定，脑干的一部分下丘脑对控制人类睡眠很重要，而在衰老和阿尔茨海默病中，下丘脑神经元的丧失与睡眠减少和碎片化有关。对苍蝇的研究发现，在一个类似于哺乳动物下丘脑的区域有一组神经元，当它们被激活时，就会导致睡眠。此外，睡眠剥夺会增加这些细胞中氧化剂的浓度，而增加的氧化剂水平会增加神经元的活动，这为果蝇体内的稳态机制提供了线索。因此，本项目将重点关注细胞内氧化剂和抗氧化剂的比例如何控制小鼠下丘脑神经元的活动，并研究该系统是否因此控制睡眠本身。

Sleep disorders are increasingly prevalent, with up to two thirds of adults experiencing disrupted sleep. Sleep disturbance accompanies normal aging and is also a feature of multiple diseases including metabolic disorders, Alzheimer's, Parkinson's, depression and anxiety. Poor sleep can have numerous negative impacts on health, including increased daytime sleepiness, impaired cognitive function and a higher risk of diabetes, obesity and road traffic accidents. There are proven benefits to treating sleep disorders but current medications are limited by side effects of over-sedation, forgetfulness and addiction. This project sets out to better understand how sleep is controlled in a mammalian model. By identifying the processes that control homeostatic sleep drive, we hope to identify novel targets for the development of improved medications for sleep disorders and that such treatments will reduce the risks associated with sleep deprivation. Background It is generally held that there are two main neural systems controlling sleep: the circadian clock aligns the body's internal daily rhythms to those of the sun, enabling, amongst other things, sleep to occur during hours of darkness; and, a homeostatic process that ensures a sufficient quantity of sleep occurs. The homeostatic process should measure the amount of sleep deprivation experienced and, once a sufficient threshold is reached, permit a switch from a wake-state to a sleep-state. Sleep should then reset the switch. In mammals, the sleep-dependent variables and sensor that form this homeostat not fully described. Previous work has identified the hypothalamus, part of the brainstem, as being important for controlling sleep in humans and loss of neurons in this area in aging and in Alzheimer's disease is associated with reduced and fragmented sleep. Research in a flies has identified a group of neurons in an area similar to the mammalian hypothalamus which, when activated, result in sleep. Moreover, sleep deprivation increases the concentration of oxidants in these cells, and the increased levels of oxidants increase the activity of the neurons, providing a clue as to the homeostat mechanism in flies. Therefore, this project will focus on how the ratio of intracellular oxidants and anti-oxidants govern the activity of neurons in the hypothalamus of mice and investigate whether this system thereby controls sleep itself.