Mitochondrial energy metabolism, redox state and sleep

睡眠障碍日益普遍，多达三分之二的成年人睡眠中断。睡眠障碍伴随着正常的衰老，也是包括代谢障碍、阿尔茨海默氏症、帕金森氏症、抑郁症和焦虑症在内的多种疾病的特征。睡眠不足会对健康产生许多负面影响，包括白天睡眠增加，认知功能受损，患糖尿病、肥胖症和道路交通事故的风险更高。已经证实，治疗睡眠障碍有好处，但目前的药物受到过度镇静、健忘和成瘾等副作用的限制。这个项目旨在更好地了解哺乳动物模型中睡眠是如何控制的。通过确定控制稳态睡眠驱动的过程，我们希望确定新的目标，以开发改善睡眠障碍的药物，并希望这种治疗将减少与睡眠剥夺相关的风险。背景一般认为，有两个主要的神经系统控制睡眠：生物钟使身体内部的每日节律与太阳的节律保持一致，使睡眠尤其能够在黑暗中发生；以及确保充足睡眠发生的动态平衡过程。体内平衡过程应该测量经历的睡眠剥夺的量，一旦达到足够的阈值，就允许从唤醒状态切换到睡眠状态。然后，睡眠应重置交换机。在哺乳动物中，形成这种稳态的睡眠依赖变量和感应器尚未完全描述。之前的研究已经发现，下丘脑是脑干的一部分，对控制人类的睡眠非常重要，在衰老和阿尔茨海默病中，这一区域的神经元丢失与睡眠减少和支离破碎有关。对果蝇的研究发现，在与哺乳动物下丘脑相似的区域中，有一组神经元，当激活时，会导致睡眠。此外，睡眠剥夺增加了这些细胞中氧化剂的浓度，氧化剂水平的增加增加了神经元的活动，为了解果蝇的自稳机制提供了线索。因此，该项目将重点研究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.