Mitochondrial energy metabolism, redox state and sleep

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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.