Local sleep homeostasis and single cell rest

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Sleep and wake are strictly regulated processes. The need for sleep ("sleep pressure") increases gradually during the periods that we are awake, as reflected by us feeling tired. However, this sleep need dissipates when we sleep, reaching the lowest levels just before we wake up fresh and rested. It has therefore been proposed that sleep is necessary for various restorative processes, which include metabolic recovery and renormalisation of brain functions. Suppressed immune function, reduced mood, and increased risk of obesity and cardiovascular disease are only a few of many detrimental effects resulting from chronic sleep deprivation or disrupted and mistimed sleep. Most direct evidence for the immediate consequences of sleep deprivation comes from psychological experiments. Impairments range from the slowing of responsiveness, reduced attention and increased variability in task performance, to the reduction of higher order brain functions such as executive functions, memory or emotional control. This indicates that the brain is among the first targets that are impacted by sleep deprivation. However, despite this extensive knowledge of the importance of sleep, much controversy remains about the biological mechanisms that convey the numerous benefits of sleep to the brain and body.The predominant idea that sleep plays a "restorative" role fits well with our subjective experience. However, the question remains: what precisely needs to be restored after a period of wakefulness and how do restorative changes occurring at the level of individual cells benefit from a global shut down occurring during sleep? We have recently advanced a new hypothesis that the biological function of sleep is to allow for vital "repair and maintenance" of the neurons in our brains. We have also proposed that these repair functions can only occur if the rest periods of individual neurons are aligned precisely at a time scale of seconds or less. The reasoning for this is that we have billions of neurons in our brain, and each of them is connected with thousands of other neurons, all of whom are constantly talking to one another. Therefore, it appears that our neurons cannot rest and repair themselves independently, but must shut down at the same time so that they do not disturb one another and allow each individual cell to obtain the rest it needs. The flip side of this is that when areas of our brain are unable to "fall asleep", they remain in a state of "local wakefulness" that leads to us experiencing a bad night's sleep. Indeed, there are intriguing parallels between the repair processes in brain cells after waking and those observed in muscle cells after exercise. However, whilst you can rest your muscles while being awake, to rest the brain during waking is much more difficult. If neurons attempt to obtain rest while we are awake, it is not only much less efficient but also has serious negative effects on our performance. Similar phenomena can be found outside of biology. The London Underground system, for example, can only function properly during the day because it has extensive maintenance every night, during which all trains stop running between the interconnected stations. We suggest that sleep allows a similar period of maintenance for the brain. In our project we will combine expertise in cutting edge techniques, including electrophysiology, molecular-genetics and pharmacology, and will perform research at several distinct scales - from single cells, to local networks of cells, to the behaviour of the organism. Our project will thus make a major advance in the field of sleep neuroscience and the knowledge obtained will benefit numerous clinical applications that are concerned with the prevention and treatment of sleep disturbances, including improving the management of sleep in shift workers and the prognosis of patients suffering from neurodegenerative disorders, such as Alzheimer's disease.