Distinct forebrain system regulating arousal

点击翻译按钮获取中文摘要

Insomnia affects up to 30% of the adult population in the UK, reducing the beneficial effects of sleep and increasing the incidence of daytime drowsiness. Regular lack of sleep has profound consequences for physical and mental health, shortens life expectancy and puts individuals at risk of serious medical conditions, including obesity, diabetes and heart disease. Furthermore, as people age, they tend to have a harder time falling asleep and more trouble staying asleep. Many older adults report being less satisfied with sleep and more tired during the day. There are effective drugs to help people to get to sleep at night, or alternatively to help them stay awake during the day. However, long-term use of these drugs can be dangerous as can cause drowsiness or they may be abused. Thus, it is imperative that we are able to understand and, ultimately, better regulate our sleep either by lifestyle changes or with safer drugs. This project will study a recently described protein, called QRFP that acts in the brain as a messenger to regulate arousal.Mice are nocturnal animals, meaning that they are normally asleep during the day. We have found that when mice are given QRFP during the daytime they become aroused from their sleep. Conversely, we have bred a mouse that does not produce QRFP and which displays more sleep: it appears to find it difficult to wake up at the beginning of the night, when mice are usually their most active. There is a possibility that, in the future, we may be able to develop drugs which mimic the effects of QRFP and help humans stay awake, or perhaps drugs which block the action of QRFP and help humans get more sleep. As QRFP is a natural messenger and seems to be relatively selective in its effects, it may be possible to produce drugs which are less dangerous than those currently available. However, before that can happen, we must get a better understanding of how QRFP functions in the brain.We already know about some of the complex circuits in the brain that control sleep and wakefulness. So, we want to learn how the cells (neurones) which produce QRFP fit into these circuits. We have bred another type of mouse which allows us to control QRFP neurones. Firstly, this means we can make QRFP neurones "shine" fluorescently so that we can cut slices of brain, see where the cells are and make recordings of their electrical activity. We have found that QRFP neurones are located exclusively in a small area of the brain, called the hypothalamus, where they intermingle with other cells which have an established role in affecting arousal. Also, QRFP neurones send long fibres to distant parts of the brain that control wakefulness. Thus, they would appear to be well placed. However, just because they send fibres to these other parts of the brain does not mean that they are functionally connected. To test this we can make QRFP neurones express a special light-sensitive receptor, similar to that which is found in the human eye. By shining a blue light on the cell bodies we can make QRFP neurones start firing and measure what affect this has on sleep and arousal. Moreover, we can also activate QRFP-containing fibres by shining the blue light in specific target regions of the brain. If this, in turn, switches on other types of neurone in the target regions then we can be sure that they a functionally connected and regulated by QRFP neurones. Finally, we can record from QRFP neurones in brain slices and measure how they respond to different hormones and drugs which are already known to affect sleep and wakefulness. Together this information will teach us about the physiology of QRFP that will underpin future development of QRFP as a potential drug for use in humans.