Distinct forebrain system regulating arousal

在英国，失眠影响了多达30%的成年人，减少了睡眠的有益影响，增加了白天嗜睡的发生率。经常缺乏睡眠对身心健康有着深远的影响，缩短了预期寿命，并使个人面临严重的医疗条件，包括肥胖，糖尿病和心脏病。此外，随着年龄的增长，人们往往更难入睡，更难保持睡眠。许多老年人报告对睡眠不满意，白天更累。有一些有效的药物可以帮助人们在晚上入睡，或者帮助他们在白天保持清醒。然而，长期使用这些药物可能是危险的，因为可能会导致嗜睡或滥用。因此，我们必须能够理解并最终通过改变生活方式或使用更安全的药物来更好地调节我们的睡眠。该项目将研究一种最近描述的蛋白质，称为QRFP，它在大脑中作为信使调节唤醒。老鼠是夜行动物，这意味着它们通常在白天睡觉。我们发现，当老鼠在白天服用QRFP时，它们会从睡眠中醒来。相反，我们培育了一只不产生QRFP的小鼠，它表现出更多的睡眠：它似乎很难在夜晚开始时醒来，而这时候小鼠通常是最活跃的。在未来，我们有可能开发出模仿QRFP作用的药物，帮助人类保持清醒，或者阻止QRFP作用的药物，帮助人类获得更多的睡眠。由于QRFP是一种天然的信使，并且其作用似乎具有相对的选择性，因此有可能生产出比目前可用的药物危险性更小的药物。然而，在此之前，我们必须更好地了解QRFP在大脑中的功能，我们已经知道大脑中控制睡眠和觉醒的一些复杂回路。因此，我们想了解产生QRFP的细胞（神经元）如何适应这些回路。我们培育了另一种小鼠，使我们能够控制QRFP神经元。首先，这意味着我们可以让QRFP神经元发出荧光，这样我们就可以切开大脑切片，看到细胞的位置，并记录它们的电活动。我们已经发现，QRFP神经元只位于大脑的一个小区域，称为下丘脑，在那里它们与其他细胞混合，这些细胞在影响唤醒方面具有既定的作用。此外，QRFP神经元将长纤维发送到控制清醒的大脑远端。因此，他们似乎处于有利地位。然而，仅仅因为它们将纤维发送到大脑的其他部分并不意味着它们在功能上是连接的。为了测试这一点，我们可以让QRFP神经元表达一种特殊的光敏受体，类似于人眼中发现的受体。通过在细胞体上照射蓝光，我们可以使QRFP神经元开始放电，并测量这对睡眠和觉醒的影响。此外，我们还可以通过在大脑的特定目标区域照射蓝光来激活含有QRFP的纤维。如果这反过来又打开了靶区域中的其他类型的神经元，那么我们可以肯定它们在功能上是连接的，并受到QRFP神经元的调节。最后，我们可以记录大脑切片中的QRFP神经元，并测量它们对已知影响睡眠和觉醒的不同激素和药物的反应。总之，这些信息将教会我们关于QRFP的生理学，这将支持QRFP作为一种潜在的人类药物的未来发展。

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.