Distinct forebrain system regulating arousal

独特的前脑系统调节唤醒

• 批准号: BB/R003858/1
• 负责人: Simon Luckman
• 金额: $ 62.41万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR003858%2F1
• 关键词: Distinct; forebrain; system; regulating; arousal

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.

失眠影响了英国多达30%的成年人，减少了睡眠的有益作用，增加了白天困倦的发生率。经常睡眠不足会对身心健康产生深远影响，缩短预期寿命，并使个人面临罹患严重疾病的风险，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，更难以保持睡眠状态。许多老年人报告说，他们对睡眠不太满意，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，因为它们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。这个项目将研究最近发现的一种叫做QRFP的蛋白质，它在大脑中作为信使调节觉醒。老鼠是夜行动物，也就是说它们通常在白天睡觉。我们发现，当老鼠在白天被给予QRFP时，它们会从睡眠中被唤醒。相反，我们培育了一种不产生QRFP的老鼠，它表现出更多的睡眠：它似乎很难在夜晚开始时醒来，而这通常是老鼠最活跃的时候。有一种可能性是，在未来，我们可能能够开发出模仿QRFP作用的药物，帮助人类保持清醒，或者可能是阻止QRFP作用的药物，帮助人类获得更多的睡眠。由于QRFP是一种天然信使，其作用似乎相对有选择性，因此有可能生产出比现有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清醒的一些复杂回路。因此，我们想了解产生QRFP的细胞（神经元）是如何适应这些回路的。我们培育了另一种老鼠，可以控制QRFP神经元。首先，这意味着我们可以让QRFP神经元发出荧光，这样我们就可以切下大脑的切片，看到细胞在哪里，并记录它们的电活动。我们发现QRFP神经元只位于大脑的一个小区域，叫做下丘脑，在那里它们与其他细胞混合在一起，这些细胞在影响觉醒方面发挥着既定的作用。此外，QRFP神经元将长纤维发送到大脑控制清醒的遥远部分。因此，他们似乎处于很好的位置。然而，仅仅因为它们将纤维输送到大脑的其他部分，并不意味着它们在功能上是相连的。为了验证这一点，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。如果这反过来开启了目标区域中其他类型的神经元，那么我们就可以确定它们在功能上是由QRFP神经元连接和调节的。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清醒的不同激素和药物的反应。总之，这些信息将使我们了解QRFP的生理学，这将为QRFP作为一种潜在的人类药物的未来发展奠定基础。

项目成果

The hypothalamic RFamide, QRFP, increases feeding and locomotor activity: The role of Gpr103 and orexin receptors.

• DOI: 10.1371/journal.pone.0275604
• 发表时间: 2022
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Cook, Chris;Nunn, Nicolas;Worth, Amy A.;Bechtold, David A.;Suter, Todd;Gackeheimer, Susan;Foltz, Lisa;Emmerson, Paul J.;Statnick, Michael A.;Luckman, Simon M.
• 通讯作者: Luckman, Simon M.

Central administration of ghrelin induces conditioned avoidance in rodents.

• DOI: 10.1016/j.euroneuro.2017.05.001
• 发表时间: 2017-08
• 期刊: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
• 作者: Schéle E;Cook C;Le May M;Bake T;Luckman SM;Dickson SL
• 通讯作者: Dickson SL