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.

在英国，失眠影响了多达30%的成年人口，减少了睡眠的有益影响，增加了白天嗜睡的发生率。经常缺乏睡眠会对身心健康造成严重后果，缩短预期寿命，并使个人面临严重疾病的风险，包括肥胖、糖尿病和心脏病。此外，随着人们年龄的增长，他们往往更难入睡，更难保持睡眠。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昏昏欲睡或被滥用。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。这个项目将研究一种最近被描述的蛋白质，称为QRFP，它在大脑中充当调节唤醒的信使。小鼠是夜间活动的动物，这意味着它们通常在白天睡觉。我们发现，当小鼠在白天服用QRFP时，它们会从睡眠中唤醒。相反，我们培育出了一种不产生QRFP、睡眠时间更长的小鼠：似乎很难在黑夜开始时醒来，而此时小鼠通常是最活跃的。在未来，我们有可能开发出模仿QRFP的作用并帮助人类保持清醒的药物，或者也许能够阻止QRFP的作用并帮助人类获得更多睡眠的药物。由于QRFP是一种天然的信使，其作用似乎具有相对选择性，因此有可能生产出比目前可用的药物危害更小的药物。然而，在这之前，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电路。因此，我们想要了解产生QRFP的细胞(神经元)是如何进入这些回路的。我们培育出了另一种可以控制QRFP神经元的小鼠。首先，这意味着我们可以让QRFP神经元发出荧光光，这样我们就可以切开大脑切片，看到细胞在哪里，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在一起，这些细胞在影响觉醒方面具有既定的作用。此外，QRFP神经元将长纤维发送到大脑中控制清醒的遥远部分。因此，他们似乎处于有利地位。然而，仅仅因为它们向大脑的这些其他部分发送纤维并不意味着它们在功能上是相互联系的。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，类似于在人眼中发现的受体。通过向细胞体照射蓝光，我们可以让QRFP神经元开始放电，并测量这对睡眠和唤醒的影响。此外，我们还可以通过在大脑的特定靶区照射蓝光来激活含有QRFP的纤维。如果这反过来开启了靶区中其他类型的神经元，那么我们可以肯定它们在功能上是相互连接的，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，并测量它们对不同激素和药物的反应，这些激素和药物已经知道会影响睡眠和清醒。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