Genetics of sleep regulation and function: the AKR genes in Drosophila

睡眠不需要介绍。我们人类一生中大约三分之一的时间都在睡觉，但没有人知道为什么。令人惊讶的是，尽管经过几十年的研究，睡眠仍然是生物学中最令人困惑的问题之一。虽然人们对睡眠发生的调控机制有所了解，但对睡眠的功能却一无所知：为什么睡眠不足会对身体和大脑产生有害影响？为什么睡眠可以恢复体力？当我们睡觉时，我们的细胞里发生了什么？为什么不同个体的睡眠结构和睡眠需求如此不同？为什么它们会随着年龄的增长而发生如此大的变化？这些问题的答案很可能在我们的基因中：基因活动可能解释了当我们睡觉时细胞水平上发生的事情，以及当我们剥夺自己休息的时候发生的事情。本实验室选择果蝇黑腹果蝇作为动物模型，探索睡眠遗传学。果蝇可以说是最强大和最常用的遗传动物模型。重要的是，果蝇不仅睡觉，而且它们的睡眠极大地让人想起人类的睡眠：果蝇和我们一样在晚上睡觉；它们的睡眠是恢复健康的；睡眠不足会导致不利的表现，并最终导致死亡；它们的睡眠是自我平衡调节的(即，剥夺睡眠的果蝇会有更大的睡眠压力)，重要的是，它们的睡眠受到咖啡因或莫达非尼等已知影响人类睡眠的化合物的药理调节，这表明睡眠的功能和遗传学在进化上是保守的。了解睡眠的基本生物学不仅是一个有趣的科学难题：它也是理解和减轻社交睡眠剥夺、失眠或睡眠障碍的影响的关键--这是当今社会非常迫切的需求。最近，我们发现了一种名为整夜的新基因。通宵基因突变的果蝇睡眠时间比正常果蝇少得多(减少50%)。我们的目标是阐明这一观察背后的生物学原理。我们正在解决的一些问题是：通宵如何调节睡眠时间？整夜的变异苍蝇是如何应对睡眠不足的？彻夜不停地在果蝇的大脑中活动，如果是的话，具体是在什么神经元中？通宵的一般作用机制是什么？在其他物种中是否存在与通宵功能相当的通宵？最后，通宵基因与其他已知的影响苍蝇和啮齿动物睡眠的基因有相似之处：我们的目标也是探索这些联系，认为这将为揭示睡眠功能的奥秘提供一个新的视角。

Sleep needs no introduction. We humans spend about one third of our lifetime asleep but no one knows why. Astonishingly, sleep still remains one of the most puzzling problems of biology despite decades of research. While something is known about the mechanisms regulating occurrence of sleep, nothing is known about its functions: why sleep deprivation has detrimental effects on the body and the brain? Why is sleep restorative? What happens in our cells as we sleep? Why sleep architecture and sleep needs are so different amongst different individuals and why do they change so much as we age? The answer to those questions is likely to be in our genes: gene activity may explain what happens at the cellular level when we sleep and similarly when we deprive ourselves from resting. Our laboratory has chosen to explore genetics of sleep using the fruit fly Drosophila melanogaster as animal model. Drosophila is arguably the most powerful and most commonly used genetic animal model. Importantly, not only do flies sleep but in fact their sleep vastly reminds of human sleep: flies sleep at night like us; their sleep is restorative; sleep deprivation leads to detrimental performances and eventually to death; their sleep is homeostatically regulated (i.e. a sleep deprived fly will have stronger sleep pressure) and, importantly, their sleep is modulated pharmacologically by the same compounds that are known to affect human sleep, such as caffeine or modafinil, suggesting an evolutionary conservation for functions and genetics of sleep. Understanding the basic biology of sleep is not just a fascinating scientific puzzle: it is also key to understand and mitigate the effects of social sleep deprivation, insomnia or sleep disorders - a very pressing need for today's society.Recently we have identified a new gene called allnighter. Flies that are mutant in the allnighter gene sleep considerably less than normal (50% less). We aim to elucidate the biology behind this observation. Some of the questions we are addressing are: how does allnighter work to regulate sleep duration? How do allnighter mutant flies cope with sleep deprivation? Is allnighter acting in the brain of the fly and , if yes, in what neurons exactly? What is the general mechanism of action of allnighter and is there a functional allnighter equivalent in other species? Finally, the allnighter gene shares similarities with other known genes affecting sleep in flies and rodents: we aim at exploring those connections too, arguing this will provide a new perspective on the mystery of sleep function.