The ninna nanna gene: an insight into an archetypal circuit integrating circadian and homeostatic drive to regulate sleep

我们为什么睡觉仍然是一个未解的生物学之谜。为什么人类一生中有三分之一的时间处于极度无意识的状态，这使他们变得脆弱和濒危？我们从中得到了什么？我们仍然没有找到这个问题的答案，但我们认为它一定是非常重要的东西，而且考虑到睡眠似乎不仅对人类，而且对所有动物——包括果蝇——都是必要的。睡眠的一个特别有趣的进化保守特征是我们所说的“睡眠稳态”，也就是说：基于先前睡眠量的先天睡眠压力调节。如果我们睡了一个长时间的午觉，我们可能会在晚上更难入睡；相反，如果我们在周日晚上开通宵派对，第二天早上我们在办公室就会很辛苦。这就是睡眠稳态。在所有动物中，睡眠被认为受到两种独立机制的控制：一种是体内平衡调节机制，另一种是昼夜节律调节机制。这一所谓的“双过程模型”是30多年前由borb郁闷提出的，它仍然被普遍认为是睡眠调节的参考模型。然而，在其提出三十年后，该模型背后的生物学原理仍然难以捉摸，我们仍然忽略了稳态和昼夜节律过程如何在细胞和生物水平上整合。控制睡眠压力的两种内在驱动力是如何在细胞水平上整合的？参与这个过程的神经元和基因是什么？我们最近发现了一种新的基因，它被称为“ninna nanna”，在意大利语中是摇篮曲的意思，它似乎与这个过程有关。ninna nanna基因在果蝇的大脑中一分钟内表达，但功能重要的神经元回路似乎包括与生物钟有关的神经元和与内稳态压力感知有关的神经元。我们不知道该基因的分子功能，但我们知道它编码两种酶，预测它们对略有不同的分子具有亲和力。我们提出这些分子（NADH和NADPH）可以作为睡眠压力的分子标记，例如，当我们感到疲倦或不疲倦时，它们的数量会增加或减少。这是第一次将睡眠调节的两个过程整合在一起的神经元回路被勾画出来，我们的目标是更详细地研究它，最终理解睡眠的生物学。

Why we sleep remains an unresolved mystery of biology. Why do humans have to spend one-third of their lifetime in a status of profound unconsciousness which leaves them vulnerable and endangered? What do we gain from it? We still do not possess an answer to this question but we assume that it must be something tremendously important, also considered that sleep appears to be a necessity not just in humans but in all animals - including fruit flies. A particularly intriguing evolutionary conserved feature of sleep is what we call "sleep homeostasis", that is: the innate modulation of sleep pressure based on previous sleep amount. If we have a good long nap, we may have a harder time falling asleep at night; conversely, if we pull an all-nighter partying on Sunday night, we are going to have a hard time at the office on the following morning. That is sleep homeostasis.In all animals, sleep is considered to be under control of two independent mechanisms: a homeostatic regulator and a circadian regulator. This so-called "two-process model" was formulated more than 30 years ago by Borbély and it is still universally considered the reference model for sleep regulation. However, after three decades from its formulation, the very biology underlying this model remains elusive and we still ignore how the homeostatic and circadian processes integrate at a cellular & biological level. How do the two intrinsic drives that command sleep pressure integrate at a cellular level? What are the neurons and genes involved with this process?We recently characterised a new gene - called "ninna nanna" after the Italian term for lullaby - that appears to be involved with this process. The ninna nanna gene is expressed in the brain of fruitflies in a minute but functionally important neuronal circuit that appears to encompass neurons involved with the circadian clock and neurons involved with the perception of homeostatic pressure.We do not know the molecular function of the gene but we know that encodes for two enzymes with a predicted affinity for slightly different molecules. We propose that these molecules (NADH and NADPH) could work as a molecular marker for sleep pressure, for instance increasing or decreasing in amount when we are more or less tired.This is the first time that a neuronal circuit integrating the two processes underpinning sleep regulation has been sketched and we aim to study it in greater detail to ultimately understand the biology of sleep.