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生物学上一个尚未解开的谜团。为什么人类一生中有三分之一的时间处于深度无意识的状态，这让他们变得脆弱和危险？我们从中得到了什么？我们仍然没有这个问题的答案，但我们认为这肯定是非常重要的事情，也认为睡眠似乎不仅是人类的必需品，也是所有动物的必需品--包括果蝇。睡眠的一个特别耐人寻味的进化保守特征是我们所说的“睡眠动态平衡”，即：基于先前的睡眠量对睡眠压力的先天调节。如果我们睡了很长时间，我们可能会在晚上更难入睡；相反，如果我们在周日晚上彻夜狂欢，第二天早上我们在办公室就会很难熬。在所有动物中，睡眠被认为受两个独立的机制控制：一个是自我平衡调节器，另一个是昼夜节律调节器。这种所谓的“两个过程模型”是由Borbély在30多年前提出的，至今仍被普遍认为是睡眠调节的参考模型。然而，在其形成30年后，这个模型背后的生物学基础仍然难以捉摸，我们仍然忽视了动态平衡和昼夜节律过程是如何在细胞和生物水平上整合的。这两种控制睡眠压力的内在驱动力是如何在细胞水平上整合的？参与这一过程的神经元和基因是什么？我们最近描述了一种新基因的特征，它似乎与这一过程有关--尼娜nanna源于意大利语中摇篮曲的意思。NINNA nanna基因立即在果蝇的大脑中表达，但功能上重要的神经回路似乎包括与生物钟有关的神经元和与动态平衡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，预计与略有不同的分子有亲和力。我们认为这些分子(NADH和NADPH)可以作为睡眠压力的分子标记，例如当我们或多或少疲倦时，睡眠压力的增加或减少。这是第一次勾勒出整合支持睡眠调节的两个过程的神经元电路，我们的目标是对其进行更详细的研究，以最终了解睡眠的生物学。

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.