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

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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.