Genetics of sleep and sleep disorders

Abstract

Sleep remains one of the least understood phenomena in biology--even its role in synaptic plasticity remains debatable. Since sleep was recognized to be regulated genetically, intense research has launched on two fronts: the development of model organisms for deciphering the molecular mechanisms of sleep and attempts to identify genetic underpinnings of human sleep disorders. In this Review, we describe how unbiased, high-throughput screens in model organisms are uncovering sleep regulatory mechanisms and how pathways, such as the circadian clock network and specific neurotransmitter signals, have conserved effects on sleep from Drosophila to humans. At the same time, genome-wide association studies (GWAS) have uncovered ∼14 loci increasing susceptibility to sleep disorders, such as narcolepsy and restless leg syndrome. To conclude, we discuss how these different strategies will be critical to unambiguously defining the function of sleep.

Figure 1. An example of a conserved mechanism underlying sleep

In both Drosophila and mammals, an arousal promoting peptide (PDF and hypocretin, respectively) is secreted by cells within, or in the vicinity of, the central clock network. In mammals, hypocretin-producing neurons in the lateral hypothalamus receive circadian inputs from the central clock in the suprachaismatic nucleus (SCN) via the Dorsomedial Hypothalamus (DMH). They are inhibited by GABAergic inputs from the ventrolateral preoptic (VLPO) area. In Drosophila, the large ventral lateral neurons (lLNvs) are part of the clock network although they are not required for free-running circadian rhythms. Instead they mediate light-driven arousal, at least in part through the release of PDF. As in mammals, GABAergic inputs to these neurons promote sleep.