Hunt for mammalian sleep-regulating genes

Genetics is one of the various approaches adopted to understand and control mammalian sleep. Reverse genetics, which is usually applied to analyze sleep in gene-deficient mice, has been the mainstream field of genetic studies on sleep for the past three decades and has revealed that various molecules, including orexin, are involved in sleep regulation. Recently, forward genetic studies in humans and mice have identified gene mutations responsible for heritable sleep abnormalities, such as SIK3, NALCN, DEC2, the neuropeptide S receptor, and β1 adrenergic receptor. Furthermore, the protein kinase A-SIK3 pathway was shown to represent the intracellular neural signaling for sleep need. Large-scale genome-wide analyses of human sleep have been conducted, and many gene loci associated with individual differences in sleep have been found. The development of genome-editing technology and gene transfer by an adeno-associated virus has updated and expanded the genetic studies on mammals. These efforts are expected to elucidate the mechanisms of sleep–wake regulation and develop new therapeutic interventions for sleep disorders.