Research Progress on the Molecular Pathways Regulating Mammalian Sleep–Wake Rhythms

Abstract

The mammalian brain governs the timing of sleep and wakefulness with considerable precision, yet the mechanism underlying this timing is not a single switch. Work over the past two decades has uncovered a layered molecular architecture in which neurotransmitter systems, neuropeptide signaling, and circadian clock genes play distinct but interacting parts. Three pathways are examined here, and their coordination sustains the sleep–wake rhythm. Sleep onset falls to GABAergic inhibitory circuits organized around the ventrolateral preoptic nucleus (VLPO), a small hypothalamic cell group whose reciprocal inhibition of arousal nuclei has been modeled as a bistable switch. Wakefulness is held in place by orexin (hypocretin) neurons of the lateral hypothalamus, and the translation of this pathway into dual orexin receptor antagonists (DORAs)—suvorexant and daridorexant—has given insomnia pharmacotherapy a new drug class. Beneath both lies a cell-autonomous molecular clock built from CLOCK, BMAL1, PER and CRY, which generates endogenous rhythmicity through a transcription–translation feedback loop (TTFL); across mammalian species, free-running periods usually fall between 22 and 26 hours. Three advances have reshaped the field in the past five years. MARK2 has been identified as the kinase phosphorylating PER2 at S662—the long-sought FASP-site kinase. Single-cell transcriptomics has traced homeostatic sleep pressure to mitochondrial metabolism. Network meta-analysis across more than 5,000 randomized patients has confirmed DORA efficacy and safety.