Fig. 3 |. Melatonin and orexin signalling in circadian rhythm.

a | Melatonin promotes sleep at night: the nightly release of noradrenaline (NE; in orange) stimulated by the suprachiasmatic nucleus (SCN) induces melatonin synthesis in the pineal gland (blue circle)³⁶. Melatonin functions through activation of two G-protein-coupled receptors, melatonin receptor 1 (MT₁) and melatonin receptor 2 (MT₂) mainly in the SCN^38,39. By interacting with pertussis toxin-sensitive Gα_i, MT₁ receptor can inhibit cAMP-response element-binding protein (CREB) phosphorylation, thus is crucial for the suppression (minus symbols) of neuronal firing, whereas MT₂ receptor exerts a phase-shifting effect^38,40,41 and shortens the circadian period of bioluminescence in SCN explant cultures from Clock/+ mutant mice²⁴². b | Orexin promotes wakefulness during daytime. The SCN receives signals from light through the retinohypothalamic tract (RHT) and activates orexinergic neurons (purple circle) in the lateral hypothalamic area⁴⁶. Activated orexinergic neurons release orexin A and orexin B and project signals by binding to orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R) in various neurons located throughout the central nervous system (CNS): (1) the locus coeruleus; (2) the tuberomammillary nucleus; (3) the dorsal raphe and median raphe nuclei; (4) the laterodorsal tegmental nucleus; and (5) the pedunculopontine tegmental nucleus⁴⁷. Together, these activating neurons constitute the ascending reticular activating system (ARAS) and directly activate (plus symbols) the cortex, thus promoting wakefulness. Furthermore, OX2R has a major role in stabilization of wakefulness and suppression of sleep. NREM sleep, non-rapid-eye-movement sleep; REM sleep, rapid eye movement sleep.