The role of orexin/hypocretin in regulating the sleep: Wake cycle

The neurons of the lateral hypothalamus that synthesize peptides hypocretin/orexin from a common precursor pre-pro-orexin/preprohypocretin are the key stabilizers of sleep-wake cycle. Regulation of sleep-wake cycle is achieved through a functional interaction between orexinergic neurons of the hypothalamus, monoaminergic/cholinergic neurons of the brainstem and GABAergic/galanin neurons of the ventrolateral preoptic nucleus. Orexins/hypocretins originating from the hypothalamus excite monoaminergic neurons. In contrast to this, excited monoaminergic neurons reciprocally inhibit orexinergic neurons. GABAergic neurons, which also include galanin, send inhibitory signals to monoaminergic and orexinergic neurons, while monoaminergic neurons send inhibitory signals to GABAergic neurons who are active during sleep. Such an organization, with mutual influences is of great importance for the stabilization of sleep-wake cycle. Studies have also shown that the loss of orexinergic neurons is directly related to narcolepsy, a form of hypersomnia which is characterized by the sudden intrusion of NREM and REM sleep phase to wakefulness and frequent transitions between state of sleep and wakefulness. Narcolepsy may be accompanied by cataplexy, which is manifested by the sudden weak-ness of muscle tone. Discovery of the connection between the loss of orexinergic signaling and human narcolepsy-cata-plexy has led to new diagnostic and therapeutic options in the treatment of this disease.