The dual role of the orexin/hypocretin system in modulating wakefulness and respiratory drive

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Abstract
Today, numerous studies show that orexin peptides act as regulators of many functions including the control of sleep-wake states, breathing, and central chemosensitivity. However, little is known on neuronal mechanisms by which orexin regulates breathing in a state-dependent manner. This review summarizes recent data on the control of neuronal circuits by orexin, with a special emphasis on breathing, central chemosensitivity, and obstructive sleep apneas. Activity of hypothalamic orexinergic neurons is subjected to maturation and is mandatory to maintain long bouts of wakefulness in adults. At wake onset, this activity progressively builds up as a result of synaptic interactions and reinforces the awake state. Orexin deficiency attenuates the hypercapnic reflex only during wakefulness and is correlated with an increase in sleep apneas. Intrinsic sensitivity to CO2/pH of orexin neurons may impact on brainstem chemosensitive neurons, and this effect likely involves TWIK (tandem of P domains in a weak inwardly rectifying K+ channel)-related acid sensitive K+ (TASK)-like potassium currents. Orexin signaling is directly involved in the control of upper airway patency in particular during wakefulness, whereas decreasing activity of orexinergic neurons may contribute to upper airway collapse during sleep causing obstructive sleep apnea. Future research should focus on the role of orexin in upper airway control, which may lead to new clinical strategies for treating breathing disorders associated with sleep.