Study of the mechanisms that regulate the activity of orexin-producing neuron.

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The implication of orexin in narcolepsy suggests the importance of orexin in the normal regulation and maintenance of vigilance states. Orexin neurons project from the LHA to the monoaminergic and cholinergic nuclei in the brainstem to regulate sleep/wakefulness states as well as feeding. The activity of orexin neurons is inhibited by glucose and leptin, and stimulated by ghrelin. In accordance with the previous report that prepro-orexin mRNA is up-regulated by fasting, this observation suggests that orexin neurons sense the animal's nutritional state by monitoring humoral factors such as leptin and glucose. We also found that orexin neurons are inhibited by serotonin and noradrenaline, while excited by acetylcholine. We recently found that orexin neurons are innervated by multiple specific brain regions implicated in the regulation of sleep/wakefulness states. This study revealed that orexin neural network ensures"flip-flop"mechanisms between the POA sleep-active neurons and monoaminergic neurons. Thus, orexin neurons have functional interactions with hypothalamic feeding pathways and monoaminergic/cholinergic centers, and provide a critical link between peripheral energy balance and the CNS mechanisms that coordinate sleep/wakefulness and motivated behavior such as food seeking.