Metabolic state signalling through central hypocretin/orexin neurons

Hypothalamic neurons that produce the peptide transmitters hypocretins/orexins have attracted much recent attention. They provide direct and predominantly excitatory inputs to all major brain areas except the cerebellum, with the net effect of stimulating wakefulness and arousal. These inputs are essential for generating sustained wakefulness in mammals, and defects in hypocretin signalling result in narcolepsy. In addition, new roles for hypocretins/orexins are emerging in reward-seeking, learning, and memory. Recent studies also indicate that hypocretin/orexin neurons can alter their intrinsic electrical activity according to ambient fluctuations in the levels of nutrients and appetite-regulating hormones. These intriguing electrical responses are perhaps the strongest candidates to date for the elusive neural correlates of after-meal sleepiness and hunger-induced wakefulness. Hypocretin/orexin neurons may thus directly translate rises and falls in body energy levels into different states of consciousness.