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The role of orexin in motivated behaviours

A Corrigendum to this article was published on 20 October 2014

Key Points

  • Orexins are lateral hypothalamic neuropeptides that have a highly important role in the regulation of wakefulness.

  • To support feeding behaviour, orexin neurons are excited by food-related cues and/or low energy balance through neuronal connections with the limbic system and through factors that indicate energy balance.

  • Orexins simultaneously increase food intake and energy expenditure, but the net effect of increasing orexinergic tone is a decrease in body weight.

  • Emotive information from the limbic system excites orexin neurons to increase sympathetic outflow to regulate the cardiovascular function.

  • Orexins play an important part in the formation of cued fear memory through activation of noradrenergic neurons in the locus coeruleus.

  • Cues and contexts associated with rewards, including food, sex and drugs, influence the activity of orexin neurons to evoke behaviours in response to these stimuli.

  • Orexins are essential in reward seeking: they do not influence the primary reinforcing or priming effects of rewards, but they support motivated behaviour.

  • Orexin receptor type 2 (OX2R) has been thought to have a major role in maintaining wakefulness, but orexin receptor type 1 (OX1R) is likely to be involved in a broad range of functions, including emotion, reward and autonomic regulation.

  • Orexin-producing neurons reside in the lateral hypothalamic area and link forebrain structures — such as the amygdala, bed nucleus of the stria terminalis and nucleus accumbens — that are implicated in the processing of emotion and motivation with brain-stem regions that regulate wakefulness and reward.


Wakefulness and vigilance levels are required for maintaining purposeful activities and motivated behaviours, which are often triggered by sensory information conveying external cues. An increasing body of work has suggested that orexins (also known as hypocretins) — a pair of neuropeptides that are crucial for maintaining wakefulness — are also involved in the regulation of motivated behaviours, including feeding, emotional behaviour and reward seeking, and that these functions are mediated by two subtypes of orexin receptors. Autonomic and endocrine responses, which accompany these motivated behaviours, are also influenced by the orexin system. Orexin-producing neurons act as a hub that links information about the internal and external environments of an animal to vigilance levels and internal bodily functions to support various motivated behaviours.

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Figure 1: Input and output of orexin neurons.
Figure 2: Orexin neurons in the regulation of feeding.
Figure 3: Orexin neurons in the regulation of autonomic function.
Figure 4: Orexin neurons in the consolidation of cue-dependent fear memory.
Figure 5: Orexin neurons influence the reward-processing system.


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Correspondence to Takeshi Sakurai.

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PowerPoint slides



A sudden weakening of muscle tone that often accompanies narcolepsy.


A sleep disorder caused by a specific loss of hypothalamic orexin neurons.


Abnormally increased levels of CO2 in the blood.

Obstructive sleep apnoea syndrome

A condition characterized by repetitive pauses in breathing during sleep (known as apnoeas) caused by obstruction in the upper airway.

Resident–intruder paradigm

An experimental design in which a new ('intruder') mouse is placed in the home cage of another ('resident') mouse. The effect of the stress is then assessed in the resident mouse.

Defence response

The visceral and hormonal changes that accompany fear reactions. They are adaptations that prepare an animal to cope with an emergency, and specifically to perform the extreme muscular exertion of flight or attack.

Pressor response

An increase in arterial blood pressure in response to an internal or external trigger.


An abnormally high heart rate.


An abnormally low heart rate.

Depressor response

A decrease in arterial blood pressure in response to an internal or external trigger.

Head-up tilt

A test to find the autonomic response in humans. The test involves lying quietly on a bed and being tilted at different angles (30 to 60 degrees) for a period of time while blood pressure, heart rates and blood-oxygen level are monitored.

Valsalva manoeuvre

Attempted exhalation against a closed airway: subjects are usually instructed to blow out as if blowing up a balloon while keeping their mouth closed and pinching their nose shut.

Cold pressor test

A test to assess the effect of cold-water immersion (of all or part of the body) on blood pressure.


Loss of muscle tone.

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Sakurai, T. The role of orexin in motivated behaviours. Nat Rev Neurosci 15, 719–731 (2014).

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