How orexin signals bias action: Hypothalamic and accumbal circuits

Survival-maximizing, well-timed actions are a key responsibility of the brain. Hypothalamic neurons containing neurotransmitters orexins/hypocretins are important players in this process. Individuals without orexin neurons display inappropriately-timed transitions between arousal states, and other behavioural abnormalities including increased risk-taking. Deciphering neural circuits through which orexin neurons control brain states and behavior thus illuminates brain mechanisms of context-appropriate actions. This review outlines and puts into broader context recent examples of orexin circuit analyses in the lateral hypothalamus (LH) and the nucleus accumbens (NAc), two brain regions clasically implicated in context-appropriate actions. In the LH, orexin neurons excite GAD65-expressing neurons. The LH(GAD65) neuron excitation induces elevated locomotor activity, while inhibition of LH(GAD65) neuron natural activity depresses voluntary locomotion. The orexin → LH(GAD65) circuit may therefore assist in creating the drive to run. In the NAc shell region, orexin axons excite D2 neurons (dopamine-inhibited neurons expressing dopamine type-2 receptor). NAc(D2) cell activation increases risk-avoidance behaviors, while NAc(D2) cell inhibition reduces risk-avoidance. The excitatory orexin → NAc(D2) circuit may thus assist in reducing risk-taking, and oppose the inhibitory VTA(dopamine) → NAc(D2) circuit during computation of risk appetite. Neural computation in these local and long-range orexin circuits may thus assist in generating risk-avoiding locomotor responses to stressors known to activate orexin neurons, such as body energy depletion or potential external threats. A model is proposed where orexin-opposing, inhibitory inputs acting on the orexin target neurons may context-specifically channel orexin-induced brain excitation towards particular sets of actions.