Do orexin/hypocretin neurons signal stress or reward?

Hypothalamic neurons that produce the peptide transmitters orexins/hypocretins (HONs) broadcast their predominantly neuroexcitatory outputs to the entire brain via their extremely wide axonal projections. HONs were originally reported to be activated by food deprivation, and to stimulate arousal, energy expenditure, and eating. This led to extensive studies of HONs in the context of nutrient-sensing and energy balance control. While activation of HONs by body energy depletion continues to be supported by experimental evidence, it has also become clear that HONs are robustly activated not only by nutrient depletion, but also by diverse sensory stimuli (both neutral and those associated with rewarding or aversive events), seemingly unrelated to each other or to energy balance. One theory that could unify these findings is that all these stimuli signal "stress" - defined either as a potentially harmful state, or an awareness of reward deficiency. If HON activity is conceptualized as a cumulative representation of stress, then many of the reported HONs outputs - including EEG arousal, sympathetic activation, place avoidance, and exploratory behaviours - could be viewed as logical stress-counteracting responses. We discuss evidence for and against this unifying theory of HON function, including the alterations in HON activity observed in anxiety and depression disorders. We propose that, in order to orchestrate stress-countering responses, HONs need to coactivate motivation and aversion brain systems, and the impact of HON stimulation on affective states may be perceived as rewarding or aversive depending on the baseline HON activity.