Orexin as a modulator of fear-related behavior: Hypothalamic control of noradrenaline circuit

Fear is an important physiological function for survival. It appears when animals or humans are confronted with an environmental threat. The amygdala has been shown to play a highly important role in emergence of fear. Hypothalamic orexin neurons are activated by fearful stimuli to evoke a 'defense reaction' with an increase in arousal level and sympathetic outflow to deal with the imminent danger. However, how this system contributes to the emergence of fear-related behavior is not well understood. Orexin neurons in the hypothalamus send excitatory innervations to noradrenergic neurons in the locus coeruleus (NA^LC) which express orexin receptor 1 (OX1R) and send projections to the lateral amygdala (LA). Inhibition of this di-synaptic orexin → NA^LC → LA pathway by pharmacological or opto/chemogenetic methods reduces cue-induced fear expression. Excitatory manipulation of this pathway induces freezing, a fear-related behavior that only occurs when the environment contains some elements suggestive of danger. Although, fear memory helps animals respond to a context or cue previously paired with an aversive stimulus, fear-related behavior is sometimes evoked even in a distinct context containing some similar elements, which is known as fear generalization. Our recent observation suggests that the orexin → NA^LC → LA pathway might contribute to this response. This review focuses on recent advances regarding the role of hypothalamic orexin neurons in behavioral fear expression. We also discuss the potential effectiveness of orexin receptor antagonists for treating excessive fear response or overgeneralization seen in anxiety disorder and post-traumatic stress disorder (PTSD).