Dysregulation of the orexinergic system: A potential neuropeptide target in depression

Abstract Orexins are highly involved in regulating the circadian rhythm, the brain’s reward mechanism, and the neuroendocrine response to stress. The disruption of orexin regulation is known to be associated with depression. Preclinical studies in rodents have identified the dorsomedial/perifornical and lateral areas of the hypothalamus as the population of orexinergic neurons that are primarily responsible for mediating depression-induced neuroanatomical changes in the brain. There is still no consensus regarding whether hyperactivity or hypoactivity of orexin signaling is responsible for producing depressive-like behaviour. Likewise, clinical studies indicated a general disruption in orexin signaling in depressive patients, but did not report definitive evidence of either hyperactivity or hypoactivity. Nevertheless, given the various reciprocal connections between orexin neurons and multiple brain regions, it is plausible that this involves a differential signaling network with orexin neurons as the coordination center. Here, an overview of preclinical and clinical evidence is provided as a basis for understanding the consequences of altered orexin signaling on neural circuitries modulating different aspects of the physiopathology of depression.