Recent advances in understanding the roles of hypocretin/orexin in arousal, affect, and motivation

Abstract

The hypocretins (Hcrts) are two alternatively spliced neuropeptides (Hcrt1/Ox-A and Hcrt2/Ox-B) that are synthesized exclusively in the hypothalamus. Data collected in the 20 years since their discovery have supported the view that the Hcrts play a broad role in the control of arousal with a particularly important role in the maintenance of wakefulness and sleep-to-wake transitions. While this latter point has received an overwhelming amount of research attention, a growing literature has begun to broaden our understanding of the many diverse roles that the Hcrts play in physiology and behavior. Here, we review recent advances in the neurobiology of Hcrt in three sections. We begin by surveying findings on Hcrt function within normal sleep/wake states as well as situations of aberrant sleep (that is, narcolepsy). In the second section, we discuss research establishing a role for Hcrt in mood and affect (that is, anxiety, stress, and motivation). Finally, in the third section, we briefly discuss future directions for the field and place an emphasis on analytical modeling of Hcrt neural activity. We hope that the data discussed here provide a broad overview of recent progress in the field and make clear the diversity of roles played by these neuromodulators.

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“…Orexins have important roles in the regulation of sleep and arousal states, as well as appetite, food intake, and energy homeostasis [90]. Orexin antagonists can also attenuate depression severity, at least in part via their impact on the sleep–wake circadian cycle [91].…”

Central regulation of breast cancer growth and metastasis

“…The lateral hypothalamus (LH) is a highly heterogeneous structure that serves a primary role in arousal, metabolism, and motivated behavior [24] . A neural population that has been intensely studied in this area are those that express the excitatory neuromodulators hypocretin-1 and hypocretin-2 (aka orexin-A and -B; HO) [26,27] . Discovered by two groups at essentially the same time [28,29] , these neurons are critical for maintaining wakefulness, as their destruction results in the sleep disorder narcolepsy [30][31][32][33] .…”

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“…The hypocretin-system plays a role in the regulation of sleep-wake transition, but the various effects on these processes are regulated by different brain regions and systems. Research indicates that hypocretin acts as a coordinator for maintenance of sleep and wakefulness and the transition between these, rather than generating sleep directly (67). The pathways through which it interacts are thought to be via many neurotransmitter systems (29,67,68).…”