A unified survival theory of the functioning of the hypocretinergic system

Abstract

This article advances the theory that the hypocretinergic (orexinergic) system initiates, coordinates, and maintains survival behaviors and survival-related processes (i.e., the Unified Survival Theory of the Functioning of the Hypocretinergic System or "Unified Hypocretinergic Survival Theory"). A priori presumptive support for the Unified Hypocretinergic Survival Theory emanates from the fact that neurons that contain hypocretin are located in the key executive central nervous system (CNS) site, the lateral hypothalamus, that for decades has been well-documented to govern core survival behaviors such as fight, flight, and food consumption. In addition, the hypocretinergic system exhibits the requisite morphological and electrophysiological capabilities to control survival behaviors and related processes. Complementary behavioral data demonstrate that all facets of "survival" are coordinated by the hypocretinergic system and that hypocretinergic directives are not promulgated except during survival behaviors. Importantly, it has been shown that survival behaviors are selectively impacted when the hypocretinergic system is impaired or rendered nonfunctional, whereas other behaviors are relatively unaffected. The Unified Hypocretinergic Survival Theory resolves the disparate, perplexing, and often paradoxical-appearing results of previous studies; it also provides a foundation for future hypothesis-driven basic science and clinical explorations of the hypocretinergic system.

Motivational activation: a unifying hypothesis of orexin/hypocretin function

“…Thus, we hypothesize that both SCN-dependent tonic excitation and phasic orexin neuron burst firing help to produce and maintain wakefulness—the latter as a consequence of increased motivation to engage adaptive challenges or opportunities. This is consistent with the view that orexins prolong arousal in the service of managing environmental threats or opportunities 4,10,19,22–24 .…”

“…Orexin circadian rhythmicity is controlled closely (though likely indirectly) by the suprachiasmatic nucleus (SCN), which causes basal excitation of orexin neurons during the active period 6,11 . Orexin neuron firing also varies substantially throughout wakefulness, with both tonic activity 13,18 and rapid firing specifically during periods of adaptive behavior, such as exploration, play, predation and grooming, but not during other behaviors matched for physiological arousal and locomotor activity 12,19,20 . This is consistent with the role we propose for orexins in the motivational processes underlying these adaptive behaviors (associated with phasic firing), which is overlaid on circadian oscillations in tonic activity, excitability or peptide release (Fig.…”

“…This hypothesis explains dysregulated sleep/wake cycling associated with orexin neuron loss in NC, but does not explain cataplexy symptoms. How cataplexy relates to motivational or arousal functions of the orexin system is controversial, but a link to emotional arousal is clear 7,11,19,23,27–29 (Box 1). …”

“…Orexin neuron activity (red line) has a circadian pattern, but also phasic bursts during waking as a function of motivational state and adaptive behavior. Orexins excite wake-active (for example, LC and dorsal raphe) and inhibit sleep-active brain regions (for example, medullary REM muscle atonia circuit), so discharge of orexin neurons during wakefulness helps to counteract sleep pressure and decrease the probability of sleep initiation, especially during emotionally arousing situations 4,11,19 . For purposes of clarity, sleep and wake periods have been depicted as uninterrupted, although rodents typically display multiple sleep/wake transitions in both light and dark phases.…”

Heart rate variability during carbachol-induced REM sleep and cataplexy

“…Hypocretinergic neurons project directly to motoneurons, and produce motor activation during emotionallydriven or survival-related waking behaviors [41][42][43][44][45]. Following a emotional stimuli, due to the dysfunction of the hypocretinergic system there is a drastic reduction in the degree of activation of the somatic motor system and/or, the REM sleep atonia network may be inadequately activated [46], which may be responsible for the episodes of cataplexy [13].…”