Motivational activation: a unifying hypothesis of orexin/hypocretin function

Abstract

Orexins (hypocretins) are two peptides (orexin A and B) produced from the pre-pro-orexin precursor and expressed in a limited region of dorsolateral hypothalamus. Orexins were originally thought to specifically mediate feeding and promote wakefulness, but it is now clear that they participate in a wide range of behavioral and physiological processes under select circumstances. Orexins primarily mediate behavior under situations of high motivational relevance, such as during physiological need states, exposure to threats or reward opportunities. We hypothesize that many behavioral functions of orexins (including regulation of sleep/wake cycling) reflect a fundamentally integrated function for orexins in translating motivational activation into organized suites of psychological and physiological processes supporting adaptive behaviors. We also discuss how numerous forms of neural heterogeneity modulate this function, allowing orexin neurons to organize diverse, adaptive responses in a variety of motivationally relevant situations. Thus, the involvement of orexins in diverse behaviors may reflect a common underlying function for this peptide system.

Figure 1

Model of orexins’ functions in sleep/wake regulation. Left, sleep/wake activity is homeostatically controlled, with sleep pressure (black solid line) increasing as a function of time awake and subsiding gradually over time asleep until sufficiently reduced to allow waking. Conversely, wakefulness is driven by a circadian signal (dashed gray line) that activates orexins and other arousal systems^,,,,. 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^,,. 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. Right, in orexin-deficient subjects (for example, NC humans, or animal models of NC), even relatively low levels of unopposed sleep pressure can result in inappropriate intrusions of sleep, regardless of circadian phase or motivational state. Conversely, lower peaks of homeostatic sleep pressure (resulting from decreased wake epoch durations) result in shorter periods of recovery sleep to regain homeostasis, allowing inappropriate intrusion of waking in the rest phase. This mechanism might account for rapid sleep/wake transitions seen in narcoleptics and orexin-deficient animals.