A Physiologically Based Model of Orexinergic Stabilization of Sleep and Wake

Ben D Fulcher,Andrew J K Phillips,Svetlana Postnova,Peter A Robinson,Ralph E Mistlberger

doi:10.1371/journal.pone.0091982

Ben D Fulcher, Andrew J K Phillips + Show 3 more

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https://doi.org/10.1371/journal.pone.0091982

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Abstract

The orexinergic neurons of the lateral hypothalamus (Orx) are essential for regulating sleep-wake dynamics, and their loss causes narcolepsy, a disorder characterized by severe instability of sleep and wake states. However, the mechanisms through which Orx stabilize sleep and wake are not well understood. In this work, an explanation of the stabilizing effects of Orx is presented using a quantitative model of important physiological connections between Orx and the sleep-wake switch. In addition to Orx and the sleep-wake switch, which is composed of mutually inhibitory wake-active monoaminergic neurons in brainstem and hypothalamus (MA) and the sleep-active ventrolateral preoptic neurons of the hypothalamus (VLPO), the model also includes the circadian and homeostatic sleep drives. It is shown that Orx stabilizes prolonged waking episodes via its excitatory input to MA and by relaying a circadian input to MA, thus sustaining MA firing activity during the circadian day. During sleep, both Orx and MA are inhibited by the VLPO, and the subsequent reduction in Orx input to the MA indirectly stabilizes sustained sleep episodes. Simulating a loss of Orx, the model produces dynamics resembling narcolepsy, including frequent transitions between states, reduced waking arousal levels, and a normal daily amount of total sleep. The model predicts a change in sleep timing with differences in orexin levels, with higher orexin levels delaying the normal sleep episode, suggesting that individual differences in Orx signaling may contribute to chronotype. Dynamics resembling sleep inertia also emerge from the model as a gradual sleep-to-wake transition on a timescale that varies with that of Orx dynamics. The quantitative, physiologically based model developed in this work thus provides a new explanation of how Orx stabilizes prolonged episodes of sleep and wake, and makes a range of experimentally testable predictions, including a role for Orx in chronotype and sleep inertia.

Highlights

Since the discovery of the orexin A and orexin B neurotransmitters by Sakurai et al [1] and de Lecea et al [2] in 1998, the orexinergic neurons of the lateral hypothalamic area (Orx) have been implicated in a wide range of neurological processes, including a key role in the regulation of sleep and wake [3,4]
Populations other than the ventrolateral preoptic neurons of the hypothalamus (VLPO) have been implicated as having a role in inducing and/or maintaining sleep, including the median preoptic nuclei (MnPO) [19], melanin-concentrating hormone cells in the hypothalamus [53], neurons in the striatum and globus pallidus [54], the rostral medullary brainstem [55], and thalamus [56], here we focus on the important role of the VLPO [57] and note that this component of the model could in principle represent one or more sleep-promoting centers that act in concert
(iv) While previous models have captured sleep inertia using ad hoc processes, an asymmetry between sleep-to-wake and wake-to-sleep transitions is predicted to result from adding Orx to the model, producing sleep inertia on the timescale of Orx dynamics, tx

Summary

Introduction

Since the discovery of the orexin A and orexin B neurotransmitters ( termed hypocretin 1 and 2) by Sakurai et al [1] and de Lecea et al [2] in 1998, the orexinergic neurons of the lateral hypothalamic area (Orx) have been implicated in a wide range of neurological processes, including a key role in the regulation of sleep and wake [3,4]. The orexins have been shown to have a role in feeding, emotion, reward function, and motivation [1,5,6,7,8]. The neurodegenerative disorder narcolepsy [9] is characterized by a loss of approximately 90% of Orx [10], and is a condition that affects approximately 0.05% of the population [11]. The condition is often accompanied by cataplexy, the sudden loss of muscle tone triggered by strong emotions [15], over one quarter of all narcoleptics do not have cataplexy [11], perhaps due to less severe loss of Orx [16,17]

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