Orexin in REM Sleep: Comparison
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Orexin plays a significant role in the modulation of REM sleep, as well as in the regulation of appetite and feeding. This review explores, first, the currentre is evidence on the role of orexin in the modulation of sleep and wakefulness and highlights that orexin should be considered essentially as a neurotransmitter inhibiting REM sleep and, to a lesser extent, a wake promoting agent. Subsequently, the relationship between orexin, REM sleep, and appetite regulation is examined in detail, shedding light on their interconnected nature in both physiological conditions and diseases (such as narcolepsy, sleep-related eating disorder, idiopathic hypersomnia, and night eating syndrome).

  • orexin
  • hypocretin
  • REM sleep
  • feeding
  • appetite

1. Introduction

Sleep is a complex physiological process that consists of different stages, including rapid eye movement (REM) sleep. REM sleep is characterized by vivid dreaming, rapid eye movements, and muscle atonia. Although not completely understood, it is clear that REM sleep accomplishes many fundamental functions: information processing by replaying neural activity experienced during wakefulness, modulation of synaptic and neural transmission, cortical plasticity, memory consolidation, and a series of physical functions particularly interesting, such as the regulation of feeding behavior, autonomic nervous system, body temperature, and response to stress, among many others [1].
The regulation of REM sleep is a finely tuned process involving various neurotransmitters and neuropeptides [2], among them orexin plays a pivotal role. The regulation of the sleep-wake cycle and of the various stages of sleep is very complex and still under study, according to current knowledge, among the neurons involved in the regulation of REM sleep there are the cholinergic ones, which are activated in association with fast cortical rhythms also during wakefulness, but much less during NREM sleep [3]. Much less is known about glutamatergic neurons, although it is known that, by innervating the cortex and subcortical regions that promote arousal, they appear to fire during wakefulness and REM sleep. Furthermore, the GABAergic neurons in the Pedunculopontine and Laterodorsal Tegmental Nuclei regions seem mainly wake-active, but some may be more active during REM sleep than in NREM sleep [3]. Orexin-A and -B are neuropeptides essential for regulating wake and REM sleep [1]; indeed, intracerebroventricular injection of orexin-A increases wake and suppresses REM sleep for several hours and chemogenetic activation of the orexin neurons increases wake and strongly suppresses REM sleep [4]. The orexin neurons also produce glutamate and the inhibitory neuropeptide dynorphin, and co-release of glutamate from the orexin neurons can excite target neurons [5], suggesting a close interconnection with the aforementioned neurotransmitter pathways, within the control of REM sleep, although further studies are needed.
Since its identification, in 1998, orexin has been known to regulate feeding behavior [6]. This also determined the choice of its name from the Ancient Greek word ὄρεξις (órexis, meaning “desire” or “appetite”). An independent group, at the same time, identified it as “hypocretin” [7] and underlined its similarity with the gut hormone secretin. For this reason, and due to its hypothalamic origin, these authors choose the name “hypocretin”. Soon after, orexin and hypocretin were recognized to be the same neurotransmitter and there is now a general agreement on the use of the term hypocretin to refer to the gene or genetic products and orexin to indicate the protein.
It should be said that orexin includes two similar peptides, deriving from the hypothalamic prepro-orexin, called orexin A and B, corresponding to hypocretin 1 and 2, and formed by 33 and 28 amino acids, respectively. Also, two different orexin receptors have been identified (orexin receptor 1 and 2); orexin A acts through both receptor 1 and 2 while orexin B only acts through receptor 2 [8].

2. The Role of Orexin in REM Sleep Regulation

Orexin is primarily synthesized in the lateral hypothalamus and acts as a neurotransmitter. According to the current knowledge, it plays a key role in the regulation of sleep-wake cycles, promoting wakefulness and inhibiting REM sleep. Orexin-producing neurons in the hypothalamus project to several brain regions involved in sleep regulation, such as the brainstem and thalamus [10][9].
During wakefulness, orexin neurons are highly active, releasing orexin into their target regions. The release of orexin promotes arousal, enhances alertness, and helps maintain a state of wakefulness. However, during REM sleep, the activity of orexin neurons decreases, resulting in a reduction of orexin release. Interestingly, recent studies in primates have clearly shown that the highest concentrations of orexin are recorded until just after the monkeys go to sleep and then falling through the night and reaching the lowest concentrations around wake time [11,12][10][11]. Then, orexin concentrations start rise linearly. Only after some hours of wakefulness, orexin concentrations reach a plateau during the early evening. Data in humans, although less consistently, agree with this circadian distribution of orexin levels in the cerebrospinal fluid (CSF) [13,14,15][12][13][14].
This pattern is definitely not what one should expect if one of the main roles of orexin is that of maintaining wakefulness, since it would be quite difficult to explain why orexin is at its lowest levels in the morning hours when alertness is maximum and sleepiness is unlikely and is maximum around the sleep onset, when sleepiness is likely to be maximum. On the contrary, it fits quite well with the notion that it inhibits REM sleep and, indeed, it decreases gradually during the night, concurrently with the well know increase in REM sleep as the night progresses.
The discrepancy between the supposed alerting role of orexin and the CSF data has also been supposed to be due to a hypothetical long delay between the release of orexin and its appearance in lumbar CSF [15][14]. However, this was only a suggestion based on no evidence and a much easier interpretation of the data is that the main role of orexin is not that of promoting alertness.
Considering orexin essentially as a neurotransmitter inhibiting REM sleep and, to a lesser extent, a wake promoting agent, also fits with the objective observations reported about sleep in patients with narcolepsy type 1 in whom a deficit in orexin represents the main biological hallmark. In fact, these patients show full (sleep onset REM sleep episodes) or partial (sleep paralysis, cataplexy, hypnagogic hallucinations) intrusions of REM sleep during wakefulness. In addition, nocturnal sleep is also disturbed in these patients and is not characterized by an increased nonREM sleep time but, again, by an increase in REM sleep which also occurs early after the subjects fall asleep.
In physiological conditions, the decrease in orexin activity during the second part of the night, when REM sleep preferentially occurs, is essential for the initiation and maintenance of this sleep stage. By inhibiting orexin release, the brain allows for the expression of REM-specific features, such as muscle atonia and vivid dreaming.
There is a general idea that one of the main roles of orexin is to promote wakefulness [17][15]. This has also represented at least part of the rationale to promote orexin receptor antagonists for the treatment of insomnia and to promote sleep [18][16]. However, although several neurotransmitters, including hypocretin/orexin, histamine, norepinephrine, serotonin, dopamine, adenosine and acetylcholine, certainly contribute to the mechanisms supporting wakefulness, none of them seems to be individually necessary for maintaining wakefulness [19][17].
Orexin receptor antagonists are a class of medications designed to block the action of orexin at its receptors. By doing so, these drugs are believed to inhibit the wake-promoting effects of orexin, ultimately leading to increased sleep duration and improved sleep continuity. Numerous polysomnographic studies have investigated the effects of orexin receptor antagonists on sleep architecture in both healthy individuals and patients with sleep disorders [18][16]. These studies have consistently shown that orexin receptor antagonists improve sleep parameters and promote sleep continuity. Studies have generally reported that the administration of orexin receptor antagonists was associated with a significant increase in total sleep time and reduced sleep latency, but also enhanced or at least preserved REM sleep, unlike traditional hypnotics, and sometimes decreased nonREM sleep [20][18]. It is intuitive to think that if orexin essentially favors wakefulness, antagonizing its receptors should enhance sleep as a whole, especially nonREM sleep which is physiologically more represented than REM sleep. On the contrary, orexin receptor antagonists have shown a remarkable ability to enhance REM sleep regulation, in particular [20][18].

3. Other Functions of Orexin

Orexin, however, plays a multifunctional role in regulating various physiological processes. Besides sleep-wake regulation and appetite control, its functions encompass energy homeostasis, autonomic nervous system modulation, and cognitive function, reflecting its significance in maintaining overall homeostasis.

3.1. Energy Homeostasis

Beyond its involvement in feeding behavior, orexin is crucial in maintaining energy homeostasis. It orchestrates energy expenditure, thermogenesis, and lipid metabolism through interactions with various metabolic centers in the brain. Studies in animal models suggest that orexin deficiency can lead to reduced physical activity and increased fat accumulation, underscoring its role in energy balance [22,23][19][20].
Energy homeostasis is a crucial physiological process that maintains a balance between energy intake and energy expenditure in the body. Dysregulation of this process can lead to obesity, diabetes, and other metabolic disorders. Orexin-producing neurons in the lateral hypothalamus are activated by both fasting and food deprivation, suggesting a role in promoting food-seeking behavior [6]. These neurons project widely to other brain regions involved in appetite regulation, such as the paraventricular thalamic nucleus and the nucleus accumbens [24][21]. Activation of orexin neurons stimulates food intake, while inhibition reduces food consumption [25][22].
Beyond its role in feeding behavior, orexin also influences energy expenditure. Orexin receptors are expressed in various tissues, including brown adipose tissue and skeletal muscles, which are involved in thermogenesis and energy dissipation [26,27][23][24].
Orexin also has an impact on glucose homeostasis. It interacts with insulin-producing beta cells in the pancreas and affects glucose-stimulated insulin secretion [28,29][25][26].
Leptin, a hormone produced by adipose tissue, is a key player in energy homeostasis by regulating satiety and energy expenditure. Orexin and leptin interact in a complex manner to regulate feeding behavior and energy balance [30][27].
Thus, orexin is a neuropeptide that plays a significant role in the regulation of energy homeostasis by influencing feeding behavior, energy expenditure, and glucose homeostasis. Its complex interactions with other hormones, such as leptin, further highlight its importance in maintaining energy balance. Dysregulation of orexin signaling has been implicated in metabolic disorders, making it a potential pharmacological target for therapeutic interventions aimed at addressing obesity and related conditions.

3.2. Regulation of the Autonomic Nervous System

Orexinergic pathways also play a role in the stress response, contributing to the activation of the hypothalamic-pituitary-adrenal axis. Dysregulation of orexin signaling is associated with autonomic dysfunction and cardiovascular disorders [31,32,33][28][29][30].
The autonomic nervous system is a critical component of the peripheral nervous system responsible for regulating involuntary physiological functions, such as heart rate, blood pressure, digestion, and respiratory rate. Emerging evidence suggests that orexin also plays a significant role in modulating the autonomic nervous system and it has been shown to influence the activity of both the sympathetic [34][31] and parasympathetic [35][32] nervous systems [36][33]. Moreover, orexin is involved in the regulation of the cardiovascular [34][31] and respiratory [37][34] functions through its actions on the autonomic nervous system. Dysregulation of orexin signaling may contribute to autonomic dysfunctions, making it a potential target also for therapeutic interventions in disorders involving autonomic nervous system imbalances.

3.3. Cognitive Function

Cognitive function refers to the mental processes that enable people to perceive, think, reason, and remember. Emerging evidence suggests that orexin may also influence cognitive function, including memory consolidation and attention. Orexin receptors are found in brain areas related to memory, and studies have linked orexin to the modulation of cognitive processes. Moreover, orexin has been implicated in the regulation of emotional responses and mood, further supporting its involvement in cognitive function [38,39][35][36].
Arousal is a critical component of cognitive function, as it affects attention, alertness, and information processing. As also reported above, orexin has a significant influence on arousal and wakefulness [40][37], as well as on attention (the ability to focus on specific stimuli while filtering out irrelevant information) [41][38]. Learning and memory are fundamental cognitive functions essential for acquiring and retaining new information; orexin may influence these processes through its enhancing effects on synaptic plasticity [42][39]. However, the exact mechanisms of orexin’s impact on cognitive function certainly require further investigation, also for their potential implications for developing novel therapeutic strategies targeting cognitive dysfunction in CNS disorders.

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