Dysregulation of the orexin/hypocretin system is not limited to narcolepsy but has far‐reaching implications for neurological disorders

Berteotti, Chiara; Liguori, Claudio; Pace, Marta

doi:10.1111/ejn.15077

Cited by 23 publications

(12 citation statements)

References 182 publications

(216 reference statements)

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“…Alternatively, a sex difference in CSF OXA could be unique for nocturnal laboratory rats. Studies involving humans have mostly found similar CSF orexin in males and females (see Berteotti et al., 2020), but some of these studies had few healthy controls and may have been statistically underpowered to detect a sex differences.…”

Section: Discussionmentioning

confidence: 99%

Impact of daytime light intensity on the central orexin (hypocretin) system of a diurnal rodent (Arvicanthis niloticus)

Lonstein

Linning‐Duffy

Tang

et al. 2021

Eur J of Neuroscience

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The neuropeptide orexin/hypocretin is implicated in sleep and arousal, energy expenditure, reward, affective state and cognition. Our previous work using diurnal Nile grass rats (Arvicanthis niloticus) found that orexin mediates the effects of environmental light, particularly daytime light intensity, on affective and cognitive behaviours. The present study further investigated how daytime light intensity affects the central orexin system in male and female grass rats. Subjects were housed for 4 weeks in 12:12 hr dim light:dark (50 lux, dimLD) or in 12:12 hr bright light:dark cycle (1000 lux, brightLD). Day/night fluctuations in some orexin measures were also assessed. Despite similar hypothalamic prepro-orexin mRNA expression across all conditions, there were significantly more orexin-immunoreactive neurons, larger somata, greater optical density or higher orexin A content at night (ZT14) than during the day (ZT2), and/or in animals housed in brightLD compared to dimLD. Grass rats in brightLD also had higher cisternal CSF levels of orexin A. Furthermore, orexin receptor OX1R and OX2R proteins in the medial prefrontal cortex were higher in brightLD than dimLD males, but lower in brightLD than dimLD females. In the CA1 and dorsal raphe nucleus, females had higher OX1R than males without any significant effects of light condition, and OX2R levels were unaffected by sex or light. These results reveal that daytime light intensity alters the central orexin system of both male and female diurnal grass rats, sometimes sex-specifically, and provides insight into the mechanisms underlying how daytime light intensity impacts orexinregulated functions.

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Section: Discussionmentioning

confidence: 99%

Impact of daytime light intensity on the central orexin (hypocretin) system of a diurnal rodent (Arvicanthis niloticus)

Lonstein

Linning‐Duffy

Tang

et al. 2021

Eur J of Neuroscience

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“…Furthermore, slow metabolic state signalling to orexin neurons via nutrients and hormones (22–24) would place orexin as a centrepiece in mediating these transitions during, for example, foraging behaviours. The implications of the present results may also be useful for diagnosing orexin cell loss, which occurs in human narcolepsy and is currently diagnosed through highly invasive procedures (25), as well as give insight into other neurological disorders (26).…”

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confidence: 88%

Control and coding of pupil size by hypothalamic orexin neurons

Grujic

Tesmer

Bracey

et al. 2022

Preprint

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Brain orexin (hypocretin) neurons are implicated in sleep-wake switching and reward-seeking, but their roles in rapid arousal dynamics and reward perception remain unclear. Here, cell-specific stimulation, deletion, and in vivo recordings revealed strong correlative and causal links between pupil dilation - a quantitative arousal marker - and orexin cell activity. Coding of arousal and reward was distributed across orexin cells, indicating that they specialize in rapid, multiplexed communication of momentary arousal and reward states.

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“…Fronczek et al [ 152 ] quantified hypocretin neurons and measured hypocretin levels in the cerebrospinal fluid (CSF) of post-mortem hypothalamus of AD patients and found a 40% decrease in hypocretin neurons and a 14% decrease in CSF hypocretin-1 levels. Increased CSF-hypocretin levels, on the other hand, have been reported in some Alzheimer’s disease patients [ 153 , 154 , 155 , 156 , 157 , 158 ]. As low hypocretin decreases amyloid release, NT1 patients who have lost most of their hypocretin-containing neurons, seem to have a lower risk of developing AD [ 40 , 41 ].…”

Section: Pathophysiology and Links With Other Diseasesmentioning

confidence: 99%

Narcolepsy—A Neuropathological Obscure Sleep Disorder: A Narrative Review of Current Literature

et al. 2022

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Narcolepsy is a chronic, long-term neurological disorder characterized by a decreased ability to regulate sleep–wake cycles. Some clinical symptoms enter into differential diagnosis with other neurological diseases. Excessive daytime sleepiness and brief involuntary sleep episodes are the main clinical symptoms. The majority of people with narcolepsy experience cataplexy, which is a loss of muscle tone. Many people experience neurological complications such as sleep cycle disruption, hallucinations or sleep paralysis. Because of the associated neurological conditions, the exact pathophysiology of narcolepsy is unknown. The differential diagnosis is essential because relatively clinical symptoms of narcolepsy are easy to diagnose when all symptoms are present, but it becomes much more complicated when sleep attacks are isolated and cataplexy is episodic or absent. Treatment is tailored to the patient’s symptoms and clinical diagnosis. To facilitate the diagnosis and treatment of sleep disorders and to better understand the neuropathological mechanisms of this sleep disorder, this review summarizes current knowledge on narcolepsy, in particular, genetic and non-genetic associations of narcolepsy, the pathophysiology up to the inflammatory response, the neuromorphological hallmarks of narcolepsy, and possible links with other diseases, such as diabetes, ischemic stroke and Alzheimer’s disease. This review also reports all of the most recent updated research and therapeutic advances in narcolepsy. There have been significant advances in highlighting the pathogenesis of narcolepsy, with substantial evidence for an autoimmune response against hypocretin neurons; however, there are some gaps that need to be filled. To treat narcolepsy, more research should be focused on identifying molecular targets and novel autoantigens. In addition to therapeutic advances, standardized criteria for narcolepsy and diagnostic measures are widely accepted, but they may be reviewed and updated in the future with comprehension. Tailored treatment to the patient’s symptoms and clinical diagnosis and future treatment modalities with hypocretin agonists, GABA agonists, histamine receptor antagonists and immunomodulatory drugs should be aimed at addressing the underlying cause of narcolepsy.

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Dysregulation of the orexin/hypocretin system is not limited to narcolepsy but has far‐reaching implications for neurological disorders

Abstract: contributed equally to this work. Claudio Liguori served as consultant for EISAI and MSD.

Cited by 23 publications

References 182 publications

Impact of daytime light intensity on the central orexin (hypocretin) system of a diurnal rodent (Arvicanthis niloticus)

Impact of daytime light intensity on the central orexin (hypocretin) system of a diurnal rodent (Arvicanthis niloticus)

Control and coding of pupil size by hypothalamic orexin neurons

Narcolepsy—A Neuropathological Obscure Sleep Disorder: A Narrative Review of Current Literature

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