Control of arousal by the orexin neurons

Alexandre, C; Andermann, Mark L.; Scammell, Thomas E.

doi:10.1016/j.conb.2013.04.008

Cited by 122 publications

(89 citation statements)

References 87 publications

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“…S1A). HA mRNA was highly enriched in the hypothalamus and the basal forebrain, a site of intense projection from orexinergic neurons (22,23), compared with the rest of the brain (Fig. S1A).…”

Section: Resultsmentioning

confidence: 99%

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Bernard‐Valnet

Yshii

Quériault

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

121

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Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin + neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin + neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin + neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin + neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin + neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.arcolepsy with cataplexy, referred to as type 1 narcolepsy (T1N), is a rare and chronic neurological disease characterized by excessive daytime sleepiness, sudden loss of muscle tone triggered by emotions (cataplexy), sleep paralysis, hypnagogic hallucinations, and fragmented nocturnal sleep (1). T1N is caused by a defective neurotransmission by the orexin/hypocretin neuropeptide and is associated with a selective and almost complete loss (85-100%) of orexinergic neurons in the hypothalamus (2, 3). The mechanisms leading to this neuronal loss are not yet elucidated, although current evidence points to an autoimmune process. Indeed, T1N is tightly associated with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, carried by 98.4% of patients vs. 17.7% of the general European population (4). An independent association with HLA class I alleles was recently revealed in two independent studies (5, 6). Additionally, an association with polymorphisms in the T-cell receptor (TCR) α chain locus was found and replicated (7,8). Moreover, autoantibodies recognizing different antigenic targets expressed in the central nervous system (CNS) have been identified in the serum and cerebrospinal fluid (CSF) of narcoleptic patients (9-11)....

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Section: Resultsmentioning

confidence: 99%

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Bernard‐Valnet

Yshii

Quériault

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

121

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“…Thus, the orexinergic system has been implicated in several functions including the promotion and maintenance of arousal and wakefulness (Alexandre et al, 2013), the regulation of food consumption (Edwards et al, 1999), energy metabolism, thermoregulation and locomotion (Peyron et al, 1998;Mintz et al, 2001;Spinazzi et al, 2006). While cetaceans and artiodactyls both belong to the order Cetartiodactyla (Price et al, 2005), there are substantial differences in their life history, all of which appear to be related to functions associated with the orexinergic system.…”

Section: Introductionmentioning

confidence: 99%

“…Physiological studies demonstrate that orexinergic neuronal firing patterns are greatest during periods of wakefulness, motor activation and sustained attentiveness to external stimuli and the environment (Datta and MacLean, 2007;Alexandre et al, 2013). Thus, the orexinergic system has been implicated in several functions including the promotion and maintenance of arousal and wakefulness (Alexandre et al, 2013), the regulation of food consumption (Edwards et al, 1999), energy metabolism, thermoregulation and locomotion (Peyron et al, 1998;Mintz et al, 2001;Spinazzi et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Orexinergic bouton density is lower in the cerebral cortex of cetaceans compared to artiodactyls

Dell

Spocter

Patzke

et al. 2015

Journal of Chemical Neuroanatomy

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Highlights• The orexinergic innervation of the cerebral cortex of Cetartiodactyla is described.• All species show a similar innervation pattern.• The density of innervation is far less in cetaceans than artiodactyls. 1 AbstractThe species of the cetacean and artiodactyl suborders, which make up the cetartiodactyl order, have very different arousal thresholds and sleep-wake systems.The aim of this study was to determine whether cetaceans or artiodactyls have differently organized orexinergic arousal systems by examining the density of orexinergic innervation to the cerebral cortex. This study provides a comparison of orexinergic bouton density in the cerebral cortex of twelve cetartiodactyl species by means of immunohistochemical staining and stereological analysis. It was observed that the morphology of the axonal projections of the orexinergic system to the cerebral cortex was similar across all species, as the presence, size and proportion of large and small orexinergic boutons were similar. Despite this, orexinergic bouton density was lower in the cerebral cortex of cetaceans compared to artiodactyls, even when corrected for brain mass, neuron density, glial density and glial: neuron ratio. Glial density was identified as the major determinant for the observed differences. It appears a synergy exists between the orexinergic neurons and their projections, glial cells, and the biochemical correlates of appetitive drive and arousal, but further studies need to be performed to understand the full extent of the orexinergic system and its role in sustained arousal.

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“…This arousalpromoting effect of orexins may be realized by excitatory actions on multiple subcortical arousal systems and the cerebral cortex [5][6][7][8] . Two G protein-coupled receptors (orexin receptor 1 and 2) are involved in maintaining a long, consolidated awake period [5,9,10] .…”

Section: Introductionmentioning

confidence: 99%

Orexin A attenuates the sleep-promoting effect of adenosine in the lateral hypothalamus of rats

et al. 2014

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Orexin neurons within the lateral hypothalamus play a crucial role in the promotion and maintenance of arousal. Studies have strongly suggested that orexin neurons are an important target in endogenous adenosine-regulated sleep homeostasis. Orexin A induces a robust increase in the firing activity of orexin neurons, while adenosine has an inhibitory effect. Whether the excitatory action of orexins in the lateral hypothalamus actually promotes wakefulness and reverses the sleep-producing effect of adenosine in vivo is less clear. In this study, electroencephalographic and electromyographic recordings were used to investigate the effects of orexin A and adenosine on sleep and wakefulness in rats. We found that microinjection of orexin A into the lateral hypothalamus increased wakefulness with a concomitant reduction of sleep during the first 3 h of post-injection recording, and this was completely blocked by a selective antagonist for orexin receptor 1, SB 334867. The enhancement of wakefulness also occurred after application of the excitatory neurotransmitter glutamate in the fi rst 3 h post-injection. However, in the presence of the NMDA receptor antagonist APV, orexin A did not induce any change of sleep and wakefulness in the first 3 h. Further, exogenous application of adenosine into the lateral hypothalamus induced a marked increase of sleep in the fi rst 3-h post-injection. No signifi cant change in sleep and wakefulness was detected after adenosine application followed by orexin A administration into the same brain area. These findings suggest that the sleep-promoting action of adenosine can be reversed by orexin A applied to the lateral hypothalamus, perhaps by exciting glutamatergic input to orexin neurons via the action of orexin receptor 1.

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Control of arousal by the orexin neurons

Cited by 122 publications

References 87 publications

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Orexinergic bouton density is lower in the cerebral cortex of cetaceans compared to artiodactyls

Orexin A attenuates the sleep-promoting effect of adenosine in the lateral hypothalamus of rats

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