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The neural circuit of orexin (hypocretin): Maintaining sleep and wakefulness

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DOI: 10.1038/nrn2092 · Source: PubMed

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 REVIEWS
The neural circuit of orexin
(hypocretin): maintaining sleep
and wakefulness
Takeshi Sakurai
Abstract | Sleep and wakefulness are regulated to occur at appropriate times that are in
accordance with our internal and external environments. Avoiding danger and finding food,
which are life-essential activities that are regulated by emotion, reward and energy balance,
require vigilance and therefore, by definition, wakefulness. The orexin (hypocretin) system
regulates sleep and wakefulness through interactions with systems that regulate emotion,
reward and energy homeostasis.

Narcolepsy
The neuropeptides orexin A and orexin B (also known Together, these observations suggest that, broadly
A neurological condition as hypocretin 1 and hypocretin 2), produced in speaking, orexin neurons are involved in sensing the
mostly characterized by hypothalamic neurons, are crucial regulators of sleep body’s external and internal environments and regulate
excessive daytime sleepiness, and wakefulness. These peptides activate wake-active states of sleep and wakefulness accordingly, which is bene-
uncontrollable sleep attacks
monoaminergic and cholinergic neurons in the hypotha- ficial for survival. This review will discuss the mechanisms
and disorder of REM sleep.
lamus and brain stem to maintain a long, consolidated by which the orexin system maintains sleep and wakeful-
Limbic system awake period, and it is this role in particular that will ness, and how this mechanism relates to other systems
A collection of cortical and form the focus of this review. that regulate emotion, reward and energy homeostasis.
subcortical structures Orexins were initially identified as endogenous
important for processing
memory and emotional
ligands for two orphan G-protein-coupled receptors1 Narcolepsy and orexins
information. Prominent (BOX 1). They were recognized as regulators of feeding The symptoms and pathophysiology of the sleep dis-
structures include the behaviour, firstly because of their exclusive produc- order narcolepsy, caused by an orexin deficiency 5–8
hippocampus and amygdala. tion in the lateral hypothalamic area (LHA), a region (BOX 2) , provide insight into the physiological roles
known as the feeding centre, and secondly owing to their of orexin. Narcolepsy is characterized by the inability
Ghrelin
Stomach-derived orexigenic pharmacological activity; intracerebroventricular (ICV) to maintain vigilance states, pathological intrusion of
peptide. injection of orexins during the light period induces rapid eye movement sleep (REM sleep) and/or non-REM
feeding behaviour in rats and mice1–4. Subsequently, the (NREM) sleep into wakefulness, and frequent transitions
Leptin finding that an orexin deficiency causes narcolepsy in between states of sleep and wakefulness, which indicates
An adipocyte-derived protein
hormone that has a key role in
humans and animals indicated that these hypothalamic that orexins have important roles in the maintenance
regulating energy intake and neuropeptides also have a crucial role in regulating sleep and stabilization of sleep and wakefulness.
energy expenditure. and wakefulness5–9. The first clues towards an involvement of the orexins
Recent studies of orexin-producing neurons’ efferent in narcolepsy came from animal models; mice lacking the
Department of Pharmacology,
and afferent systems, as well as phenotypic characteriza- orexin gene and dogs with null mutations in the orexin
Institute of Basic Medical tions of mice with genetic alterations in the orexin system, receptor 2 (OX2R) gene show phenotypes remarkably
Science, University of have suggested further roles for orexin in the coordination similar to humans with narcolepsy7,8 (see Supplementary
Tsukuba, Ibaraki 305-8575, of emotion, energy homeostasis, reward, drug addiction information S1 (table)). Mice lacking the orexin precur-
Japan and the Yanagisawa
and arousal10–17. sor prepro-orexin, orexin neuron-ablated (orexin/ataxin 3
Orphan Receptor Project,
ERATO, Japan Science and Orexin neurons receive abundant input from the transgenic) mice and OX1R/OX2R double knockout mice
Technology Agency, limbic system14,15, which might be important for increas- exhibit similar phenotypes that have strong parallels to the
Tokyo 135-0064, Japan. ing arousal during emotional stimuli. Orexin neurons are human condition. These are characterized by behavioural
e-mail: also regulated by peripheral metabolic cues, including arrests that are similar to a condition called cataplexy
[email protected]
ghrelin, leptin and glucose, indicating that orexin neurons (BOX 2), occasional direct transitions to REM sleep from
doi:10.1038/nrn2092
Published online might provide a link between energy homeostasis and wakefulness, and highly fragmented sleep-wake cycles7,9,
14 February 2007 vigilance states11. all of which are important elements of narcolepsy.

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Rapid eye movement sleep The link between orexin dysfunction and narcolepsy, The orexin system’s role in wakefulness
(REM sleep) The stage of sleep especially when accompanied by cataplexy (narcolepsy– How do the orexins physiologically regulate sleep and
characterized by rapid cataplexy), has since been supported by findings in human wakefulness, and why does a lack of orexin signalling
movements of the eyes. patients. A post-mortem study of human narcolepsy result in narcolepsy? In this section, I will discuss the
Cataplexy
patients found that orexin peptides were undetectable in mechanisms of action of these peptides at both
An episodic condition featuring the cortex and pons, in which orexinergic projections are the cellular and the systems level.
loss of muscle function, ranging normally found (FIG. 1), and that there was an 80–100%
from slight weakness (such as reduction in the number of neurons containing detect- Orexins stabilize wakefulness. It has been shown that
limpness at the neck or knees,
able prepro-orexin mRNA or orexin-like immunoreac- ICV injection of orexin A or orexin B in rats during
sagging facial muscles or
inability to speak clearly) to
tivity in the hypothalamus5,6. This supports earlier reports the light (rest) period, the equivalent of night-time
complete body collapse. that orexin A was undetectable in the cerebrospinal fluid in humans, increases awake time and decreases REM
of narcolepsy patients18. Approximately 90% of patients and NREM sleep time23. By what mechanisms does the
with narcolepsy, especially those with narcolepsy– orexin system evoke this pharmacological effect?
cataplexy, show decreased orexin A levels in the cerebro- Orexin neurons originate in the hypothalamus and
spinal fluid19. Therefore, a low cerebrospinal fluid level are almost exclusively localized in the LHA and pos-
of orexin A is now one of the diagnostic criteria for terior hypothalamus24–26. These neurons are variable in
narcolepsy–cataplexy, according to the 2nd edition of the size (the cell body diameter ranges from 15–40 μm) and
international classification of sleep disorders20. shape (spherical, fusiform or multipolar), and have been
A recent finding showing concomitant loss of dynor- assumed to number around 3000 in the rat brain, or
phin, neuronal activity-regulated pentraxin and orexin, 7000 in the human brain25,26. From these regions, orexin
which colocalize in orexin neurons, further indicates neurons project widely to the entire neuroaxis,
a loss of orexin neurons in narcolepsy–cataplexy21. The excluding the cerebellum 24–26 (FIG. 1) . The densest
cause of the specific loss or degradation of orexin neurons staining of orexin-immunoreactive nerve endings
in narcolepsy has been unknown so far, but because of its in the brain is found in the paraventricular nucleus
strong association with certain human leukocyte antigen of the thalamus, the arcuate nucleus and, most notably, the
(HLA) alleles22 it is possible that narcolepsy could result locus coeruleus (LC, containing noradrenergic
from selective immune-mediated degeneration of orexin neurons), dorsal raphe (DR, which contains sero-
neurons, although no specific antibody against tonergic neurons) and tuberomammillary nucleus
orexin neurons has been found in the serum of affected (TMN, containing histaminergic neurons) 5,24,25 .
individuals. Regardless of the cause of the neuron loss, The distribution of mRNA for the orexin receptors
the orexin signalling deficiency in narcolepsy–cataplexy is consistent with these projection sites; within the
shows that this neuropeptide system has an important role brain, OX1R mRNA is most abundantly expressed in
in the regulation of sleep and wakefulness, especially in the LC, whereas OX2R mRNA is highly expressed in the
the maintenance of long, consolidated awake periods. TMN27. Both regions are important for the maintenance
of arousal27. The DR and ventral tegmental area (VTA)
contain both OX1R and OX2R mRNA27. These observa-
Box 1 | Overview of the orexin/hypocretin system tions indicate that these monoaminergic regions are
important effector sites of orexins.
Orexin A and orexin B were identified by our group as endogenous ligands for two Consistent with this hypothesis, electrophysiological
orphan G-protein-coupled receptors1. Orexin A and B are derived from a common
experiments using brain slice preparations or isolated
precursor peptide, prepro-orexin. An mRNA encoding the same precursor peptide was
independently isolated as a hypothalamus-specific transcript98. It was predicted that the
cells have shown that cells of these nuclei are activated by
transcript encoded a polypeptide precursor that is cleaved to form two neuropeptides, orexins in vitro. Indeed, noradrenergic cells of the LC23,28,
termed hypocretin 1 and hypocretin 2. To avoid confusion, the orexin nomenclature is dopaminergic cells of the VTA29, serotonergic cells of
used throughout this review, but it should be noted that the names ‘orexin’ and the DR30,31 and histaminergic cells of the TMN32 have
‘hypocretin’ are currently used synonymously in many papers. all been shown to be activated by orexins. Many of these
Orexins constitute a novel peptide family, with no significant homology with any monoaminergic neurons are implicated in increasing
previously described peptides41. Orexin A is a 33 amino acid peptide with an amino arousal and promoting wakefulness. The activity of mono-
(N)-terminal pyroglutamyl residue, two intra-chain disulphide bonds and carboxy aminergic neurons in the TMN, LC and DR is known to
(C)-terminal amidation. This structure is completely conserved among several be synchronized and strongly associated with sleep and
mammalian species (human, rat, mouse, cow, sheep, dog and pig). Orexin B is a 28 amino
wakefulness: the neurons fire tonically during wakeful-
acid, C-terminally amidated linear peptide. The C-terminal half of orexin B is very similar
to that of orexin A, whereas the N-terminal half is more variable.
ness, less during NREM sleep, and not at all during REM
The actions of orexins are mediated by two receptors, named orexin 1 (OX1R) and sleep33. These observations indicate that orexin-mediated
orexin 2 (OX2R) receptors (also known as HCRTR1 and HCRTR2). OX1R has one-order-of- arousal results from the activation of these wake-active
magnitude greater affinity for orexin A than orexin B. By contrast, orexin A and orexin B monoaminergic neurons. Specifically, orexin neurons,
bind OX2R with similar affinities1. OX1R is thought to transmit signals through the Gα11 activated during wakefulness, exert an excitatory influ-
class of G protein, which results in the activation of phospholipase C with subsequent ence on these wake-active neurons, thereby sustaining
triggering of the phosphatidylinositol cascade and influx of extracellular Ca2+, probably their activity.
through transient receptor potential (TRP) channels. OX2R is thought to be coupled to Additional evidence for a role of orexin in wakeful-
both Gα11 and inhibitory Gi G proteins99. OX1R and OX2R mRNAs exhibit a markedly ness is provided by the strong, direct excitatory effect of
different and basically complementary distribution, indicating that these receptors have
orexins on cholinergic neurons in the basal forebrain34,
distinct physiological roles27.
which are important for maintaining arousal 35 .

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Box 2 | What is narcolepsy (narcolepsy–cataplexy)?

Narcolepsy is a serious neurological disorder that affects approximately 1 in 2000 individuals in the United States100.
Onset of the condition is usually during adolescence (around 12–14 years old). A cardinal symptom of the disorder is
excessive daytime sleepiness (an insurmountable urge to sleep), which manifests itself primarily as the subject falling
asleep at inappropriate times (‘sleep attacks’). The latency of rapid eye movement (REM) sleep is notably reduced in
narcolepsy patients, and the existence of ‘sleep onset REM periods’ (that is, REM sleep directly preceded by an awake
period) is one of the diagnostic criteria for narcolepsy. Nocturnal sleep is often disturbed by sleep fragmentation
combined with the occurrence of hypnagogic hallucinations, vivid dreaming and sleep paralysis, which usually occur
when patients fall asleep. Narcolepsy patients often suffer from a condition called ‘cataplexy’, which is characterized by a
sudden weakening of muscle tone, ranging from jaw dropping and speech slurring to complete bilateral collapse of the
postural muscles. These attacks are triggered by emotional stimuli. Consciousness is preserved during cataplexy.
Narcolepsy with cataplexy is sometimes referred as ‘narcolepsy–cataplexy’.
Symptoms of narcolepsy–cataplexy can be divided into two pathological phenomena. One is an inability to maintain a
long awake period, characterized by abrupt transition to non-REM (NREM) sleep (dysregulation of NREM sleep onset).
This phenomenon manifests clinically as excessive daytime sleepiness or a sleep attack. Recent studies suggested that it
largely results from lack of OX2R activation42. Psychostimulant drugs, such as modafinil, methyl phenidate, amphetamine
and caffeine are used to treat these symptoms. The other key phenomenon is the pathological intrusion of REM sleep into
wakefulness (dysregulation of REM sleep onset); it is during these periods that the patient might experience cataplexy,
hypnagogic hallucinations and sleep paralysis. Available therapy for this symptom consists of tricyclic antidepressants
such as imipramine and selective serotonin reuptake inhibitors101. Lack of signalling from both receptors is critically
associated with this symptom.

In addition, orexin neurons project directly to the However, one should not disregard the importance
laterodorsal tegmental/pedunculopontine tegmental of OX1R in the regulation of sleep and wakefulness. The
nucleus (LDT/PPT) cholinergic neurons, some popu- behavioural and electroencephalographic phenotype
lations of which are implicated in the in the mainte- of prepro-orexin-knockout mice and double-receptor
nance of wakefulness36. Other populations of LDT/PPT knockout (OX1R- and OX2R-null) mice41, which seem
neurons are implicated in the regulation of REM sleep to have similar phenotypes41, is more severe than that of
and muscle atonia during REM sleep36. Direct injection OX2R-knockout mice42, supporting an important but less
of orexin A into the LDT of cats results in an increased significant contribution of OX1R (FIG. 2; Supplementary
awake time and a decreased REM sleep time37. In addi- information S1 (table)). OX 2R-knockout and pre-
tion, several reports have shown that orexin induces pro-orexin-knockout mice are similarly affected by
long-lasting excitation of cholinergic neurons in the behaviourally abnormal attacks of NREM sleep (sleep
LDT38. However, more recent work has shown that attacks)42, but OX2R-knockout mice show a lower degree
orexin A inhibits cholinergic neurons in the PPT through of disrupted wakefulness compared with double-receptor
activation of GABA (γ-aminobutyric acid)-containing knockouts42 (FIG. 2). In particular, OX2R-knockout mice
local interneurons and GABA-containing neurons in the are only mildly affected by cataplexy and direct transi-
substantia nigra pars reticulata39. These results indicate tions to REM sleep from awake states42, whereas prepro-
that hypothalamic orexin neurons affect the activity of orexin-knockout mice and double-receptor knockout
LDT/PPT cholinergic neurons both directly and indi- mice are severely affected7,41,42 (FIG. 2). These observations
rectly to regulate arousal and REM sleep. However, fur- indicate that OX1R has additional effects on sleep–wake
ther studies are needed to understand the precise effects regulation, especially the regulation of REM sleep.
of orexins on LDT/PPT cholinergic neurons. So, despite the lack of an overt OX1R–/– phenotype, loss
of signalling through both receptor pathways seems to
Orexin receptors in sleep and wakefulness. Some reports be necessary for the emergence of a complete narcoleptic
have indicated that the effect of orexin on wakefulness is phenotype, indicating that both receptors are involved in
largely mediated by activation of the histaminergic sys- the regulation of sleep and wakefulness.
tem through the OX2R. In rats, ICV injection of orexin
during the light period potently increases the duration Orexinergic activity in the sleep–wake cycle. In trans-
of wakefulness, and this effect is markedly attenuated genic mice with constitutive activation of orexinergic
by the histamine H1 receptor antagonist, pyrilamine32. tone (CAG/orexin mice), orexin is expressed in a dif-
This pharmacological effect of orexin A on awake time fuse, ectopic pattern in the brain in an unregulated
is almost completely absent in H1-deficient mice40. fashion43. The mice exhibited abnormal sleep and wake-
Furthermore, whereas OX1R-knockout mice show only fulness patterns, including fragmented NREM sleep
a mild fragmentation of sleep and awake states41, OX2R- in the light period and incomplete REM sleep atonia
knockout mice exhibit a narcoleptic phenotype42 (FIG. 2; with abnormal myoclonic activity during REM sleep
Supplementary information S1 (table)). OX2R is abun- (T.S., unpublished observations). These results indicate
dantly expressed in the histaminergic TMN, whereas that orexin neurons need to be switched off to maintain
OX1R is highly expressed in the noradrenergic LC, indi- consolidated NREM sleep and the muscle atonia that
cating that the TMN might be an important effector site accompanies REM sleep, but have to be activated during
of orexin for the regulation of sleep and wakefulness. awake periods.

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Orthodromic and Consistent with this idea, Fos expression (a marker of waking, decreased discharge during quiet waking, and
antidromic activation neuronal activity) in orexin neurons in rats is increased virtually ceased firing during both REM and NREM
Neural stimulation in the same during the dark, active period in which the awake state sleep. Orexin neurons increased firing before the end of
and the opposite direction of is dominant44. Moreover, orexin levels in cerebrospinal REM sleep and thereby heralded by several seconds the
the physiological nerve
conductance, respectively.
fluid peak during the dark period and decrease during return of the awake state. Although the numbers of cells
the light period in which the sleep state is dominant45. examined are too small to provide a complete picture
Recent in vivo recording studies revealed further changes of orexin neurons’ activity across the sleep–wake cycle,
of orexin neuronal activity across the sleep–wake cycle. these seminal studies provide the strongest evidence
Mileykovskiy et al. recorded orthodromic and antidromic that these cells are activated during wakefulness, and
activity of VTA and LC to identify orexin neurons in inhibited during sleep.
unanaesthetized, unrestrained rats46. They found that
orexin neurons were relatively inactive in quiet waking Other functions of orexins
but were transiently activated during sensory stimula- Feeding behaviour and energy homeostasis. Narcolepsy
tion. Furthermore, the neurons were silent during NREM patients have a decreased caloric intake but an increased
sleep and tonic periods of REM sleep, with occasional body mass index, indicating that the abnormality that
burst discharges during phasic REM sleep. gives rise to narcolepsy has links to a reduced energy
Lee et al. also recorded from orexin neurons, identi- expenditure or a low metabolic rate48,49. Orexin neurons
fied using a combination of neurobiotin labelling and have been shown to have a role in the regulation of energy
immunohistochemistry, in the LHA of head-fixed rats47. homeostasis. For example, orexin neuron-ablated mice
They found that the orexin neurons fired during active exhibit hypophagia and late-onset obesity, although the
extent to which this is the case critically depends on
the genetic backgrounds of the mice9,50.
Supporting the physiological relevance of orexin in
the control of feeding, ICV administration of an anti-
orexin antibody or an OX1R-selective antagonist reduced
food intake3,51, and prepro-orexin-knockout mice and
transgenic mice lacking orexin neurons ate less than
control wild-type mice9,41. Moreover, an OX1R-selective
antagonist reduced food intake and ameliorated obesity
in leptin-deficient ob/ob mice2.
Consistent with the dense projection of orexin
neurons to the arcuate nucleus24,26,52, several studies
have suggested that the increased food intake following
orexin A administration is at least partly mediated by
the activation of neuropeptide Y neurons in the arcuate
nucleus52,53. Other events involved in orexin-induced
feeding behaviour include the inhibition of pro-
LHA/PH opiomelanocortin neurons in the arcuate nucleus, which
LC OX1R are thought to have an important role in leptin-mediated
TMN OX2R inhibition of food intake53. Recent reports also showed
that infusions of orexin A into the shell of the nucleus
Raphe
accumbens (NAc) increase feeding behaviour54. In addi-
LDT
OX1R and OX2R tion, infusions of the GABAA receptor agonist muscimol
VTA into the NAc shell strongly induced food intake and
PPT simultaneously increased Fos expression specifically in
orexin neurons55. These findings indicate that reciprocal
Figure 1 | Schematic drawing showing main projections of orexin neurons.
This figure summarizes predicted orexinergic projections in the human brain. Please interactions between the orexin and limbic systems have
note that distributions of orexin fibres and receptors (OX1R, OX2R) are predicted from a role in the regulation of feeding.
the results of studies on rodent brains, as it is on rodents that most histological studies Orexin-mediated maintenance of consolidated wake-
on the orexin system have been carried out. Circles show regions with strong receptor fulness might also be important in feeding behaviour,
expression and dense orexinergic projections. Orexin neurons originating in the lateral because maintenance of arousal during food search-
hypothalamic area (LHA) and posterior hypothalamus (PH) regulate sleep and ing and intake is essential for an animal’s survival. For
wakefulness and the maintenance of arousal by sending excitatory projections to the example, when faced with reduced food availability,
entire CNS, excluding the cerebellum, with particularly dense projections to animals adapt with a longer awake period, which dis-
monoaminergic and cholinergic nuclei in the brain stem and hypothalamic regions24–32,38,
rupts the normal circadian pattern of activity11,56,57. This
including the locus coeruleus (LC, containing noradrenaline), tuberomammillary
response is absent in transgenic mice with ablated orexin
nucleus (TMN, containing histamine), raphe nuclei (Raphe, containing serotonin) and
laterodorsal/pedunclopontine tegmental nuclei (LDT/PPT), containing acetylcholine). neurons11, indicating that these neurons are crucial for
Orexin neurons also have links with the reward system through the ventral tegmental evoking adaptive maintenance of arousal during fast-
area (VTA, containing dopamine) and with the hypothalamic nuclei that stimulate ing. In other words, if energy stores are low, the activ-
feeding behaviour. Anatomical image adapted, with permission, from REF. 108 © (1996) ity of orexin neurons could be modulated to maintain
Appleton & Lange. wakefulness, allowing more time to search for food.

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R WT DMH and orexin neurons has a key role, as a central

S food-entrainable oscillator, in the feeding-mediated
W
regulation of circadian behaviours.
Sleep–wake state

R
S OX R KO
1 Orexin and the autonomic nervous system. Several stud-
W
ies have clearly shown that orexins have a role in regulat-
R OX R KO
2
ing autonomic function. It has been demonstrated that
S ICV orexin injections increase blood pressure and heart
W
OX R KO/OX R DKO
1 2
rate, and that these effects are abolished by the admin-
R istration of drugs that block α- or β-adrenoceptors60.
S Moreover, blood pressure in orexin-deficient mice is
W
10–15 mmHg lower than in wild-type littermates61,62.
20:00 22:00 24:00 02:00 04:00 06:00 These results indicate that orexins physiologically
Time stimulate sympathetic outflow and provide a pos-
Figure 2 | Sleep state abnormalities in orexin receptor-knockout mice. Typical sible explanation for the increased body mass index
representative 12 hour dark period (20:00–08:00) hypnograms for wild-type (WT), OX1R- observed in conditions of low orexin: orexin deficiency
knockout (OX1R KO), OX2R-knockout (OX2R KO) and double-receptor knockout mice might decrease sympathetic tone, which could result
(OX1R/OX2R DKO), all on a C57B/6J background, are shown. The different levels above
in decreased energy expenditure. As might be expected in
the baseline indicate states of sleep and wakefulness (R, rapid eye movement (REM)
a system geared for weight gain, orexins do not slow the
sleep; S, non-REM (NREM) sleep; W, awake) of the mouse at the time. Episodes of direct
transition from wakefulness to REM sleep are shown by red arrowheads. Note the greater metabolic rate. Instead, they increase both food intake
awake/NREM sleep episode fragmentation and reduced duration of wakefulness in the and metabolic rate63. Because animals must be vigilant and
hypnograms of OX2R-knockout and double-receptor knockout mice compared with active when they seek and eat food, an orexin-induced
wild-type and OX1R-knockout mice. Episodes of direct transition from wakefulness to increase in sympathetic nerve activity might be important
REM sleep were not observed in OX1R-knockout mice, and barely in OX2R-knockout for feeding behaviour.
mice, whereas they were frequently observed in double-receptor knockout mice. As discussed later, the orexin-mediated increase in
Hypnograms were obtained by simultaneous electroencephalography (EEG) and sympathetic tone could also be involved in the mechanisms
electromyography (EMG) recording for 4 weeks (N = 18–40). by which the limbic system modulates the sympathetic
outflow responding to emotional stimuli61,62.
The activity of orexin neurons also contributes to
the promotion and maintenance of food anticipatory Orexin and the reward system. Anatomically, orexin
activity (FAA)12,13. Daily restricted feeding produces an neurons are well-positioned to alter reward function-
anticipatory locomotor activity rhythm and entrains a ing. Orexin neurons project to reward-associated brain
molecular oscillator that is independent of the central regions, including the NAc and VTA, and orexin directly
clock, which is located in the suprachiasmatic nucleus activates VTA dopaminergic neurons through OX1R29
(SCN). Restricted feeding shifts the peak of Fos (FIG. 3) . This indicates a possible role for orexins in
expression in orexin neurons from night to the period reward function and motivation, consistent with previ-
during which feeding was restricted, indicating that ous studies implicating orexins in feeding. In fact, the
orexin neurons are activated when animals need to be activation of orexin neurons was shown to be strongly
awake and seek food12,13. The establishment of FAA linked to preferences for cues associated with drug and
was severely impaired in orexin/ataxin 3 transgenic food rewards16. Dopaminergic neurons that originate
mice, in which orexin neurons are ablated12,13. The in the VTA and project into the forebrain, particularly
transgenic mice also showed reduced expression of the NAc, have classically been identified as the ‘reward
mRNA for murine period 1 (mPer1), brain and muscle pathway’. Drugs of abuse stimulate this pathway. ICV
arnt-like protein 1 (Bmal1) and neuronal PAS domain or local VTA infusions of orexin have been shown to
protein 2 (Npas2), a transcription factor thought to be reinstate drug-seeking or food-seeking behaviour in
Food anticipatory activity
(FAA). Behavioural activation involved in regulating the food-entrainable oscillator. rodents10,16. Conversely, the subcutaneous morphine
induced by restricted access These observations indicate that orexin neurons con- (μ-opioid receptor agonist)-induced place preference
to food; a manifestation of the vey an efferent signal from a putative food-entrainable and hyperlocomotion observed in wild-type mice were
food-entrained oscillator. oscillator or oscillators to increase wakefulness and abolished in mice that lacked the prepro-orexin gene17,
mPer1
locomotor activity. Recently, a part of the dorsomedial and injections of an OX1R antagonist into the VTA block
The PER1 gene is a core clock hypothalamic nucleus (DMH) was shown to have a the development of morphine-conditioned place pref-
factor that has an essential role robust oscillation of mPer gene expression only under erence17. These observations indicate the strong func-
in generating circadian restricted feeding 58. The oscillation persisted for tional interaction between orexinergic pathways and the
rhythms. mPer1 is the mouse
at least 2 days, even when mice were given no food dopaminergic system.
counterpart of the human
PER1 gene. during the expected feeding period after the establish- Recent work has provided interesting insights into
ment of the FAA. It has also been demonstrated that the cellular and molecular mechanisms underlying
Bmal1 lesions in the DMH in rats blocked food entrainment these effects by showing that orexin A input to the
Bmal1 (brain and muscle arnt- of wakefulness, locomotor activity and core body VTA potentiates NMDAR (N-methyl-d-aspartate
like protein 1) is a putative
clock gene which encodes a
temperature59. Taken in conjunction with recent find- receptor)-mediated neurotransmission through a
basic helix-loop-helix-PAS ings that DMH neurons project to orexin neurons14,15, protein kinase C-dependent insertion of NMDARs in
transcription factor. these results indicate that the connection between the VTA dopamine neuron synapses in slice preparations64.

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Furthermore, in vivo administration of an OX 1 R the periventricular hypothalamic nucleus (PVN) and

antagonist blocks locomotor sensitization to cocaine the central nucleus of the amygdala (CeA)68. The link
and occludes cocaine-induced potentiation of excita- between the CRF system and orexin neurons is recipro-
tory currents in VTA dopamine neurons 64. These cal69, and might maintain wakefulness during stressful
results suggest an important role for orexin signal- events.
ling in the VTA in the neural plasticity associated
with reward, and indicate that orexins also contribute Mechanisms regulating orexin neuron activity
to cocaine-induced psychomotor sensitization and To establish the physiological relevance of orexins,
reward-seeking. These findings highlight the key understanding the system that regulates the activity of
role of orexin in the mechanisms of reward and drug orexin neurons is key. This section discusses several
addiction. Consistently, prepro-orexin-knockout mice factors and systems involved in this regulation.
are less susceptible than wild-type animals to develop-
ing morphine dependence, as measured by physical Neurotransmitters and neuromodulators. Electro-
withdrawal responses65. Interestingly, some narcolepsy physiological studies have identified several neuro-
patients with daytime sleepiness who were treated with transmitters and neuromodulators that activate or
amphetamine-like stimulants and/or sodium oxybate inhibit the activity of orexin neurons (TABLE 1). By
(γ-hydroxybutyrate, also known as GHB) for a long recording from hypothalamic slices of transgenic mice
time rarely developed drug abuse66. that express green fluorescent protein (GFP) selec-
tively in orexin neurons, it was shown that agonists
Orexin and the stress response. Orexin influences of ionotropic glutamate receptors (AMPA (α-amino-
neuroendocrine function, and thereby affects arousal 3-hydroxy-5-methyl-4-isoxazole propionic acid) and
and the stress response. For example, ICV injection of NMDA) excite orexin neurons, whereas glutamate
orexin stimulates the hypothalamic–pituitary–adrenal antagonists (AP5 (D(–)-2-amino-5-phosphonovaleric
(HPA) axis67 and decreases prolactin secretion23. ICV acid), CNQX (6-cyano-7-nitroquinoxaline-2,3-dione)
administration of orexin A strongly activates cortico- or NBQX (6-nitro-7-sulphamoylbenzo(f)quinoxaline-
tropin releasing factor (CRF)-expressing neurons in 2,3-dione)) reduce their activity 70,71. These results
indicate that orexin neurons are tonically activated by
glutamatergic neurons.
SCN LDT/PPT In addition, several other neurotransmitters
Acetylcholine have been shown to influence the activity of orexin
Amygdala VTA
neurons. Importantly, both noradrenaline and serotonin
and BST DMH Dopamine (5-hydroxytryptamine, 5-HT) hyperpolarize and
LC inhibit GFP-expressing orexin neurons through the
Noradrenaline activation of G-protein-regulated inwardly rectifying
LHA DR K+ (GIRK or Kir3) channels by α2-adrenoceptors and
VLPO Serotonin 5-HT 1A receptors, respectively 70–72. The cholinergic
Orexin
GABA
PH agonist carbachol activates 27% and inhibits 6% of
TMN orexin neurons14,71, whereas histamine seems to have
Histamine
no effect on orexin neurons. These observations
OX R SNr
1

GABA indicate that serotonin and noradrenaline neurons

OX R Glucose Ghrelin Leptin
2 might send inhibitory feedback projections to orexin
Excitatory Pheripheral neurons. Furthermore, although orexin neurons
metabolic cues
Inhibitory do not express functional dopamine receptors,
dopamine can inhibit orexin neurons by acting on
Figure 3 | Interactions of orexin neurons with other brain regions implicated in α2-adrenoceptors71,72.
sleep and wakefulness. Orexin neurons in the lateral hypothalamic area (LHA) and
A recent study showed that a short 2 hour period
posterior hypothalamus (PH) are anatomically well placed to provide a link between the
limbic system, systems involved in energy homeostasis and monoaminergic and of total sleep deprivation changed the action of
cholinergic neurons in the brain stem. Solid arrows show excitatory projections, and noradrenaline on orexin neurons from excitation to
broken lines inhibitory ones. Wake-active regions, sleep-active regions and REM-active inhibition. This mechanism might contribute to the
regions are shown by red, blue and green boxes, respectively. Orexin neurons promote growing sleepiness that accompanies sleep depriva-
wakefulness through the monoaminergic nuclei that are wake-active. Stimulation of tion73, although this phenomenon was not observed
dopaminergic centres by orexins can modulate reward systems (purple). Peripheral in mice72.
metabolic signals such as leptin, ghrelin and glucose influence orexin neuronal activity to Using transgenic mice in which orexin neurons spe-
coordinate arousal and energy homeostasis. The nucleus suprachiasmaticus (SCN), the cifically express a genetically encoded intracellular cal-
central body clock, sends signals to orexin neurons via the dorsomedial hypothalamus cium indicator (Yellow Cameleon, Yc2.1), we screened
(DMH). The DMH acts as a food-entrainable ossilator, and influences orexin neuronal
for factors that affect the activity of orexin neurons and
activity. Input from the limbic system (amygdala and bed nucleus of the stria terminalis
(BST)) might regulate the activity of orexin neurons upon emotional stimuli to evoke found that a sulphated octapeptide form of cholecysto-
emotional arousal or fear-related responses61,62. VLPO, ventrolateral preoptic area; DR, kinin (CCK-8S), as well as neurotensin, oxytocin and
dorsal raphe; GABA, γ-aminobutyric acid; LC, locus coeruleus; LDT, laterodorsal tegmental vasopressin activate orexin neurons74, whereas GABA,
nucleus; PPT, pedunculopontine tegmental nucleus; SNr, substantia nigra pars reticulata; glucose, serotonin, noradrenaline and leptin inhibit
TMN, tuberomammillary nucleus. them (TABLE 1). Finally, a recent paper described how

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Table 1 | Factors that influence the activity of orexin neurons tion and an increase in action potential frequency11.
By contrast, bath-application of leptin was found to
Factor Receptor involved References
robustly inhibit most of the orexin neurons examined,
Excitatory causing hyper polarization and a decrease in firing
Glutamate AMPAR, NMDAR, mGluRs 11,70 rate11. Notably, insulin exerted no direct effect on orexin
Ghrelin GHSR 71 neurons11.
The above findings show that peripheral humoral
Cholecystokinin CCK-A 74 factors that are related to energy metabolism influ-
Neurotensin ND 74 ence the activity of orexin neurons. In addition, orexin
Vasopressin V1a 74 expression in wild-type and ob/ob mice is negatively
correlated with changes in blood glucose, leptin and
Oxytocin V1a 74
food intake11. This is consistent with the idea that orexin
Glucagon-like peptide 1 ND 105 neurons act as sensors of the nutritional status of the
CRF CRFR1 69 body1,11,41.
mACh (effect in 27% of orexin neurons) M3 14 Orexin neurons have been shown to be stimulated by
hypoglycemia at least partly via the nucleus of the soli-
ATP P2X 106
tary tract (NTS)78,79, indicating that peripheral metabolic
Inhibitory cues might also influence the activity of orexin neurons
Glucose Unknown 11 indirectly through vagal afferents and the NTS.
GABA GABAA, GABAB 11,70,89 What is the physiological relevance of the regulation
of orexin neurons by factors that act as indicators of an
Serotonin 5-HT1A 71,91
animal’s nutritional state? When faced with a negative
Noradrenaline α2 71,72 energy balance due to reduced food availability, mam-
Dopamine α2 71 mals respond behaviourally with phases of increased
wakefulness and alertness that presumably enhance the
Neuropeptide Y Y1 107
ability to find food56,57. Orexin neuron-ablated mice fail
Leptin OB-R 11 to exhibit this fasting-induced arousal11, indicating that
mACh (effect in 6% of orexin neurons) ND 14,71 orexin neurons are necessary for evoking adaptive behav-
Adenosine A1 75 ioural arousal during fasting. So, nutritional depletion-
α2, α2 adrenergic receptor; 5-HT1A, 5-hydroxytryptamine receptor 1A; AMPAR, α-amino-3-
induced metabolic cues activate orexin neurons, and
hydroxy-5-methyl-4-isoxazole propionic acid receptor; CCK-A, cholecystokinin receptor A; orexin increases arousal, thereby reinforcing food-
CRFR1, corticotropin-releasing factor receptor 1; GABA, γ-aminobutyric acid; GHSR, growth- seeking/feeding pathways. These mechanisms might
hormone secretagogue receptor; mACh, muscarinic acetylcholine; mGluRs, metabotropic
glutamate receptors; ND, not determined; NMDAR, N-methyl-d-aspartate receptor; also be important in the maintenance of prolonged
OB-R, leptin receptor; P2X, purinocepter. wakefulness during the active period; in the regulation
of energy homeostasis that helps to ensure survival; and,
adenosine inhibits orexin neurons via the adenosine interestingly, might hinder attempts to treat obesity by
A 1 receptor 75. This mechanism might relate to the food restriction. This might also explain why orexin
sleep-promoting effect of adenosine75. receptor antagonists decrease food intake3.

Humoral factors. Metabolic signals also contribute to Neuronal input. Until recently, very little was known
the regulation of orexin neuron activity: decreasing the about the synaptic input into hypothalamic orexin
extracellular glucose concentration produced depolari- neurons, and this seems to be largely because of the
zation and increased the frequency of action potentials challenges associated with the cells being dispersed
in orexin neurons, whereas increasing it induced marked mediolaterally within the LHA. In mice with a geneti-
hyperpolarization and cessation of action potentials in cally encoded retrograde tracer, the neuronal popula-
the same neurons11,76. Importantly, this mechanism is tions that send afferent innervations to orexin neurons
sufficiently sensitive to encode variations in glucose were mapped14. Labelled cells were identified in multiple
levels reflecting those occurring physiologically between brain regions, including the basal forebrain cholinergic
normal meals11,76. neurons, GABA-containing neurons in the ventrolateral
A recent study demonstrated that the inhibition of preoptic nucleus (VLPO), neurons in the posterior/
orexin neurons by glucose is mediated by tandem-pore dorsomedial hypothalamus and serotonergic neurons in
K+ (K2P) channels77. Glucose seemed to act at an extra- the raphe nuclei. Labelled neurons were also found
cellular site on orexin neurons, as it inhibited orexin in regions associated with emotion including the amyg-
neurons only when applied extracellularly77. An undeter- dala, infralimbic cortex, NAc shell, lateral septum and
mined intracellular messenger that was not ATP, Ca2+ or the bed nucleus of the stria terminalis (BST).
glucose itself transmitted this information to the chan- By combining antero- and retrograde tracers, a study
nels77. These results reveal an unexpected energy-sensing mapped afferents of orexin neurons in rats and found
pathway in neurons that regulates states of wakefulness that hypothalamic orexin neurons received abundant
and energy balance77. projections from the lateral septum, preoptic area, BST
Ghrelin applied in a superfused solution activated and posterior hypothalamus15. In addition, it was found
60% of dispersed orexin neurons, with depolariza- that hypothalamic regions preferentially innervated

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Box 3 | The extended amygdala and emotion knockout mice83. Similarly, air-jet stress-induced eleva-
tions of blood pressure and heart rate were attenuated in
A key component of the neural circuitry of emotion in animals is the amygdala and its conscious orexin/ataxin 3 transgenic mice, in which orexin
related regions (extended amygdala), which consist of a well-defined subcortical nuclear neurons are ablated62.
group that in vertebrates is a centre for emotional responses, including fear102–104. The
Limbic inputs to orexin neurons include the CRF
amygdala receives many kinds of sensory information directly from the periphery, or via
neurons that originate in the amygdala69. They activate
the thalamus and cortex. For example, sensory stimuli that predict an aversive outcome
will change neural transmission in the amygdala to produce the somatic, autonomic and orexin neurons through the CRF-R1 receptor69. The
endocrine signs of fear, as well as increased attention and arousal to that stimulus. reciprocal link between the CRF system and orexin
Consolidation of emotional memory involves lateral and basolateral parts of the neurons might maintain wakefulness during stressful
amygdala, where the association between incoming sensory stimuli leads to events. Indeed, activation of orexin neurons by foot shock
potentiation of synaptic transmission. These parts project to the central amygdala stress is severely impaired in CRF-R1-deficient mice,
(CeA), which in turn sends efferents to the hypothalamus and brain stem that trigger indicating that such activation is mediated by CRF69.
the expression of emotions including arousal, autonomic and endocrine responses. The The neural input from the limbic system to orexin
regions closely associated with the amygdala are also important for fear learning, and neurons might be implicated in the pathophysiology of
include the bed nucleus of the stria terminalis (BST). Orexin neurons have been shown
cataplexy, because strong, generally positive emotional
to receive innervations from these regions14,15, indicating that these cells have a role in
stimuli are known to trigger cataplexy in narcolepsy–
the emergence of emotional responses, such as increased arousal and sympathetic
outflow during fearful events. cataplexy patients. A local injection of orexin into the
PPT strongly inhibited REM-related atonia in cats39.
Cholinergic neurons in the LDT/PPT are implicated in
the medial and perifornical parts of the orexin neuron REM-related atonia84, and the same pathway is implicated
field, but most projections from the brainstem targeted in cataplexy. Therefore, emotional stimuli might increase
the lateral part of the field, indicating a functional orexin release in the PPT to prevent muscle atonia
dichotomy of orexin neurons. in wild type animals. Projections to orexin neurons
However, tracing studies might not show all input to from the limbic system might also be important for
orexin neurons. Monoaminergic and peptidergic systems maintaining orexin neuron activity during the active
sometimes use ‘volume transmission’, which includes period by conveying various emotional stimuli to orexin
short- (but larger than the synaptic cleft, that is, roughly neurons (FIG. 3).
20 nm) and long-distance diffusion of signals through the The limbic input to orexin neurons might also be
extracellular and cerebrospinal fluid80. Therefore, although involved in the regulation of feeding behaviour, because
tracing studies showed that projections of noradrenergic some of the affective content of the perception of food
and dopaminergic neurons to orexin neurons are sparse, it is thought to be processed in the amygdala and limbic
is important not to disregard the effects that these factors system85, and this information might be passed on to
might have on orexin neurons (TABLE 1). orexin neurons. Food perception often evokes cataplexy
Some studies have revealed that orexin neurons in narcoleptic dogs86, indicating that orexin signalling
show apposition from peptidergic fibres, including is physiologically activated on perception of food, and
neuropeptide Y, pro-opiomelanocortin and galanin-like that this system is necessary to evoke proper feeding
peptide fibres81,82. Again, these data must be interpreted behaviour.
carefully; such chemically defined ‘apposition’ does not
necessarily mean that the nerve terminals functionally Input from preoptic areas. The preoptic area, especially
synapse onto orexin neurons. the VLPO, seems to have a crucial role in NREM sleep
Finally, not only synaptic receptors contribute to initiation and maintenance. Neurons in the VLPO fire
regulating neuronal activity. Extrasynaptic receptors at a rapid rate during sleep, with attenuation of firing
can sense ambient ligands such as CCK, leptin and during wakefulness. GABA and galanin are the primary
glucose, which can act as a neuromodulators on orexin inhibitory neurotransmitters of the VLPO87, which sends
neurons11,74 (TABLE 1). out multiple inhibitory projections to the LC, TMN
and DR87,88.
Interactions with other neuronal systems Orexin neurons, which are innervated by GABA-
Orexin neurons interact with multiple neuronal systems containing cells in the VLPO14,15, are strongly inhibited
(FIG. 3). These interactions provide a key to understanding by both the GABAA agonist muscimol and the GABAB
the physiological roles of orexin neurons. receptor agonist bacrofen11,89, indicating that the VLPO
might be a source of GABA-containing inhibitory projec-
Input from the limbic system. Arousal resulting from tions to orexin neurons. This pathway might be important
emotional stimuli or fear-related responses increases for turning off orexin neurons during sleep (FIGS 3,4).
sympathetic outflow. Orexin neurons receive input
from the limbic system14,15,69, indicating a role for this Input from the SCN. Although direct input to
system in the regulation of orexin neuron activity (BOX 3). orexin neurons from the SCN seems to be sparse, orexin
Indeed, the importance of this connection is readily appar- neurons receive abundant innervations from the BST,
ent in the defence, or ‘fight or flight’, response: mice tested supraventricular zone and DMH14,15, all of which receive
in a resident–intruder paradigm show cardiovascular and input from the SCN. This indicates that orexin neurons
locomotor responses to the emotional stress evoked by this might receive circadian influences indirectly from the
test, but these responses are diminished in prepro-orexin- SCN via these regions90.

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a Awake state Figure 4 | Mechanisms by which the orexin system

Limbic system stabilizes sleep and wakefulness. The figures represent
Orexin functional interactions between orexin neurons,
SCN neurons monoaminergic wake-active centres and the ventrolateral
Energy balance preoptic area (VLPO) sleep-active centre during various
states of sleep and wakefulness. Solid arrows show
Monoaminergic excitatory input, and broken lines inhibitory input. The
neurons
VLPO thickness of arrows and lines represents the relative
strength of excitatory and inhibitory input, respectively.
Circle sizes represent relative activities of each region.
a | Awake state. Orexin neurons send excitatory influences
Thalamus
Cortex to monoaminergic neurons, which send inhibitory
b Sleep state Orexin feedback projections to orexin neurons. This system might
neurons maintain the activity of monoaminergic neurons. A slight
decrease in input to the monoaminergic neurons results in
decreased inhibitory influence to orexin neurons. Orexin
Monoaminergic neurons, therefore, are disinhibited and increase excitatory
VLPO neurons influence to monoaminergic cells to maintain their activity.
These monoaminergic cells send excitatory projections to
the thalamus and cerebral cortex, and send inhibitory
Thalamus
Cortex projections to the VLPO sleep centre. These mechanisms
maintain wakefulness states. b | Sleep state. VLPO sleep-
c Narcolepsy Orexin active neurons are activated and send inhibitory
neurons projections to monoaminergic neurons and orexin neurons
to maintain sleep. c | Narcolepsy. If orexin neurons are
Monoaminergic removed, monoaminergic neurons and VLPO neurons set
VLPO neurons
up a mutually inhibitory circuit, which can cause unwanted
and abrupt transitions between the states. Activity in one
of the competing sides shuts down inhibitory inputs from
Inhibitory the other side, and therefore disinhibits its own action. So,
Thalamus
Excitatory Cortex when either side begins to overcome the other, the switch
abruptly turns into the alternative state.

Mechanisms that stabilize sleep and wakefulness VLPO sleep-active neurons and vice versa97. In such a
Orexin neurons are an important component of the circuit, when activity on either side begins to overcome
neural circuits that regulate sleep and wakefulness. How, the other, the system will flip into one of two possible
then, do these neurons stabilize sleep and wakefulness extremes, because when a small perturbation gives one
through these circuits? side a sudden ‘advantage’, it will turn off the alternative side
As previously discussed, a feedback loop between abruptly96. A circuit of this type is thought to underlie
orexin neurons and monoaminergic neurons in the the pathology of narcolepsy (FIG. 4).
brain stem including the LC and DR71,72,91 might main-
tain the activity of monoaminergic neurons. Decreases Sleep modulation using the orexin system
in monoaminergic neuron activity will decrease the Because narcolepsy–cataplexy is a disorder of sleep–wake
inhibitory influence on orexin neurons. This disinhi- cycle organization resulting from the absence of orexin,
bition of orexin neurons then increases the excitatory it is perhaps logical to consider that replacement therapy
influence on monoaminergic cells, thereby increasing using orexin receptor agonists could provide an effective
their activity (FIG. 4). treatment for this disorder. Indications that this might be
Sleep-active, GABA-containing neurons in the VLPO successful came from a study which showed that chronic
send descending projections that terminate within overproduction of orexin peptides from an ectopically
wake-promoting populations in the TMN, LC and DR88. expressed transgene prevented the development of a
During sleep, VLPO sleep-active neurons are thought to narcolepsy syndrome in orexin neuron-ablated (orexin/
be activated by sleep substances such as adenosine92–94, ataxin 3 transgenic) mice43. Acute ICV administration of
and send inhibitory influences to monoaminergic orexin A also maintained wakefulness, suppressed sleep
neurons in the brain stem and hypothalamus. As discussed and inhibited cataplectic attacks in orexin/ataxin 3 mice43.
above, the sleep-active neurons also send inhibitory In fact, ICV administration of orexin A had stronger
projections to hypothalamic orexin neurons15,95. arousal effects in orexin/ataxin 3 transgenic mice than
These circuits are important for the regulation in wild-type controls43. The greater effectiveness might
of wakefulness. If orexin neurons are removed from not have resulted from increased expression of orexin
this system, as is the case in narcolepsy–cataplexy, the receptors43. Rather, in the orexin/ataxin 3 mice, mono-
sleep-active neurons in the VLPO and monoaminergic aminergic neurons in the brain stem became more sensi-
neurons exhibit a ‘flip-flop’ property, owing to the mutual tive to various stimuli (T.S., unpublished observations).
inhibition between these two neuronal elements96: This mechanism might explain why narcoleptics cannot
monoaminergic neurons send inhibitory influences to maintain long, consolidated NREM sleep periods.

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The effectiveness of ICV-administered orexin in ani- systems, and send excitatory signals to monoaminergic
mals with a narcoleptic phenotype indicates that orexin and cholinergic nuclei in the brain stem. Interactions
receptor agonists would be of potential value for treating with these systems indicate physiological functions of
narcolepsy. However, as mentioned above, chronic over- orexin neurons, as discussed in this review. These func-
expression of orexin in an unregulated fashion results tions should be further explored in future studies using
in disruption of NREM sleep, and therefore it will be conditional knockouts of receptors that are expressed
beneficial for therapeutically relevant orexin agonists to in orexin neurons. A more precise understanding of the
have a short half-life (< 12 hours). Conversely, orexin mechanisms that regulate orexin neurons might provide
antagonists might be effective as a sleep-inducing drug. further insights into how the systems that regulate emo-
tion, energy homeostasis and reward interact with the
Conclusion and perspectives mechanism that regulates sleep and wakefulness.
The symptoms and the cellular and systems-level bases
of narcolepsy–cataplexy unequivocally show that orexins Note added in proof
and orexin receptors are important regulators of sleep and A recent paper showed that a new, potent, orally avail-
wakefulness and of arousal maintenance by regulating able dual orexin receptor antagonist, ACT-078573, which
monoaminergic and cholinergic nuclei in the brain. blocks both OX1R and OX2R, effectively promotes sleep
Orexin neurons receive afferents from multiple neuronal in rats, dogs and humans109.

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