Hypocretins and the neurobiology of sleep–wake mechanisms

doi:10.1016/B978-0-444-59489-1.00003-3

Progress in Brain Research

Volume 198, 2012, Pages 15-24

https://doi.org/10.1016/B978-0-444-59489-1.00003-3 Get rights and content

Abstract

In 1998, our group discovered a cDNA that encoded the precursor of two putative neuropeptides that we called hypocretins for their hypothalamic expression and their similarity to the secretin family of neuropeptides. In the past 15 years, numerous studies have placed the hypocretin system as an integrator of homeostatic functions with a crucial, nonredundant function as an arousal stabilizer. Here, we discuss some of the data that have accumulated over the years on the integrating capacity of these hypothalamic neurons and their role on sleep-to-wake transitions.

Introduction

In the past few years, the hypocretins (also known as orexins) have been shown to be critical components of the brain circuitry that modulates the states of vigilance (Mignot et al., 2002, Sutcliffe and de Lecea, 2002, Willie et al., 2001). Recent advances are yielding a clearer picture as to the mechanism of action of these peptides, and how they control multiple circuits to produce a coherent behavioral output. Here, I review the interactions of the hypocretinergic system with the major neurotransmitter networks and discuss the role of the neurons that contain hypocretin in integrating information that dictates the state of arousal.

Section snippets

Discovery and properties of the hypocretins

Analysis of the expression patterns of subtracted hypothalamus-enriched sequences (Gautvik et al., 1996) revealed that one of these was expressed exclusively by a bilaterally symmetric structure within the posterior hypothalamus (Fig. 1). Its nucleotide sequence (de Lecea et al., 1998) encoded a 130-residue putative secretory protein (preprohypocretin) with an apparent signal sequence and three additional sites for potential proteolytic maturation. Two of the 4 putative products of proteolysis

Loss of function

The studies showing that hypocretin mRNA is absent from narcoleptic brains (Peyron et al., 2000) and that Hcrt immunoreactivity is highly decreased in narcoleptic hypothalami (Thannickal et al., 2000) provide compelling evidence that the main function of the hypocretinergic system is the regulation of arousal circuits.

Narcoleptic patients with cataplexy have non- or barely detectable levels of Hcrt1 in the cerebrospinal fluid, (Nishino et al., 2000) in addition to the absence of preproHcrt gene

Hypocretin neuronal activity

Recordings of Hcrt neuronal activity in freely moving (Mileykovskiy et al., 2005) and in head restraint (Lee et al., 2005) rats revealed that Hcrt neurons fire phasically in correlation with the locomotor activity and are mostly silent during NREM and REM sleep. Interestingly, the highest frequency of activity was found during the transitions of vigilance states and in anticipation of a reward signal. This phasic pattern of activity questioned the behavioral effects of the pharmacological

Hypothalamus

Hcrt neurons are localized in the lateral hypothalamus, an area long known as a key center for the regulation of energy homeostasis. Therefore, it was only logical that the first hypotheses about Hcrt function involved feeding and energy balance (Sakurai et al., 1998). Indeed, Hcrt neurons are connected with the main networks regulating feeding. The connectivity between NPY-positive neurons in the arcuate nucleus and Hcrt neurons has been demonstrated (Broberger et al., 1998, Elias et al., 1998

The hypocretins as an integrator circuit in arousal

The anatomical localization and functional connectivity of Hcrt neurons reveals a prominent role in homeostatic control of physiological switches. Data from multiple laboratories have shown a very diverse set of classical and peptide transmitters as well as metabolites that modulate Hcrt activity. Recent data showing phasic activity of Hcrt in correlation with goal oriented behaviors, locomotor activity, and behavioral state transitions also suggest that these neurons provide physiological

References (75)

M. Blanco et al.
Cellular localization of orexin receptors in human adrenal gland, adrenocortical adenomas and pheochromocytomas
Regulatory Peptides
(2002)
S.L. Borgland et al.
Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine
Neuron
(2006)
R.M. Chemelli et al.
Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation
Cell
(1999)
Y. Date et al.
Distribution of orexin/hypocretin in the rat median eminence and pituitary
Brain Research. Molecular Brain Research
(2000)
R.A. Espana et al.
Wake-promoting and sleep-suppressing actions of hypocretin (orexin): Basal forebrain sites of action
Neuroscience
(2001)
J. Fadel et al.
Anatomical substrates of orexin-dopamine interactions: Lateral hypothalamic projections to the ventral tegmental area
Neuroscience
(2002)
M.A. Greco et al.
Hypocretin receptor protein and mRNA expression in the dorsolateral pons of rats
Brain Research. Molecular Brain Research
(2001)
J. Hara et al.
Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity
Neuron
(2001)
T. Ida et al.
Possible involvement of orexin in the stress reaction in rats
Biochemical and Biophysical Research Communications
(2000)
B.E. Jones
The role of noradrenergic locus coeruleus neurons and neighboring cholinergic neurons of the pontomesencephalic tegmentum in sleep–wake states
Progress in Brain Research
(1991)

M.M. Karnani et al.

Activation of central orexin/hypocretin neurons by dietary amino acids

Neuron

(2011)

G.M. Leinninger et al.

Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding

Cell Metabolism

(2009)

M. Lopez et al.

Leptin regulation of prepro-orexin and orexin receptor mRNA levels in the hypothalamus

Biochemical and Biophysical Research Communications

(2000)

L.K. Malendowicz et al.

Orexins stimulate corticosterone secretion of rat adrenocortical cells, through the activation of the adenylate cyclase-dependent signaling cascade

The Journal of Steroid Biochemistry and Molecular Biology

(1999)

G. Martin et al.

Interaction of the hypocretins with neurotransmitters in the nucleus accumbens

Regulatory Peptides

(2002)

B.Y. Mileykovskiy et al.

Behavioral correlates of activity in identified hypocretin/orexin neurons

Neuron

(2005)

T. Nakamura et al.

Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system

Brain Research

(2000)

T. Nanmoku et al.

Effects of orexin on cultured porcine adrenal medullary and cortex cells

Regulatory Peptides

(2002)

S. Nishino et al.

Narcolepsy: Genetic predisposition and neuropharmacological mechanisms

Sleep Medicine Reviews

(2000)

T. Sakurai et al.

Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior

Cell

(1998)

W.K. Samson et al.

Cardiovascular regulatory actions of the hypocretins in brain

Brain Research

(1999)

T. Shirasaka et al.

Neuronal effects of orexins: Relevant to sympathetic and cardiovascular functions

Regulatory Peptides

(2002)

A. Stricker-Krongrad et al.

Orexins/hypocretins in the ob/ob mouse: Hypothalamic gene expression, peptide content and metabolic effects

Regulatory Peptides

(2002)

N. Takahashi et al.

Stimulation of gastric acid secretion by centrally administered orexin-A in conscious rats

Biochemical and Biophysical Research Communications

(1999)

T.C. Thannickal et al.

Reduced number of hypocretin neurons in human narcolepsy

Neuron

(2000)

P. Trivedi et al.

Distribution of orexin receptor mRNA in the rat brain

FEBS Letters

(1998)

J.T. Willie et al.

Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: Molecular genetic dissection of non-REM and REM sleep regulatory processes

Neuron

(2003)

R.A. Wise

Brain reward circuitry: Insights from unsensed incentives

Neuron

(2002)

M. Xi et al.

Effects on sleep and wakefulness of the injection of hypocretin-1 (orexin-A) into the laterodorsal tegmental nucleus of the cat

Brain Research

(2001)

A. Yamanaka et al.

Hypothalamic orexin neurons regulate arousal according to energy balance in mice

Neuron

(2003)

A. Adamantidis et al.

Neural substrates of awakening probed with optogenetic control of hypocretin neurons

Nature

(2007)

A. Albanese et al.

Organization of the ascending projections from the ventral tegmental area: A multiple fluorescent retrograde tracer study in the rat

The Journal of Comparative Neurology

(1983)

S.L. Borgland et al.

Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers

The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

(2009)

P. Bourgin et al.

Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons

The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

(2000)

B. Boutrel et al.

Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior

Proceedings of the National Academy of Sciences of the United States of America

(2005)

C. Broberger et al.

Hypocretin/orexin- and melanin-concentrating hormone expressing cells form distinct populations in the rodent lateral hypothalamus: Relationship to neuropeptide Y innervation

The Journal of Comparative Neurology

(1998)

S. Burlet et al.

Direct and indirect excitation of laterodorsal tegmental neurons by hypocretin/orexin peptides: Implications for wakefulness and narcolepsy

The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

(2002)

Cited by (63)

Repeated measures of hypocretin-1 in Danish and Italian patients with narcolepsy and in controls
2023, Sleep Medicine
The assay currently used worldwide to measure cerebrospinal fluid hypocretin-1 (CSF-hcrt-1) for diagnosing narcolepsy uses a competitive radioimmunoassay with polyclonal anti-hcrt-1 antibodies. This assay detects multiple hypocretin-1 immunoreactive species in the CSF that are all derived from full-length hcrt-1. We aimed to revalidate CSF-hcrt-1 cut-offs for narcolepsy type 1 (NT1) diagnosis and to evaluate temporal changes in CSF-hcrt-1 levels in patients suspected of having central hypersomnia.
We carried out a repeat lumbar puncture with a mean follow-up of 4.0 years, to measure CSF-hcrt-1 in patients suspected of having central hypersomnia in a follow-up study. Data from CSF samples of patients with NT1 and of controls without known hypersomnia, from the Italian–Stanford and Danish populations, were examined using a receiver-operating characteristic analysis.
The optimal CSF-hcrt-1 cut-offs for identifying NT1 were 129 pg/ml and 179 pg/ml for the Italian-Stanford and Danish populations, respectively. The sensitivity was 0.93–0.99 and the specificity was 1.
Follow-up lumbar puncture measurements of CSF-hcrt-1 were obtained from 73 patients. 30 of 32 patients with low CSF-hcrt-1 levels continued to be categorized as low, with an unaltered diagnosis; two patients showed a marked increase in CSF-hcrt-1, attaining normal values at follow-up. One of these patients relapsed to low CSF-hcrt-1 after follow-up. All 41 patients with normal CSF-hcrt-1 at baseline had normal CSF-hcrt-1 at follow-up.
CSF-hcrt-1 measurement can provide an accurate test for diagnosing NT1, although it is important to validate the CSF-hcrt-1 cut-off for specific testing locations. Stable CSF-hcrt-1 levels support the already established prognosis of narcolepsy as permanent once the disorder has fully developed.
Circadian circuits
2022, Neurocircuitry of Addiction
Substance use disorders (SUDs) are associated with disruptions to sleep and circadian rhythms. There is a bidirectional relationship between sleep, rhythms, and addiction, whereby repeated use of substances leads to sleep and circadian rhythm disruptions, while chronic disruptions in sleep and rhythms contribute to substance use risk and dependence vulnerability. Repeated substance use and withdrawal can also lead to persistent, long-lasting effects on circadian rhythms that promote craving and relapse. In addition, prolonged circadian misalignment (e.g., social “jet-lag” and shift work) or evening preference (i.e., night owls) are risk factors for substance use and dependence. Substance use is also highly comorbid with other psychiatric disorders that are linked to sleep and circadian rhythm disruptions, including depression and bipolar disorder. For some suffering with mood disorders, substance use may be an attempt to ameliorate mood instability and sleep issues, further compounding mood and substance use-related health problems. Depression susceptibility also varies by season and peaks along with substance use during winter months, suggesting possible circadian involvement in seasonality of substance use and mood liability. Circadian rhythms also regulate diurnal variations in the sensitivity and responsivity to nearly every substance. For example, the hedonic value of alcohol, cocaine, and morphine peaks and troughs at different times of day, indicating circadian modulation of reward responses to substances. Thus, both the response to substances and the vulnerability to substance dependence are influenced by circadian rhythms.
The Dual Orexin Receptor Antagonist DORA-22 Improves Mild Stress-induced Sleep Disruption During the Natural Sleep Phase of Nocturnal Rats
2021, Neuroscience
Dual orexinergic antagonists (DORAs) have been recently developed as a pharmacotherapy alternative to established hypnotics. Hypnotics are largely evaluated in preclinical rodent models in the dark/active period yet should be ideally evaluated in the light/inactive period, analogous to when sleep disruption occurs in humans. We describe here the hypnotic efficacy of DORA-22 in rodent models of sleep disturbance produced by cage changes in the light/inactive period. Rats were administered DORA-22 or the GABA receptor-targeting hypnotic eszopiclone early in the light period, then exposed to six hourly clean cage changes with measurements of NREM sleep onset latency. Both compounds initially promoted sleep (hours 1 and 2), with DORA-22 exhibiting a more rapid hypnotic onset; and exhibited extended efficacy, evident six hours after administration in a sleep latencies test. A common complaint concerning hypnotic use is lingering hypersomnolence, and this is a concern in pharmacotherapy of the elderly. A second study was designed to determine a minimal dose of DORA-22 which would initially promote sleep but exhibit minimal extended hypnotic effect. Animals were administered DORA-22, then exposed for six hours to a single cage previously dirtied by a conspecific, followed by return to home cage. EEG measures indicated that all DORA-22 doses largely promoted sleep in the first hour. The lowest dose (1 mg/kg) did not decrease sleep onset latency at the six-hour timepoint, suggesting no residual hypersomnolence. We described here DORA-22 hypnotic efficacy during the normal sleep period of nocturnal rats, and demonstrate that well-chosen (low) hypnotic doses of DORA-22 may be hypnotically effective yet have minimal lingering effects.
Orexin-A signaling in the paraventricular nucleus modulates spontaneous firing of glucose-sensitive neurons and promotes food intake via the NPY pathway in rats
2018, Biochemical and Biophysical Research Communications
Citation Excerpt :
Orexin neurons are primarily located in the lateral hypothalamus area (LHA) [2,3] and their fibers widely project to the other brain area, including the PVN [4] and the dorsomedial nucleus of hypothalamus (DMH) and so on [5]. Orexin has been found to regulate many physiological processes related to obesity including sleep/wakefulness states [6,7], energy homeostasis [8], reward [9] and autonomic functions [10,11]. Studies have shown that intracerebroventricular (icv) injection of orexin-A induces feeding behavior in a dose-dependent manner.
Understanding the mechanisms regulating feeding is crucial to unraveling the pathogenesis of obesity. The study primary explored the effects of orexin-A and neuropeptide Y (NPY) signaling in the hypothalamic paraventricular nucleus (PVN) on feeding and glucose-sensitive (GS) neuron activity in rats. Microinjection of orexin-A into the PVN promoted feeding and modulated the spontaneous firing of GS neurons. Those effects were eliminated by pre-injection of the orexin-A receptor-1 (OX1R) antagonist SB-334867 and weaken by the NPY-1 receptor (NPY-1R) antagonist BMS-193885. After orexin-A administration into the PVN, the number of c-fos cells in the arcuate nucleus (ARC) was significantly higher than that in the group receiving normal saline. Furthermore, most cells exhibited co-expression of NPY and c-fos, indicating activation of NPY neurons in the ARC by PVN-administered orexin-A, which might be involved in feeding regulation. These findings indicate that orexin-A and NPY signaling in the PVN are essential to regulating GS neuronal excitability and feeding in rats.
The latest research progress of daridorexant, a dual orexin receptor antagonist for insomnia
2023, Chinese Journal of New Drugs
The orexin story and orexin receptor antagonists for the treatment of insomnia
2023, Journal of Sleep Research

View all citing articles on Scopus

View full text

Chapter 3 - Hypocretins and the neurobiology of sleep–wake mechanisms

Abstract

Introduction

Section snippets

Discovery and properties of the hypocretins

Loss of function

Hypocretin neuronal activity

Hypothalamus

The hypocretins as an integrator circuit in arousal

Regulatory Peptides

Neuron

Cell

Brain Research. Molecular Brain Research

Neuroscience

Neuroscience

Brain Research. Molecular Brain Research

Neuron

Biochemical and Biophysical Research Communications

Progress in Brain Research

Neuron

Cell Metabolism

Biochemical and Biophysical Research Communications

The Journal of Steroid Biochemistry and Molecular Biology

Regulatory Peptides

Neuron

Brain Research

Regulatory Peptides

Sleep Medicine Reviews

Cell

Brain Research

Regulatory Peptides

Regulatory Peptides

Biochemical and Biophysical Research Communications

Neuron

FEBS Letters

Neuron

Neuron

Brain Research

Neuron

Neural substrates of awakening probed with optogenetic control of hypocretin neurons

Nature

Organization of the ascending projections from the ventral tegmental area: A multiple fluorescent retrograde tracer study in the rat

The Journal of Comparative Neurology

Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers

The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons

The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior

Proceedings of the National Academy of Sciences of the United States of America

Hypocretin/orexin- and melanin-concentrating hormone expressing cells form distinct populations in the rodent lateral hypothalamus: Relationship to neuropeptide Y innervation

The Journal of Comparative Neurology

Direct and indirect excitation of laterodorsal tegmental neurons by hypocretin/orexin peptides: Implications for wakefulness and narcolepsy

The Journal of Neuroscience: The Official Journal of the Society for Neuroscience