Inactivation of hypocretin receptor-2 signaling in dopaminergic neurons induces hyperarousal and enhanced cognition but impaired inhibitory control.

Hypocretin/Orexin (HCRT/OX) and dopamine (DA) are both key effectors of salience processing, reward and stress-related behaviors and motivational states, yet their respective roles and interactions are poorly delineated. We inactivated HCRT-to-DA connectivity by genetic disruption of Hypocretin receptor-1 (Hcrtr1), Hypocretin receptor-2 (Hcrtr2), or both receptors (Hcrtr1&2) in DA neurons and analyzed the consequences on vigilance states, brain oscillations and cognitive performance in freely behaving mice. Unexpectedly, loss of Hcrtr2, but not Hcrtr1 or Hcrtr1&2, induced a dramatic increase in theta (7-11 Hz) electroencephalographic (EEG) activity in both wakefulness and rapid-eye-movement sleep (REMS).

Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy.

Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved.

The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio.

Hypocretin (Hcrt), also known as orexin, neuropeptide signaling stabilizes sleep and wakefulness in all vertebrates. A lack of Hcrt causes the sleep disorder narcolepsy, and increased Hcrt signaling has been speculated to cause insomnia, but while the signaling pathways of Hcrt are relatively well-described, the intracellular mechanisms that regulate its expression remain unclear. Here, we tested the role of microRNAs (miRNAs) in regulating Hcrt expression.

LMOD3 gene variant in familial periodic hypersomnolence.

Introduction: Kleine-Levin syndrome (KLS) is a rare and debilitating disorder presenting with periodic hypersomnolence, cognitive, psychiatric and behavioral disturbances. In the absence of biomarkers it can be difficult to diagnose. Rare LMOD3 variants in a family and in seven sporadic cases with KLS have been described.

Neurobiology of cataplexy.

Cataplexy is the pathognomonic and the most striking symptom of narcolepsy. It has originally been, and still is now, widely considered as an abnormal manifestation of rapid eye movement (REM) sleep during wakefulness due to the typical muscle atonia. The neurocircuits of cataplexy, originally confined to the brainstem as those of REM sleep atonia, now include the hypothalamus, dorsal raphe (DR), amygdala and frontal cortex, and its neurochemistry originally focused on catecholamines and acetylcholine now extend to hypocretin (HCRT) and other neuromodulators.

The Swiss Primary Hypersomnolence and Narcolepsy Cohort study (SPHYNCS): Study protocol for a prospective, multicentre cohort observational study.

Narcolepsy type 1 (NT1) is a disorder with well-established markers and a suspected autoimmune aetiology. Conversely, the narcoleptic borderland (NBL) disorders, including narcolepsy type 2, idiopathic hypersomnia, insufficient sleep syndrome and hypersomnia associated with a psychiatric disorder, lack well-defined markers and remain controversial in terms of aetiology, diagnosis and management. The Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (SPHYNCS) is a comprehensive multicentre cohort study, which will investigate the clinical picture, pathophysiology and long-term course of NT1 and the NBL.

Hypocretinergic interactions with the serotonergic system regulate REM sleep and cataplexy.

Loss of muscle tone triggered by emotions is called cataplexy and is the pathognomonic symptom of narcolepsy, which is caused by hypocretin deficiency. Cataplexy is classically considered to be an abnormal manifestation of REM sleep and is treated by selective serotonin (5HT) reuptake inhibitors. Here we show that deleting the 5HT transporter in hypocretin knockout mice suppressed cataplexy while dramatically increasing REM sleep.

Molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons.

Hypocretin/orexin (HCRT) and melanin concentrating hormone (MCH) neuropeptides are exclusively produced by the lateral hypothalamus and play important roles in sleep, metabolism, reward, and motivation. Loss of HCRT (ligands or receptors) causes the sleep disorder narcolepsy with cataplexy in humans and in animal models. How these neuropeptides are produced and involved in diverse functions remain unknown.

Narcolepsy - clinical spectrum, aetiopathophysiology, diagnosis and treatment.

Narcolepsy is a rare brain disorder that reflects a selective loss or dysfunction of orexin (also known as hypocretin) neurons of the lateral hypothalamus. Narcolepsy type 1 (NT1) is characterized by excessive daytime sleepiness and cataplexy, accompanied by sleep-wake symptoms, such as hallucinations, sleep paralysis and disturbed sleep. Diagnosis is based on these clinical features and supported by biomarkers: evidence of rapid eye movement sleep periods soon after sleep onset; cerebrospinal fluid orexin deficiency; and positivity for HLA-DQB1*06:02.

Sleep modulates haematopoiesis and protects against atherosclerosis.

Sleep is integral to life. Although insufficient or disrupted sleep increases the risk of multiple pathological conditions, including cardiovascular disease, we know little about the cellular and molecular mechanisms by which sleep maintains cardiovascular health. Here we report that sleep regulates haematopoiesis and protects against atherosclerosis in mice.

T cells in patients with narcolepsy target self-antigens of hypocretin neurons.

Narcolepsy is a chronic sleep disorder caused by the loss of neurons that produce hypocretin. The close association with HLA-DQB1*06:02, evidence for immune dysregulation and increased incidence upon influenza vaccination together suggest that this disorder has an autoimmune origin. However, there is little evidence of autoreactive lymphocytes in patients with narcolepsy.

Lauflumide (NLS-4) Is a New Potent Wake-Promoting Compound.

Psychostimulants are used for the treatment of excessive daytime sleepiness in a wide range of sleep disorders as well as in attention deficit hyperactivity disorder or cognitive impairment in neuropsychiatric disorders. Here, we tested in mice the wake-promoting properties of NLS-4 and its effects on the following sleep as compared with those of modafinil and vehicle. C57BL/6J mice were intraperitoneally injected with vehicle, NLS-4 (64 mg/kg), or modafinil (150 mg/kg) at light onset.

Kleine-Levin syndrome is associated with LMOD3 variants.

Kleine-Levin syndrome (KLS) is a rare periodic hypersomnia with associated behavioural abnormalities but with often favourable prognosis. There is excess risk of KLS in first-degree relatives, suggesting a strong genetic contribution. So far, no mutation is identified in KLS and comprehensive genetic analysis of affected individuals is lacking.

In vitro Cortical Network Firing is Homeostatically Regulated: A Model for Sleep Regulation.

Prolonged wakefulness leads to a homeostatic response manifested in increased amplitude and number of electroencephalogram (EEG) slow waves during recovery sleep. Cortical networks show a slow oscillation when the excitatory inputs are reduced (during slow wave sleep, anesthesia), or absent (in vitro preparations). It was recently shown that a homeostatic response to electrical stimulation can be induced in cortical cultures.

Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.

Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity.

Cerebral mGluR5 availability contributes to elevated sleep need and behavioral adjustment after sleep deprivation.

Increased sleep time and intensity quantified as low-frequency brain electrical activity after sleep loss demonstrate that sleep need is homeostatically regulated, yet the underlying molecular mechanisms remain elusive. We here demonstrate that metabotropic glutamate receptors of subtype 5 (mGluR5) contribute to the molecular machinery governing sleep-wake homeostasis. Using positron emission tomography, magnetic resonance spectroscopy, and electroencephalography in humans, we find that increased mGluR5 availability after sleep loss tightly correlates with behavioral and electroencephalographic biomarkers of elevated sleep need.

Rare missense mutations in P2RY11 in narcolepsy with cataplexy.

The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocretin (orexin) neurons, leading to the hypothesis that the condition is caused by an immune or autoimmune mechanism. All genetic variants associated with narcolepsy are immune-related. Among these are single nucleotide polymorphisms in the P2RY11-EIF3G locus.

Measurement of narcolepsy symptoms: The Narcolepsy Severity Scale.

Objective: To validate the Narcolepsy Severity Scale (NSS), a brief clinical instrument to evaluate the severity and consequences of symptoms in patients with narcolepsy type 1 (NT1).

Methods: A 15-item scale to assess the frequency and severity of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis, and disrupted nighttime sleep was developed and validated by sleep experts with patients' feedback. Seventy untreated and 146 treated adult patients with NT1 were evaluated and completed the NSS in a single reference sleep center.

ERK signaling pathway regulates sleep duration through activity-induced gene expression during wakefulness.

Wakefulness is accompanied by experience-dependent synaptic plasticity and an increase in activity-regulated gene transcription. Wake-induced genes are certainly markers of neuronal activity and may also directly regulate the duration of and need for sleep. We stimulated murine cortical cultures with the neuromodulatory signals that are known to control wakefulness in the brain and found that norepinephrine alone or a mixture of these neuromodulators induced activity-regulated gene transcription.

Sleep characteristics and cognitive impairment in the general population: The HypnoLaus study.

Objective: To assess the association between sleep structure and cognitive impairment in the general population.

Methods: Data stemmed from 580 participants aged >65 years of the population-based CoLaus/PsyCoLaus study (Lausanne, Switzerland) who underwent complete sleep evaluation (HypnoLaus). Evaluations included demographic characteristics, personal and treatment history, sleep complaints and habits (using validated questionnaires), and a complete polysomnography at home.

The NoSAS score for screening of sleep-disordered breathing: a derivation and validation study.

Background: Diagnosis of sleep-disordered breathing requires overnight recordings, such as polygraphy or polysomnography. Considering the cost and low availability of these procedures, preselection of patients at high risk is recommended. We aimed to develop a screening tool allowing identification of individuals at risk of sleep-disordered breathing.

The European Narcolepsy Network (EU-NN) database.

Narcolepsy with cataplexy is a rare disease with an estimated prevalence of 0.02% in European populations. Narcolepsy shares many features of rare disorders, in particular the lack of awareness of the disease with serious consequences for healthcare supply.