Mehdi Tafti

• Professor
• Professor (Full) at University of Lausanne

Many neuropsychiatric disorders involve dysregulation of the dopaminergic (DA) input to the forebrain. Of particular relevance are DA projections originating from the midbrain ventral tegmental area (VTA). A key neuromodulatory influence onto DAVTA neurons arises from the dense axonal projections emanating from lateral hypothalamic area hypocretin/...

Solriamfetol [(R)-2-amino-3-phenylpropylcarbamate hydrochloride], a phenylalanine derivative initially developed as potential antidepressant, was shown by our group in 2009 to have potent, dose-dependent wake-promoting activity in mice. Solriamfetol (Sunosi) is used since 2019 to counteract excessive daytime sleepiness (EDS) in patients with narcol...

Adherens junction–associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively ex...

Brain resident macrophages such as microglia and CNS-associated macrophages (CAMs) are already established before birth and play therefore a crucial role for normal brain functioning during development. However, their involvement in fine-tuning complex physiological functions such as vigilance states (VS) after birth remains poorly understood. Here...

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), o...

Hypocretin/orexin neurons are essential to stabilize sleep, but the underlying mechanisms remain elusive. We report that hypocretin neurons of the perifornical hypothalamus are highly active during rapid eye movement sleep and show state-specific correlation with noradrenergic neurons. Deletion of hypocretin gene significantly increased periodic re...

Hypocretin/Orexin (HCRT/OX) and dopamine (DA) are two key effectors of salience processing, reward and stress-associated behavior and motivational states, yet their respective roles and interactions are poorly delineated. We inactivated HCRT-to-DA connectivity by genetic disruption of Hypocretin receptor type-1 (Hcrtr1), Hypocretin receptor type-2...

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...

Introduction: Orexin/Hypocretin deficiency causes the neurological disease narcolepsy, with excessive sleepiness, state fragmentation, emergence of rapid-eye-movement sleep (REMS)-related states into wake, and cataplexy. Several mouse models phenocopy narcolepsy remarkably well by inactivation of the Hypocretin (Hcrt) gene, or ablation of Hypocreti...

Significance The hypocretin (Hcrt, also known as orexin) neuropeptides regulate sleep and wake stability, and disturbances of Hcrt can lead to sleep disorders. MicroRNAs (miRNAs) are short noncoding RNAs that fine-tune protein expression levels, and miRNA-based therapeutics are emerging. We report a functional interaction between miRNA (miR-137) an...

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. Here we report a patient an...

Both dopaminergic (DA) and orexinergic (OX) systems establish brain-wide neuromodulatory circuits that profoundly influence brain states and behavioral outputs. To unravel their interactions, we inactivated OX-to-DA neurotransmission by selective disruption of HcrtR1/OxR1, or HcrtR2/OxR2, or both receptors, in DA neurons. Chronic loss of OXR2 in DA...

Narcolepsy with cataplexy is a chronic sleep disorder characterized by hypocretin deficiency. The condition is believed to result from autoimmune destruction of hypocretin (HCRT) neurons, although direct evidence is lacking and mere Hcrt gene inactivation causes full-blown narcolepsy in mice. Here we show that the expression of another hypothalamic...

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,...

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...

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 hy...

Sleep has been conceptualized as ‘activity-dependent’, hence a response to prior waking experience, and proposed to be‘the price the brain pays for plasticity during wakefulness’. We here propose that at the level of neuronal networks, particularly those arising from isolated embryonic thalamocortical cells maintained in culture, it represents a de...

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...

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...

Sleep is integral to life¹. Although insufficient or disrupted sleep increases the risk of multiple pathological conditions, including cardiovascular disease², 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 atheroscler...

Kleine-Levin syndrome (KLS) is a rare periodic hypersomnia with associated behavioral abnormalities but with often favorable 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. Here...

Objectives/Introduction: KleineLevin syndrome (KLS) is a rare periodic hypersomnia with associated behavioral abnormalities but with often favorable prognosis. There is an 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 i...

Objectives/Introduction: Neuromodulation of cortical and subcortical circuits by the Hypocretin/Orexin (HCRT) neuropeptides is a fundamental determinant in stability and EEG spectral quality of behavioral states. Methods To investigate the specific roles of the Hypocretin-to-Noradrenergic (HCRT-to-NA), and HCRT-to Dopaminergic (HCRT-to-DA) circui...

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 p...

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 m...

Absolute spectral profiles of wake, NREM and REM sleep after drug-induced wakefulness. NLS-4 showed increased power densities in delta frequency range during wakefulness and NREM sleep and decreased power densities in theta frequency range [NLS-4: 2-way repeated measures ANOVA, “treatment” p > 0.11; F(1, 5) = 3.66, “bin” p < 0.0001, F(97, 485) = 46...

Introduction An association between sleep-disordered breathing and cardiovascular risk factors such as hypertension has been suggested. Potential mechanisms underlying this association include sleep fragmentation, intermittent hypoxia and autonomic activations. The aim of this study was to analyze the sleep determinants of incident hypertension in...

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 home...

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 heritabi...

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 sl...

Excel file with one data sheet containing the numerical values of each figure panel (A-C) of Figure 5.

Excel file with one data sheet containing the numerical values of each figure panel (A-I) of Figure 6.

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Excel file with one data sheet containing the numerical values of each figure panel (A-G) of Figure 8.

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 sl...

The two hypocretin (orexin) neuropeptides (hereafter referred to as ‘Hcrt’) have potent neuromodulatory activity in a variety of neural circuits important for motivated and survival behaviors. They were shown to be critical for the stability of behavioral states, although the mechanisms underlying this, and the symptoms that emerge in their absence...

Sleep disorders are among the most common health problems encountered in medicine and have important social and economic impacts. New technologies as well as the current progress in genome sequencing projects of different species raise new hopes to understand the molecular basis of sleep and its disorders. Substantial progress has been achieved in...

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 l...

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...

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 co...

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, p...

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 breath...

The discovery of hypocretins (orexins) and their causal implication in narcolepsy is the most important advance in sleep research and sleep medicine since the discovery of rapid eye movement sleep. Narcolepsy with cataplexy is caused by hypocretin defi ciency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. Abla...

Background Sleep-disordered breathing is associated with major morbidity and mortality. However, its prevalence has mainly been selectively studied in populations at risk for sleep-disordered breathing or cardiovascular diseases. Taking into account improvements in recording techniques and new criteria used to defi ne respiratory events, we aimed t...

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. Similar to other rare diseases, only a few European countries have registered narcolepsy cas...

Study objectives: To evaluate the association between early stages of chronic kidney disease (CKD) and sleep disordered breathing (SDB), restless legs syndrome (RLS), and subjective and objective sleep quality (SQ). Methods: Cross-sectional analysis of a general population-based cohort (HypnoLaus). 1,760 adults (862 men, 898 women; age 59.3 (±11...

Objective: Periodic limb movements during sleep (PLMS) are sleep phenomena characterized by periodic episodes of repetitive stereotyped limb movements. The aim of this study was to describe the prevalence and determinants of PLMS in a middle-to-older age general population. Methods: Data from 2162 subjects (51.2% women, mean age 58.4±11.1 years)...

Did hypocretin receptor 2 autoantibodies cause narcolepsy with hypocretin deficiency in Pandemrix-vaccinated children, as suggested by Ahmed et al.? Using newly developed mouse models to report and inactivate hypocretin receptor expression, Vassalli et al. now show that hypocretin neurons (whose loss causes narcolepsy) do not express hypocretin aut...

Objective: Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despi...

Introduction: The aim of this study was to evaluate if there is a significant effect of lunar phases on subjective and objective sleep variables in the general population. Methods: A total of 2125 individuals (51.2% women, age 58.8 ± 11.2 years) participating in a population-based cohort study underwent a complete polysomnography (PSG) at home....

Limited-channel portable monitors (PMs) are increasingly used as an alternative to polysomnography (PSG) for the diagnosis of obstructive sleep apnoea (OSA). However, recommendations for the scoring of PM recordings are still lacking. Pulse-wave amplitude (PWA) drops, considered as surrogates for EEG arousals, may increase the detection sensitivity...

In recent years, evidence has emerged for a bidirectional relationship between sleep and neurological and psychiatric disorders. First, sleep-wake disorders (SWDs) are very common and may be the first/main manifestation of underlying neurological and psychiatric disorders. Secondly, SWDs may represent an independent risk factor for neuropsychiatric...

Objective. Although sleep is a biomarker for general health and pathological conditions, its changes across age and gender are poorly understood. Methods. Subjective evaluation of sleep was assessed by questionnaires in 5,064 subjects, and 2,966 were considered without sleep disorders. Objective evaluation was performed by polysomnography in 2,160...

Objectif Investiguer la fréquence des mouvements périodiques des jambes au cours du sommeil (MPJS) et leurs déterminants dans la population générale. Méthodes Nous avons analysé les données de 2162 sujets issus de la population générale (âge moyen 58 ± 11 ; 51,2 % des femmes) participant à l’étude Hypnolaus, une cohorte communautaire basée sur un...

Objectif Le but de cette étude était de comparer les caractéristiques du sommeil chez les patients migraineux et chez des témoins appariés sur l’âge et le sexe. Méthodes Les données de 2162 participants à l’étude Hypnolaus/Psycholaus, une cohorte basée sur un échantillon représentatif de la population de Lausanne (Suisse), ont été analysées. Nous...

The discovery of hypocretins (orexins) and their causal implication in narcolepsy is the most important advance in sleep research and sleep medicine since the discovery of rapid eye movement sleep. Narcolepsy with cataplexy is caused by hypocretin defi ciency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. Abla...

The discovery of hypocretins (orexins) and their causal implication in narcolepsy is the most important advance in sleep research and sleep medicine since the discovery of rapid eye movement sleep. Narcolepsy with cataplexy is caused by hypocretin deficiency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. Ablat...

Sleep-disordered breathing is associated with major morbidity and mortality. However, its prevalence has mainly been selectively studied in populations at risk for sleep-disordered breathing or cardiovascular diseases. Taking into account improvements in recording techniques and new criteria used to define respiratory events, we aimed to assess the...

To examine the association of socioeconomic status (SES) with subjective and objective sleep disturbances and the role of socio-demographic, behavioural and psychological factors in explaining this association. Analyses are based on 3391 participants (53% female, aged 40-81 years) of the follow-up of the CoLaus study (2009-2012), a population-based...

Interactions of neurons with microglia may play a dominant role in sleep regulation. TNF may exert its somnogeneic effects by promoting attraction of microglia and their processes to the vicinity of dendrites and synapses. We found TNF to stimulate neurons (i) to produce CCL2, CCL7 and CXCL10, chemokines acting on mononuclear phagocytes and (ii) to...

We thank Drs Esquinas and Nilius for their interest in our article [1]. They suggest that transnasal insufflation (TNI) should not be used in severe OSA cases or in cases requiring intubation. We fully agree that the patient who can tolerate CPAP should use it, and we never proposed TNI as an alternative to intubation. Our results, however, suggest...

Study objectives: To evaluate the association between objective sleep measures and metabolic syndrome (MS), hypertension, diabetes, and obesity. Design: Cross-sectional study. Setting: General population sample. Participants: There were 2,162 patients (51.2% women, mean age 58.4 ± 11.1). Interventions: Patients were evaluated for hypertens...

Pediatric field encompasses a medical branch that deals with the medical care of infants, children, and new adolescents. Patients in this field are generally from birth up to 18 years of age. Although the field is known as a new medical branch, the history dates back to over thousand year ago [1] . A main part of the medical and pharmaceutical manu...

Background Studies assessing the social patterning of sleep are heterogeneous with respect to indicators of socioeconomic status (SES) and sleep characteristics considered. This study examines the association of SES with subjective and objective sleep disturbances and the role of socio-demographic, behavioural and psychological factors in explain...

Gamma-hydroxybutyrate (GHB) was originally introduced as an anesthetic but was first abused by bodybuilders and then became a recreational or club drug.1 Sodium salt of GHB is currently used for the treatment of cataplexy in patients with narcolepsy. The mode of action and metabolism of GHB is not well understood. GHB stimulates growth hormone rele...

Author Summary Large genetic association studies have revealed many genetic factors influencing common traits, such as body mass index (BMI). These studies assume that the effect of genetic variants is the same regardless of whether they are inherited from the mother or the father. In our study, we have developed a new approach that allows us to in...

Study objective: Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects. Des...

Background Diagnosis of sleep-disordered breathing requires overnight recordings, such as polygraphy or poly somno-graphy. 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 identifi cation of individuals at risk of sleep-disordered breat...

Introduction Recent research has identified relationships between sleep duration and quality and increased risk of cardiometabolic disorders. Most previous studies used self-reported sleep duration or quality, but little is known about the objective sleep parameters underlying these associations. The aim of this study was to explore the association...

Introduction Background: Upper airway resistance syndrome (UARS) shares common clinical features with obstructive sleep apnea and hypopnea (OSAH). It is characterized by repetitive respiratory effort-related arousal (RERA), which may lead to daytime sleepiness and functional impairment. Little is known about the prevalence of UARS in the general po...

Introduction Historical studies suggest that there is an increased male/female ratio in the prevalence of sleep disordered breathing (SBD). Moreover, SDB was reported to increase in postmenopausal women. The aim of this study was to assess the prevalence and the characteristics of SDB in pre-menopausal and post-menopausal women. Materials and meth...

Introduction Restless Legs Syndrome (RLS) and periodic leg movements during sleep (PLMS) can occur as a primary disorder or as a secondary condition. The claim that antidepressant use induces RLS or PLMS is controversial and has significant implications considering the widespread use of these medications. The aim of this study was to explore the as...

Astute control of brain activity states is critical for adaptive behaviours and survival. In mammals and birds, electroencephalographic recordings reveal alternating states of wakefulness, slow wave sleep and paradoxical sleep (or rapid eye movement sleep). This control is profoundly impaired in narcolepsy with cataplexy, a disease resulting from t...