Jian-Sheng Lin

Lyon Neuroscience Research Center, INSERM, CNRS, University Claude Bernard, Lyon France · Laboratory Intergrative Physiology of the Brain Arousal Systems

Long-term abolition of a brain arousal system impairs wakefulness (W), but little is known about the consequences of long-term enhancement. The histaminergic arousal system is under the negative control of H3-autoreceptors whose deletion results in permanent enhancement of histamine (HA) turnover. In order to determine the consequences of enhanceme...

Modafinil, a wake-promoting compound now used worldwide in sleep medicine, was initially regarded as a sedative compound because mice were so quiet with respect to locomotion after receiving it that this behavioral state was qualified as sedation. In the early 1980's when modafinil was first assessed by polysomnography in a cat in our laboratory, s...

Objective Narcolepsy is a sleep disorder characterized in humans by excessive daytime sleepiness and cataplexy. Greater than fifty percent of narcoleptic patients have an onset of symptoms prior to the age of 18. Current general agreement considers the loss of hypothalamic hypocretin (orexin) neurons as the direct cause of narcolepsy notably catapl...

The histaminergic system fulfills a major role in the maintenance of waking. Histaminergic neurons are located exclusively in the posterior hypothalamus from where they project to most areas of the central nervous system. The histamine H(3) receptors are autoreceptors damping histamine synthesis, the firing frequency of histamine neurons, and the r...

必妥利生(pitolisant)是由法国Bioprojet集团合成的口服小分子组胺H3受体反向激动剂,经里昂大学INSERM清醒机制研究室在正常和病理动物模型中发现其促醒效应后并经临床检验,先后于2016和2019年由欧盟医药委员会和美国食品药品管理局批准用于治疗发作性睡病白天过度嗜睡(excessive daytime sleepiness,EDS)和猝倒。该文介绍和综述本疗法的作用机制和靶点、临床特征及最新研究成果,期望未来该新药在我国临床精准应用,并探索开发新的适应症。

The ontogenetic sleep hypothesis suggested that rapid eye movement (REM) sleep is ontogenetically primitive. Namely, REM sleep plays an imperative role in the maturation of the central nervous system. In coincidence with a rapidly developing brain during the early period of life, a remarkably large amount of REM sleep has been identified in numerou...

This is the first study that reports the impact of chronic toxoplasmosis on the sleep/wake cycle. Such change in consciousness may represent another component of behavioral manipulation of the host, by which T. gondii would promote its dissemination by increasing the frequencies of encounter and interaction with host's environment.

Introduction Narcolepsy is a disabling neurological disorder characterized primarily by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis, rapid eye movement (REM) behavior disorder (RBD) and disturbed nocturnal sleep. Over 50% of children with narcolepsy are obese. Metabolic syndrome (MetS), a constellation...

Abstract Histamine (HA) and orexin (Ox, or hypocretin) neurons act distinctly and synergistically in wake control. A double knockout mouse genotype lacking both HA and Ox shows all sleep disorders of human narcolepsy. We identified in this mouse brain a sharp upregulation of a BLOC-1 gene, pallidin, that is associated with a deficient HA-transmiss...

The Pallidin protein is a component of a multimeric complex named the Biogenesis of Lysosome-related Organelles Complex-1 (BLOC1) that regulates specific endosomal function and transmembrane protein trafficking in many different cell types. In the brain, defective BLOC1 function has been linked to schizophrenia, a neuropsychiatric disorder with hig...

Objective A defect of the waking systems could constitute a factor of vulnerability for sudden infant death syndrome (SIDS). A decrease in orexin levels, which promotes wakefulness and activates histaminergic neurons (another hypothalamic wake-promoting system) has already been demonstrated between 2 and 6 months. This work aims to study the levels...

Psychostimulants such as caffeine and amphetamine constitute the first generation of wake-promoting compounds. Their use and abuse cause well-known medico-social problems e.g., behavioral overexcitation, addiction and cognitive declines. Sleep medicine had long been looking for an awakening pill with preserved cognitive abilities. In the 1980's, th...

Objectif Les études récentes par l’approche opto- ou pharmaco-génétique visant les neurones à histamine (HA) du noyau tubéromammillaire (TM) ont montré des phénotypes très discrets sur le cycle veille-sommeil. Ceci remet en question le rôle précédemment démontré du système à HA. Or, le TM par sa petite taille et localisation profonde est difficilem...

Objectif Caractériser la prévalence du syndrome métabolique (SM) chez les enfants narcoleptiques en déterminant si les différentes composantes du SM modifient leur tableau clinique. Méthodes L’étude rétrospective portait sur 58 enfants narcoleptiques : âge médian 12,7 ans, 48,3 % garçons, 94,8 % cataplexie, 100 % HLA-DQB1*06 :02. Les données conce...

Objectif Caractériser la prise de poids rapide (PPR) associée à l’apparition de narcolepsie chez l’enfant et déterminer si elle constitue un marqueur de sévérité de la maladie. Méthodes Quatre-vingt-quatre enfants narcoleptiques, d’âge médian 12 ans au diagnostic : 60 % garçons, 91 % cataplexie, 99 % positivité HLA-DQB1*06 :02. La PPR est défini à...

Objectif La régulation du cycle veille-sommeil dépend de processus cellulaires, moléculaires et métaboliques dont la connaissance est encore très parcellaire. L’identification de ces processus peut se faire par des approches « omiques » combinées à la génétique moléculaire permettant de manipuler l’expression génique dans des organismes modèles tel...

Objectives: To characterize the rapid weight gain (RWG) phenotype associated with the onset of childhood narcolepsy and to determine whether it could constitute a marker of severity of the disease. Methods: RWG was defined using the BMI z-score slope reported to one year (> 0.67 SD) from symptom onset to disease diagnosis. We compared the clinical...

Aim Toxoplasma gondii (Tg) is an intracellular parasite infecting more than a third of the human population. Yet, the impact of Tg infection on sleep, a highly sensitive index of brain functions, remains unknown. We designed an experimental mouse model of chronic Tg infection to assess the effects on sleep-wake states. Methods Mice were infected u...

The loss of hypothalamic neurons that produce wake-promoting orexin (hypocretin) neuropeptides is responsible for narcolepsy type 1 (NT1). While the number of histamine neurons is increased in patients with NT1, results on orexin-deficient mouse models of NT1 are inconsistent. On the other hand, the effect of histamine deficiency on orexin neuron n...

Driven by life and various motivations, human beings are used to restricting their own sleep, considered as time wasted, and staying awake late at night. Thus, every civilization has its own culture to enhance wake, e.g. by consuming tea and coffee. Psychostimulants like caffeine and amphetamine constitute the first generation of wake-promoting com...

Objectif Comparer les symptômes et les caractéristiques du sommeil chez les patients diagnostiqués avec narcolepsie-cataplexie (NC) avant et après l’âge de 18 ans. Méthodes Les patients de novo avec un diagnostic de NC ont rempli un questionnaire et un entretien standardisés, suivis d’une étude sur le sommeil. Les mesures cliniques du sommeil ont...

High cognitive functioning could be a protective factor for school difficulties, behavioral and mood impairments in children with narcolepsy. To investigate this factor, we studied the intellectual abilities of 74 children with narcolepsy (43 boys, 11.7 years old at diagnosis, 91% of cataplexies, 64% obese, 100% HLA positive for DR-DQB1*06:02). All...

Antihistamine medications have been suggested to elicit clinical features of restless legs syndrome. The available data are limited, particularly concerning periodic leg movements during sleep, which are common in restless legs syndrome and involve bursts of tibialis anterior electromyogram. Here, we tested whether the occurrence of tibialis anteri...

Due to the discovery of Rett Syndrome (RTT) genetic mutations, animal models have been developed. Sleep research in RTT animal models may unravel novel neural mechanisms for this severe neurodevelopmental heritable rare disease. In this systematic literature review we summarize the findings on sleep research of 13 studies in animal models of RTT. W...

Objective To compare symptoms and sleep characteristics in patients diagnosed with narcolepsy‐cataplexy (NC) before and after the age of 18 years. Methods De novo patients with NC diagnosis completed a standardized questionnaire and interview, followed by a sleep study. The clinical and sleep measures were compared between patients diagnosed befor...

Background and purpose: Cerebral organoids (COs) have been used for studying brain development, neural disorders, and species-specific drug pharmacology and toxicology, but the potential of COs transplantation therapy for brain injury remains to be answered. Methods: With preparation of traumatic brain injury (TBI) model of motor dysfunction, CO...

Sleep and wakefulness are promoted not by a single neural pathway but via wake or sleep-promoting nodes distributed across layers of the brain. We equate each layer with a brain region in proposing a layered subsumption model for arousal based on a computational architecture. Beyond the brainstem the layers include the diencephalon (hypothalamus, t...

【摘要】：睡眠障碍一直困扰人类。第一个飞越大西洋的著名飞行员查理·林格在完成他的创举后, 对记者说飞行中最艰难的是与打瞌睡搏斗, 保持清醒 ! 人类醉心熬夜, 因而世界各大文明都有自己的传统促醒文化, 比如中国人饮茶、西方人喝咖啡, 里面的有效成分咖啡因, 还有苯丙胺 (安非他明) 等中枢兴奋剂构成了第一代促醒药物。但促醒文化滥用导致人类睡眠自我剥夺、夜间失眠及白天瞌睡, 并催生种种并发症, 如多吃、肥胖、糖尿病、痴呆及抑郁症, 构成严重医学和社会问题。战争中促醒药物的滥用更不是秘密, 现代战争理论认为, 在谁都拥有能摧毁地球几次的核威力下, 谁先打磕睡谁就将失去战争, 谁不能维持清醒到最后一刻谁也将失去战争 ! 然二战中纳粹伞兵夜间特别行动中服用安非他明后竟然如此兴奋以致他们不撑伞就跳下飞...

Background: Few studies on the relationship between sleep quantity and/or quality and cognition have been conducted among preschoolers from the healthy general population. We aimed to identify, among 3-year-old children, early polysomnography (PSG) sleep factors associated with estimated intelligence quotient (IQ) using the Weschler Preschool and...

Objectif Peu d’études rapportent le lien entre la quantité et/ou la qualité du sommeil et la cognition chez l’enfant pré-scolaire. Le but était donc d’étudier les relations entre le sommeil des premiers mois de vie et les caractéristiques neurocognitives à 3 ans. Méthodes Les enfants inclus dans cette étude faisaient partie de la cohorte AuBE. Ces...

Objectif La mort subite du nourrisson (MSN) survenant au cours du sommeil, un déficit d’éveil pourrait constituer un facteur de vulnérabilité. Une baisse de l’orexine a ainsi été mise en évidence entre 2 et 6 mois, période d’incidence majeure de la MSN. Or l’orexine stimule directement les neurones histaminergiques, également impliqués dans l’éveil...

Objectif Afin de déterminer si l’histamine cérébrale (HA) est impliquée dans la narcolepsie, nous avons quantifié les niveaux d’HA et de son métabolite direct (télé-méthylhistamine, t-MeHA) dans le liquide céphalorachidien (LCR) chez l’enfant narcoleptique de type1 (NT1). Méthodes L’étude inclut 24 enfants NT1 et 21 témoins appariés en sexe et âge...

睡眠障碍一直困扰人类，第一个飞越大西洋的著名飞行员查理.林格在完成他的伟大创举后，对记者说飞行中最艰难的是与打瞌睡搏斗，保持清醒！人类一直醉心熬夜, 因而世界各大文明都有自己的促醒文化，比如中国人饮茶、西方人喝咖啡，里面的有效成分咖啡因与苯丙胺（安非他明）等中枢兴奋剂构成第一代促醒药物。但促醒文化滥用导致人类睡眠自我剥夺、夜间失眠及白天瞌睡，并催生种种并发症，如多吃、肥胖、糖尿病、痴呆及抑郁症，构成严重医学和社会问题。战争中滥用促醒药物更不是秘密。现代战争理论认为：在谁都拥有能摧毁地球几次的核威力下，谁先打磕睡谁就将失去战争；谁不能维持清醒到最后一刻谁也将失去战争! 然二战中纳粹德国伞兵夜间特别行动中服用安非他明后竟然如此兴奋以致他们不撑伞就跳下飞机！这个传说生动地展示了第一代促醒药的局限性...

Despite the presence of variable behavioural and cognitive activities during wakefulness, this vigilance state, defined classically on the EEG as cortical fast and low-amplitude voltage activities, has long been regarded as relatively homogeneous on the basis of the EEG phenomenology. Recent studies from our team show, however, that cortical activi...

Background Modafinil, a nonamphetaminic wake-promoting compound, is prescribed as first line therapy in narcolepsy, an invalidating disorder characterized by excessive daytime sleepiness and cataplexy. Although its mode of action remains incompletely known, recent studies indicated that modafinil modulates astroglial connexin-based gap junctional c...

Objectif Nous avons précédemment montré que les systèmes à histamine (HA) et à orexine (Ox), pilotés par les hormones sexuelles, jouent un rôle clé dans l’éveil lié à l’attirance sexuelle (sexual arousal). Afin de déterminer si ces hormones exercent une action directe sur les neurones à HA et à Ox, nous avons tenté d’identifier le récepteur à andro...

La communauté de recherche sur le sommeil et les neurosciences est en deuil. Le Professeur Michel Jouvet nous a quitté, laissant un vide béant dans nos cœurs, dans nos vies, lui qui a tant compté pour nous. Son esprit créatif unique est à l’origine de multiples résultats et théories fascinantes sur le sommeil tels que la découverte, chez le chat,...

Objectives Sleep problems and deprivation are common during pregnancy, particularly in the third trimester. Previous studies are mostly descriptive or focused on specific clinical groups and late pregnancy. We aimed to identify sleep duration trajectories during the pregnancy period, their associated factors, and impact on pregnancy and birth outco...

Objectif Nous avons mis en évidence pallidin, un gène différentiellement exprimé chez un modèle de souris narcoleptiques, déficientes à la fois pour l’histamine et l’orexine (Souris HO−/−) et utilisé la drosophile pour tester la fonction de ce gène. Méthodes Chez la drosophile le sommeil a été évalué par un système de détection de la locomotion Tr...

Objectif Evaluer la prevalence du syndrome metabolique chez les enfants presentant une narcolepsie idiopathique. Methodes Nous avons recueilli les donnees du bilan diagnostic de 40 enfants (21 garcons), presentant une narcolepsie idiopathique. Ces enfants ont tous ete diagnostiques entre 2010 et 2016 au centre de reference national pour la narcolep...

Objectives The temporal association between sudden infant death syndrome (SIDS) and sleep suggests that the arousability from sleep provides a protective mechanism for survival. Recently, the hypocretin system, which promotes wakefulness, has been implicated in SIDS, since it has been reported that SIDS victims have fewer hypocretin neurons than in...

Intracerebroventricular injection of NPS reduces the duration of the ketamine- or thiopental-induced loss of the righting reflex in rats. But the specific EEG activities are unknown. We therefore sought to examine the effects of the NPS-NPSR system on anesthetic-induced characteristics of EEG power spectra and sleep-wake profiles. NPS alone or toge...

Background: Few studies on the relations between sleep quantity and/or quality and cognition have been conducted among preschoolers from healthy general population. We aimed at identifying, among 36 months old children, early factors associated with intelligence quotient (IQ) estimated through the Weschler Preschool and Primary Scale Intelligence-...

Although low-frequency (LF, <10 Hz) activities have been considered as a hallmark of non-rapid eye movement (NREM) sleep, several studies have recently reported LF activities in the membrane potential of cortical neurons from different areas in awake mice. However, little is known about the spatio-temporal organization of LF activities across corti...

Histamine and orexins are wake promoters released by hypothalamic neurons. The activity of histamine neurons is increased by orexin neurons. Recently, it has been shown that orexin deficiency entails high-amplitude theta wave bursts during rapid eye movement sleep and cataplexy in narcoleptic mice. The primary aim of this study was to assess whethe...

ABSTRACT Modafinil is a non-amphetaminic wake-promoting compound used as therapy against sleepiness and narcolepsy. Its mode of action is complex but modafinil has been recently proposed to act as a cellular-coupling enhancer in glial cells, through modulation of gap junctions constituted by connexins. The present study investigated in mice the im...

Objectif La mort subite du nourrisson (MSN), décès inexpliqué d’un enfant de moins de 1 an durant son sommeil, est la première cause de mortalité entre 1 mois et 1 an. L’étude d’enregistrements polysomnographiques a montré que les victimes de MSN présentent un déficit de l’éveil. Cependant, on ne sait pas quels sont les systèmes d’éveil qui sont dé...

Objectif L’histamine(HA) maintien l’éveil(Ev) face aux défis comportementaux. Son déficit conduit à la somnolence. Il restait à déterminer quels sont les récepteurs à HA mis en jeu et comment le cerveau régule l’éveil lors du déficit d’un système éveillant. Méthodes Quatorze paires de souris H1+/+ et H1−/− de même portée ont été utilisées dans cet...

Objectif Nous avons mis en evidence pallidin, un gene differentiellement exprime chez un modele de souris knock-out, deficientes a la fois pour l’histamine et l’orexine (Souris HO−/−) et utilise la drosophile pour tester la fonction de ce gene. Methodes Chez la drosophile le sommeil a ete evalue par detection automatique de la locomotion. Des trans...

The objective of this study was to evaluate the levels of plasma bicarbonate levels in narcoleptic children. Clinical, electrophysiological data and bicarbonate levels were evaluated retrospectively in children seen in our paediatric national reference centre for hypersomnia. The cohort included 23 control subjects (11.5 4 years, 43% boys) and 51 p...

Narcolepsy type 1 is associated with loss of orexin neurons, sleep-wake derangements, cataplexy, and a wide spectrum of alterations in other physiological functions, including energy balance, cardiovascular, and respiratory control. It is unclear which narcolepsy signs are directly related to the lack of orexin neurons or are instead modulated by d...

Very preterm newborns are at high risk of neurological injury. The objective of this work was to study the impact of neurological aggression on the autonomic nervous system. We studied polysomnography recordings, at term corrected gestational age, for 38 preterm infants born at less than 28 weeks or weighing less than 1 kg. These infants were seen...

Personne n'échappe au Grand sommeil et c'est aussi vrai pour le sommeil tout court. Cet état physiologique, dont les fonctions et les mécanismes n'ont pas fini de dévoiler leurs mystères, est indispensable à l'Homme. Alors ? Que ce passe-t-il quand on ne dort pas ? Cette question est à l'origine de bien de fantasmes empruntant au registre des films...

Objectif Les neurones a histamine (HA) et a orexines (Ox) constituent deux systemes majeurs dans le controle de l’eveil. Compte tenu d’une innervation Oxrgique particulierement dense des neurones a HA, il a ete affirme que le role eveillant des Ox depend de la transmission a HA. Or, les neurones a Ox se projettent non seulement sur le systeme a HA...

Objectif Les femmes sont particulièrement à risque de perte et/ou de perturbation de sommeil au cours de la grossesse. Notre objectif est (i) d’identifier les trajectoires ou profil de durée de sommeil des femmes pendant la grossesse ; (ii) d’identifier simultanément les facteurs de risque (FR) temps-indépendants expliquant les différences entre le...

Objectif Les objectifs de cette étude sont d’étudier l’influence du tabagisme maternel sur la maturation du sommeil et les réactions d’éveil spontané dans une large étude prospective sur la maturation du sommeil et du système nerveux autonome (AuBE) et d’évaluer s’il y a une différence entre le sommeil diurne et nocturne. Méthodes Deux cent quatre...

Objectif Identifier les facteurs de risque associés à l’efficience intellectuelle à 3 ans mesurée par le WPPSI-III et estimée par le quotient intellectuel verbal (QIV), de performance (QIP) et total (QIT). Méthodes L’analyse inclus 194 enfants de la cohorte AuBE ayant bénéficié du test et pour lesquels nous disposions de données sur la mère (âge,...

ABSTRACT Modafinil is a non-amphetaminic wake-promoting compound used as therapy against sleepiness and narcolepsy. Its mode of action is complex but modafinil has been recently proposed to act as a cellular-coupling enhancer in glial cells, through modulation of gap junctions constituted by connexins. The present study investigated in mice the im...

Wakefulness and its disorders, Role of histamine via H3-receptor Inverse agoniste Pitolisant Histaminergic neurons are located in the posterior-hypothalamus and project to all brain areas promoting the neuronal activity. The histamine (HA) system fulfills a major role in maintaining wakefulness(W). The HA H3 receptors(H3R) are firstly autoreceptor...

Histaminergic neurons are located in the posterior-hypothalamus and project to all brain areas promoting the neuronal activity. The histamine (HA) system fulfills a major role in maintaining wakefulness(W). The HA H3 receptors(H3R) are firstly autoreceptors damping the HA release/synthesis and HA neuronal firing. This action extends to heterorecept...

Le bruxisme du sommeil chez l’homme est connu depuis longue date. Son taux épidémiologique peut atteindre 6% de la population, sans compter une activité rythmique des muscles masticateurs enregistrée pendant le sommeil chez une population large (jusqu’à 56%). Cependant, le bruxisme n’a jamais vraiment fait l’objet d’une recherche intense que ce soi...