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1.
Cell Rep ; 42(9): 113025, 2023 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-37682712

RESUMO

The Pallidin protein is a central subunit of a multimeric complex called biogenesis of lysosome-related organelles complex 1 (BLOC1) that regulates specific endosomal functions and has been linked to schizophrenia. We show here that downregulation of Pallidin and other members of BLOC1 in the surface glia, the Drosophila equivalent of the blood-brain barrier, reduces and delays nighttime sleep in a circadian-clock-dependent manner. In agreement with BLOC1 involvement in amino acid transport, downregulation of the large neutral amino acid transporter 1 (LAT1)-like transporters JhI-21 and mnd, as well as of TOR (target of rapamycin) amino acid signaling, phenocopy Pallidin knockdown. Furthermore, supplementing food with leucine normalizes the sleep/wake phenotypes of Pallidin downregulation, and we identify a role for Pallidin in the subcellular trafficking of JhI-21. Finally, we provide evidence that Pallidin in surface glia is required for GABAergic neuronal activity. These data identify a BLOC1 function linking essential amino acid availability and GABAergic sleep/wake regulation.

2.
Sleep ; 46(7)2023 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-36971181

RESUMO

STUDY OBJECTIVES: To determine the prevalence of metabolic syndrome (MS) in children with narcolepsy and to evaluate their clinical and sleep characteristics according to the different components of MS. METHODS: This retrospective study consisted of 58 de novo children with narcolepsy (median age: 12.7 years, 48.3% of boys). The recently published MS criteria in a French population of children were used. Clinical and sleep characteristics were compared between groups with different components of MS. RESULTS: MS was present in 17.2% of children with narcolepsy, among whom 79.3% presented with high homeostasis model assessment for insulin resistance (HOMA-IR), 25.9% with high body mass index, 24.1% with low high-density lipoprotein cholesterol (HDL-C), and 12.1% with high triglycerides. Patients with at least two MS components had more night eating behaviors and tended to have lower percentage of slow-wave sleep and more fragmented sleep. On multiple sleep latency test, they had shorter mean sleep latencies to rapid eye movement (REM), non-REM sleep and tended to have more sleep onset REM periods (SOREMPs) than those with less than two MS components. CONCLUSIONS: Insulin resistance was found to be the core metabolic disturbance in obese as well as in nonobese children with narcolepsy. Children with narcolepsy with at least two MS components presented a more severe daytime sleepiness and a higher prevalence of night-eating behaviors than those with less than two MS components. Such children might benefit from early evaluation and management in order to prevent future complications.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Resistência à Insulina , Narcolepsia , Masculino , Humanos , Criança , Estudos Retrospectivos , Narcolepsia/complicações , Narcolepsia/epidemiologia , Sono
4.
Artigo em Inglês | MEDLINE | ID: mdl-36293678

RESUMO

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 numerous behavioral and polysomnographic studies across species. The abundant REM sleep appears to serve to optimize a cerebral state suitable for homeostasis and inherent neuronal activities favorable to brain maturation, ranging from neuronal differentiation, migration, and myelination to synaptic formation and elimination. Progressively more studies in Mammalia have provided the underlying mechanisms involved in some REM sleep-related disorders (e.g., narcolepsy, autism, attention deficit hyperactivity disorder (ADHD)). We summarize the remarkable alterations of polysomnographic, behavioral, and physiological characteristics in humans and Mammalia. Through a comprehensive review, we offer a hybrid of animal and human findings, demonstrating that early-life REM sleep disturbances constitute a common feature of many neurodevelopmental disorders. Our review may assist and promote investigations of the underlying mechanisms, functions, and neurodevelopmental diseases involved in REM sleep during early life.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtornos do Sono-Vigília , Animais , Humanos , Sono REM/fisiologia , Sono , Encéfalo/fisiologia
5.
Front Pediatr ; 10: 819496, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35450108

RESUMO

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 of histamine (HA), tele-methylhistamine (t-MeHA), its direct metabolite, and t-MeHA/HA ratio in the cerebrospinal fluid (CSF) of healthy children, to evaluate the maturation of the histaminergic system and its possible involvement in SIDS. Methods: Seventy Eight French children between 0 and 20 years (48.7% boys) were included, all of whom had a clinical indication for lumbar puncture, but subsequently found to be normal. Measurements of HA and t-MeHA in CSF were performed by reverse phase liquid chromatography coupled to mass spectrometry detection. Statistical analyses were performed using Spearman correlations and Non-parametric pairwise ranking tests. Results: A negative correlation was found between age and CSF HA (r = -0.44, p < 10-4) and t-MeHA (r = -0.70, p < 10-4) levels. In pairwise comparisons, no difference in CSF HA and t-MeHA levels was observed between youngest age groups (i.e., 0-2 mo vs. 3-6 mo), but CSF HA and t-MeHA levels were significantly lower in older children (i.e., >6 mo vs. 0-6 mo). The CSF HA decrease with age was only observed in boys, who also presented global lower CSF HA levels than girls. Conclusion: CSF HA and t-MeHA levels decrease with age in boys, and global levels are lower in boys than in girls. These results reveal changes in histaminergic transmission and metabolism during maturation. Whether lower CSF histamine values in boys compared to girls could contribute to their higher risk of SIDS warrants further research.

6.
CNS Neurosci Ther ; 28(6): 829-841, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35212159

RESUMO

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, metabolic, and sleep characteristics between patients with or without RWG at diagnosis. Pharmacological management, anthropometric, and clinical progression were also evaluated during the follow-up. RESULTS: A total of 84 de novo narcoleptic pediatric patients were included; their median age at diagnosis was 12.0 years; 59.5% boys, 90.5% cataplexy, and 98.7% HLA-DQB1*06:02, 57% had RWG profile. RWG patients were younger at diagnosis than non-RWG patients, despite a shorter diagnostic delay. They had a higher BMI z-score and a higher prevalence of obesity at diagnosis, but not at symptom onset, and higher adapted Epworth Sleepiness Scale and Insomnia Severity Index scores than non-RWG patients. No differences on nocturnal polysomnography and multiple sleep latency tests were found between groups at disease diagnosis. After a median follow-up of 5 years, RWG patients still had a higher BMI z-score and a higher prevalence of obesity despite benefiting from the same therapeutic management and displaying improvement in sleepiness and school difficulties. CONCLUSIONS: Narcoleptic RWG patients were younger, sleepier, and the prevalence of obesity was higher at diagnosis despite a shorter diagnostic delay than that of non-RWG patients. These patients had also a higher risk of developing a long-term obesity, despite a positive progression of their narcoleptic symptoms. RGW could then represent a maker of a more severe phenotype of childhood narcolepsy, which should inspire a prompt and more offensive management to prevent obesity and its complications.


Assuntos
Diagnóstico Tardio , Narcolepsia , Criança , Humanos , Narcolepsia/diagnóstico , Narcolepsia/genética , Obesidade , Fenótipo , Sonolência , Aumento de Peso
7.
CNS Neurosci Ther ; 27(8): 895-907, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34085752

RESUMO

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 using cysts of the type II Prugniaud strain. We performed chronic sleep-wake recordings and monitoring as well as EEG power spectral density analysis in order to assess the quantitative and qualitative changes of sleep-wake states. Pharmacological approach was combined to evaluate the direct impact of the infection and inflammation caused by Tg. RESULTS: Infected mouse exhibited chronic sleep-wake alterations over months, characterized by a marked increase (>20%) in time spent awake and in cortical EEG θ power density of all sleep-wake states. Meanwhile, slow-wave sleep decreased significantly. These effects were alleviated by an anti-inflammatory treatment using corticosteroid dexamethasone. CONCLUSION: We demonstrated for the first time the direct consequences of Tg infection on sleep-wake states. The persistently increased wakefulness and reduced sleep fit with the parasite's strategy to enhance dissemination through host predation and are of significance in understanding the neurodegenerative and neuropsychiatric disorders reported in infected patients.


Assuntos
Fases do Sono/fisiologia , Toxoplasmose/fisiopatologia , Vigília/fisiologia , Animais , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos CBA , Sono/efeitos dos fármacos , Sono/fisiologia , Fases do Sono/efeitos dos fármacos , Toxoplasmose/tratamento farmacológico , Vigília/efeitos dos fármacos
8.
Front Neurosci ; 15: 660518, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093114

RESUMO

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 number has never been tested on mammals, even though histamine has been reported to be essential for the development of a functional orexin system in zebrafish. The aim of this study was to test whether histamine neurons are increased in number in orexin-deficient mice and whether orexin neurons are decreased in number in histamine-deficient mice. The hypothalamic neurons expressing L-histidine decarboxylase (HDC), the histamine synthesis enzyme, and those expressing orexin A were counted in four orexin knock-out mice, four histamine-deficient HDC knock-out mice, and four wild-type C57BL/6J mice. The number of HDC-positive neurons was significantly higher in orexin knock-out than in wild-type mice (2,502 ± 77 vs. 1,800 ± 213, respectively, one-tailed t-test, P = 0.011). Conversely, the number of orexin neurons was not significantly lower in HDC knock-out than in wild-type mice (2,306 ± 56 vs. 2,320 ± 120, respectively, one-tailed t-test, P = 0.459). These data support the view that orexin peptide deficiency is sufficient to increase histamine neuron number, supporting the involvement of the histamine waking system in the pathophysiology of NT1. Conversely, these data do not support a significant role of histamine in orexin neuron development in mammals.

9.
J Med Chem ; 64(12): 8246-8262, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34107215

RESUMO

Adenosine A1/A2A receptors (A1R/A2AR) represent targets in nondopaminergic treatment of motor disorders such as Parkinson's disease (PD). As an innovative strategy, multitargeting ligands (MTLs) were developed to achieve comprehensive PD therapies simultaneously addressing comorbid symptoms such as sleep disruption. Recognizing the wake-promoting capacity of histamine H3 receptor (H3R) antagonists in combination with the "caffeine-like effects" of A1R/A2AR antagonists, we designed A1R/A2AR/H3R MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl H3R pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar H3R affinities (Ki < 55 nM). Compound 4 (ST-2001, Ki (A1R) = 11.5 nM, Ki (A2AR) = 7.25 nM) and 12 (ST-1992, Ki (A1R) = 11.2 nM, Ki (A2AR) = 4.01 nM) were evaluated in vivo. l-DOPA-induced dyskinesia was improved after administration of compound 4 (1 mg kg-1, i.p. rats). Compound 12 (2 mg kg-1, p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.


Assuntos
Antagonistas do Receptor A1 de Adenosina/uso terapêutico , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Antagonistas do Receptor A1 de Adenosina/síntese química , Antagonistas do Receptor A1 de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/metabolismo , Animais , Discinesias/tratamento farmacológico , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/metabolismo , Humanos , Levodopa/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Piperidinas/síntese química , Piperidinas/metabolismo , Piperidinas/uso terapêutico , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , Pirrolidinas/síntese química , Pirrolidinas/metabolismo , Pirrolidinas/uso terapêutico , Ratos Sprague-Dawley , Receptor A2A de Adenosina/metabolismo , Receptores Histamínicos H3/metabolismo , Vigília/efeitos dos fármacos
10.
J Sleep Res ; 30(4): e13255, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33314463

RESUMO

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 anterior electromyogram bursts during non-rapid eye movement sleep is altered in histidine decarboxylase knockout mice with congenital histamine deficiency compared with that in wild-type control mice. We implanted six histidine decarboxylase knockout and nine wild-type mice to record neck muscle electromyogram, bilateral tibialis anterior electromyogram, and electroencephalogram during the rest (light) period. The histidine decarboxylase knockout and wild-type mice did not differ significantly in terms of sleep architecture. In both histidine decarboxylase knockout and wild-type mice, the distribution of intervals between tibialis anterior electromyogram bursts had a single peak for intervals < 10 s. The total occurrence rate of tibialis anterior electromyogram bursts during non-rapid eye movement sleep and the occurrence rate of the tibialis anterior electromyogram bursts separated by intervals < 10 s were significantly lower in histidine decarboxylase knockout than in wild-type mice. These data do not support the hypothesis that preventing brain histamine signalling may promote restless legs syndrome. Rather, the data suggest that limb movements during sleep, including those separated by short intervals, are a manifestation of subcortical arousal requiring the integrity of brain histamine signalling.


Assuntos
Eletromiografia , Extremidades/fisiologia , Histamina/deficiência , Síndrome das Pernas Inquietas/fisiopatologia , Sono/fisiologia , Animais , Nível de Alerta , Feminino , Histamina/metabolismo , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
11.
J Neurosci Res ; 99(2): 529-544, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32985711

RESUMO

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. We found disturbed efficacy and continuity of sleep in all genetically mutated models of mice, cynomolgus monkeys, and Drosophila. Models presented highly fragmented sleep with distinct differences in 24-hr sleep/wake cyclicity and circadian arrhythmicity. Overall, animal models mimic sleep complaints reported in individuals with RTT. However, contrary to human studies, in mutant mice, attenuated sleep delta waves, and sleep apneas in non-rapid eye movement sleep were reported. Future studies may focus on sleep structure and EEG alterations, potential central mechanisms involved in sleep fragmentation and the occurrence of sleep apnea across different sleep stages. Given that locomotor dysfunction is characteristic of individuals with RTT, studies may consider to integrate its potential impact on the behavioral analysis of sleep.


Assuntos
Modelos Animais de Doenças , Síndrome de Rett/complicações , Transtornos do Sono-Vigília/etiologia , Animais , Encéfalo/fisiopatologia , Sistemas CRISPR-Cas , Drosophila melanogaster/genética , Síndromes Epilépticas/genética , Síndromes Epilépticas/fisiopatologia , Feminino , Edição de Genes , Técnicas de Introdução de Genes , Humanos , Macaca fascicularis/genética , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Camundongos Mutantes/genética , Mutação , Síndrome de Rett/genética , Síndrome de Rett/fisiopatologia , Fases do Sono , Transtornos do Sono-Vigília/fisiopatologia , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Especificidade da Espécie
12.
J Clin Med ; 9(12)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33348677

RESUMO

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 children underwent a one-night polysomnography followed by Multiple Sleep Latency Tests, an evaluation of intelligence quotient (IQ), and filled standardized questionnaires. Thirty-eight percent had high potentialities (HP defined by IQ > 130) and 48% had school difficulties. Using non-parametric tests, we found that HP children reported less difficulties at school and tended to have less impulsivity, conduct, and learning disorders than those without HP. They also tended to be less obese and had less desaturation. Using a multivariate regression analysis, we found an association between the REM sleep percentage and the IQ. REM sleep could be involved in the dynamic changes contributing to the equilibrium of intellectual functioning. This study highlights that despite their frequent school difficulties, narcolepsy per se is unlikely to be a cause of intellectual disability in children. Prompt diagnosis and management of comorbidities such as obesity and obstructive sleep apnea (OSA) could improve cognitive and school performances in these children.

13.
CNS Neurosci Ther ; 26(10): 1092-1102, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32761857

RESUMO

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 before (46 children, median age: 12 year old) and after (46 adults, median age: 28.5 year old) 18 years of age. RESULTS: The frequency of obesity (54% vs 17%), night eating (29% vs 7%), parasomnia (89% vs 43%), sleep talking (80% vs 34%), and sleep drunkenness (69% vs 24%) were higher in children than in adults, the frequency of sleep paralysis was lower (20% vs 55%) but the frequency of cataplexy and the severity of sleepiness were not different. Children scored higher than adults at the attention-deficit/hyperactivity disorder (ADHD) scale. Depressive feelings affected not differently children (24%) and adults (32%). However, adults had lower quality of life than children. There was no difference between groups for insomnia and fatigue scores. Quality of life was essentially impacted by depressive feelings in both children and adults. Obstructive apnea-hypopnea index (OAHI) was lower in children with higher mean and minimal oxygen saturation than in adults. No between-group differences were found at the multiple sleep latency test. The body mass index (z-score) was correlated with OAHI (r = .32). CONCLUSION: At time of NC diagnosis, children have more frequent obesity, night eating, parasomnia, sleep talking, drunkenness, and ADHD symptoms than adults, even if sleepiness and cataplexy do not differ. These differences should be considered to ensure a prompt diagnosis.


Assuntos
Narcolepsia , Obesidade , Parassonias , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Cataplexia/diagnóstico , Cataplexia/epidemiologia , Cataplexia/fisiopatologia , Criança , Pré-Escolar , Comorbidade , Comportamento Alimentar/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Narcolepsia/diagnóstico , Narcolepsia/epidemiologia , Narcolepsia/fisiopatologia , Obesidade/epidemiologia , Parassonias/epidemiologia , Qualidade de Vida , Estudos Retrospectivos , Adulto Jovem
14.
Artigo em Inglês | MEDLINE | ID: mdl-32116622

RESUMO

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, thalamus), basal ganglia, and cortex. In light of existing empirical evidence, we propose that each layer have sleep and wake computations driven by similar high-level architecture and processing units. Specifically, an interconnected wake-promoting system is suggested as driving arousal in each brain layer with the processing converging to produce the features of wakefulness. In contrast, sleep-promoting GABAergic neurons largely project to and inhibit wake-promoting neurons. We propose a general pattern of caudal wake-promoting and sleep-promoting neurons having a strong effect on overall behavior. However, while rostral brain layers have less influence on sleep and wake, through descending projections, they can subsume the activity of caudal brain layers to promote arousal. The two models presented in this work will suggest computations for the layering and hierarchy. Through dynamic system theory several hypotheses are introduced for the interaction of controllers and systems that correspond to the different populations of neurons at each layer. The models will be drawn-upon to discuss future experiments to elucidate the structure of the hierarchy that exists among the sleep-arousal architecture.

16.
CNS Neurosci Ther ; 26(7): 682-697, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32087606

RESUMO

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, COs at 55 and 85 days (55 and 85 d-CO) were transplanted into damaged motor cortex separately to identify better transplantation donor for brain injury. Further, the feasibility, effectiveness, and underlying mechanism of COs transplantation therapy for brain injury were explored. RESULTS: 55 d-CO was demonstrated as better transplantation donor than 85 d-CO, evidenced by more neurogenesis and higher cell survival rate without aggravating apoptosis and inflammation after transplantation into damaged motor cortex. Cells from transplanted COs had the potential of multilinage differentiation to mimic in-vivo brain cortical development, support region-specific reconstruction of damaged motor cortex, form neurotransmitter-related neurons, and migrate into different brain regions along corpus callosum. Moreover, COs transplantation upregulated hippocampal neural connection proteins and neurotrophic factors. Notably, COs transplantation improved neurological motor function and reduced brain damage. CONCLUSIONS: This study revealed 55 d-CO as better transplantation donor and demonstrated the feasibility and efficacy of COs transplantation in TBI, hoping to provide first-hand preclinical evidence of COs transplantation for brain injury.


Assuntos
Lesões Encefálicas/terapia , Transplante de Tecido Encefálico/métodos , Células-Tronco Embrionárias/transplante , Transtornos das Habilidades Motoras/terapia , Organoides/transplante , Animais , Lesões Encefálicas/fisiopatologia , Movimento Celular/fisiologia , Células Cultivadas , Células-Tronco Embrionárias/fisiologia , Humanos , Masculino , Destreza Motora/fisiologia , Transtornos das Habilidades Motoras/fisiopatologia , Neurogênese/fisiologia , Organoides/fisiologia , Ratos , Ratos Sprague-Dawley
18.
Sleep Med ; 60: 13-19, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30718076

RESUMO

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 Primary Scale Intelligence-III test (WPPSI-III) and its indicators: full-scale (FISQ), verbal (VIQ), and performance (PIQ) intelligence quotients. METHODS: We included full-term children from the French birth-cohort AuBE with PSG recording at term (M0) and/or six months (M6), and available WPPSI-III scores at three years. Sleep and arousal characteristics of these infants were evaluated during day and night sleep periods. Relationships between IQ scores and sleep parameters were estimated using models with the child as a repeated effect adjusted for time (night/day), maturation (M0/M6), tobacco exposure (yes/no), anxiety-depressive scores during pregnancy, maternal age, duration of breastfeeding and child's gender. RESULTS: A total of 118 PSG recordings were obtained, representing a total of 78 unique children (38 with one PSG and 40 with two PSG). No correlations were found between night and day sleep durations at M0 or M6. Mean VIQ, PIQ, and FSIQ scores were within normal ranges. In multivariate models, longer sleep duration and higher sleep efficiency during the day were negatively associated with all IQ scores. More frequent arousals during the night were associated with lower VIQ scores. CONCLUSION: Early sleep characteristics such as night sleep fragmentation or longer naps could be associated with impaired cognitive function at three years of age.


Assuntos
Desenvolvimento Infantil/fisiologia , Cognição/fisiologia , Polissonografia/estatística & dados numéricos , Sono/fisiologia , Nível de Alerta/fisiologia , Pré-Escolar , Estudos de Coortes , Feminino , França , Humanos , Testes de Inteligência , Masculino
19.
CNS Neurosci Ther ; 25(3): 386-395, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30225986

RESUMO

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 cataplexy. To assess whether brain histamine (HA) is also involved, we quantified the cerebrospinal fluid (CSF) levels of HA and tele-methylhistamine (t-MeHA), the direct metabolite of HA between children with orexin-deficient narcolepsy type 1 (NT1) and controls. METHODS: We included 24 children with NT1 (12.3 ± 3.6 years, 11 boys, 83% cataplexy, 100% HLA DQB1*06:02) and 21 control children (11.2 ± 4.2 years, 10 boys). CSF HA and t-MeHA were measured in all subjects using a highly sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay. CSF hypocretin-1 values were determined in the narcoleptic patients. RESULTS: Compared with the controls, NT1 children had higher CSF HA levels (771 vs 234 pmol/L, P < 0.001), lower t-MeHA levels (879 vs 1924 pmol/L, P < 0.001), and lower t-MeHA/HA ratios (1.1 vs 8.2, P < 0.001). NT1 patients had higher BMI z-scores (2.7 ± 1.6 vs 1.0 ± 2.3, P = 0.006) and were more often obese (58% vs 29%, P = 0.05) than the controls. Multivariable analyses including age, gender, and BMI z-score showed a significant decrease in CSF HA levels when the BMI z-score increased in patients (P = 0.007) but not in the controls. No association was found between CSF HA, t-MeHA, disease duration, age at disease onset, the presence of cataplexy, lumbar puncture timing, and CSF hypocretin levels. CONCLUSIONS: Narcolepsy type 1 children had a higher CSF HA level together with a lower t-MeHA level leading to a significant decrease in the t-MeHA/HA ratios. These results suggest a decreased HA turnover and an impairment of histaminergic neurotransmission in narcoleptic children and support the use of a histaminergic therapy in the treatment against narcolepsy.


Assuntos
Histamina/líquido cefalorraquidiano , Narcolepsia/líquido cefalorraquidiano , Adolescente , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Metilistaminas/líquido cefalorraquidiano , Orexinas/líquido cefalorraquidiano , Transmissão Sináptica
20.
Sleep Med ; 49: 40-52, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30172629

RESUMO

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, surprisingly, the cat spent the whole night awake without even one minute of sleep! This initial observation resulted subsequently in a series of basic and clinical studies in order to define the pharmacological profile of modafinil and its mode of action and, notably, to identify the brain targets by which modafinil acts to promote wakefulness. These studies were undertaken using pharmacologic approach coupled with the Cerveau isolé (brain transection) preparation, c-fos labelling and knockout mouse models. It was also in this context that we have developed a purified polyclonal antibody against modafinil. We expected that using immunohistochemistry with this antibody would allow us to localize the brain distribution of modafinil dosing. Surprisingly, we found discrete modafinil immunoreactive neuronal populations in several brain areas of modafinil-naive cats, rodents and humans. The most numerous and intensely labeled modafinil-immunoreactive neurons characterized by granular staining were found in the basal forebrain. They shared the regional location with cholinergic and aspartate-containing neurons but did not colocalize with them. In summary, we here present a newly identified neuronal population located in the basal forebrain that has never previously been published and suggests that these modafinil-immunoreactive neurons might be involved in forebrain functions such as sleep-wake control and cognition. This paper briefly reviews our journey with modafinil research and presents new unpublished experimental data.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Modafinila/farmacologia , Modafinila/uso terapêutico , Narcolepsia/tratamento farmacológico , Neurônios/efeitos dos fármacos , Vigília/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Gatos , França , Humanos , Imuno-Histoquímica , Camundongos Knockout , Neurônios/fisiologia , Polissonografia , Pesquisa
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