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Since the first description of narcolepsy at the end of the 19th Century, great progress has been made. The disease is nowadays distinguished as narcolepsy type 1 and type 2. In the 1960s, the discovery of rapid eye movement sleep at sleep onset led to improved understanding of core sleep-related disease symptoms of the disease (excessive daytime sleepiness with early occurrence of rapid eye movement sleep, sleep-related hallucinations, sleep paralysis, rapid eye movement parasomnia), as possible dysregulation of rapid eye movement sleep, and cataplexy resembling an intrusion of rapid eye movement atonia during wake. The relevance of non-sleep-related symptoms, such as obesity, precocious puberty, psychiatric and cardiovascular morbidities, has subsequently been recognized. The diagnostic tools have been improved, but sleep-onset rapid eye movement periods on polysomnography and Multiple Sleep Latency Test remain key criteria. The pathogenic mechanisms of narcolepsy type 1 have been partly elucidated after the discovery of strong HLA class II association and orexin/hypocretin deficiency, a neurotransmitter that is involved in altered rapid eye movement sleep regulation. Conversely, the causes of narcolepsy type 2, where cataplexy and orexin deficiency are absent, remain unknown. Symptomatic medications to treat patients with narcolepsy have been developed, and management has been codified with guidelines, until the recent promising orexin-receptor agonists. The present review retraces the steps of the research on narcolepsy that linked the features of the disease with rapid eye movement sleep abnormality, and those that do not appear associated with rapid eye movement sleep.
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The ability to perform skilled arm movements is central to everyday life, as limb impairments in common neurologic disorders such as stroke demonstrate. Skilled arm movements require adaptation of motor commands based on discrepancies between desired and actual movements, called sensory errors. Studies in humans show that this involves predictive and reactive movement adaptations to the errors, and also requires a general motivation to move. How these distinct aspects map onto defined neural signals remains unclear, because of a shortage of equivalent studies in experimental animal models that permit neural-level insights. Therefore, we adapted robotic technology used in human studies to mice, enabling insights into the neural underpinnings of motivational, reactive, and predictive aspects of motor adaptation. Here, we show that forelimb motor adaptation is regulated by neurons previously implicated in motivation and arousal, but not in forelimb motor control: the hypothalamic orexin/hypocretin neurons (HONs). By studying goal-oriented mouse-robot interactions in male mice, we found distinct HON signals occur during forelimb movements and motor adaptation. Temporally-delimited optosilencing of these movement-associated HON signals impaired sensory error-based motor adaptation. Unexpectedly, optosilencing affected neither task reward or execution rates, nor motor performance in tasks that did not require adaptation, indicating that the temporally-defined HON signals studied here were distinct from signals governing general task engagement or sensorimotor control. Collectively, these results reveal a hypothalamic neural substrate regulating forelimb motor adaptation.SIGNIFICANCE STATEMENT The ability to perform skilled, adaptable movements is a fundamental part of daily life, and is impaired in common neurologic diseases such as stroke. Maintaining motor adaptation is thus of great interest, but the necessary brain components remain incompletely identified. We found that impaired motor adaptation results from disruption of cells not previously implicated in this pathology: hypothalamic orexin/hypocretin neurons (HONs). We show that temporally confined HON signals are associated with skilled movements. Without these newly-identified signals, a resistance to movement that is normally rapidly overcome leads to prolonged movement impairment. These results identify natural brain signals that enable rapid and effective motor adaptation.
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Membro Anterior , Acidente Vascular Cerebral , Animais , Membro Anterior/fisiologia , Humanos , Masculino , Camundongos , Movimento/fisiologia , Orexinas , Extremidade SuperiorRESUMO
Epilepsy is a common neurological disorder, affecting patients of all ages, reducing the quality of life, and associated with several comorbidities. Sleep impairment is a frequent condition in patients with epilepsy (PWE), and the relation between sleep and epilepsy has been considered bidirectional, as one can significantly influence the other, and vice versa. The orexin system was described more than 20 years ago and is implicated in several neurobiological functions other than in controlling the sleep-wake cycle. Considering the relation between epilepsy and sleep, and the significant contribution of the orexin system in regulating the sleep-wake cycle, it is conceivable that the orexin system may be affected in PWE. Preclinical studies investigated the impact of the orexin system on epileptogenesis and the effect of orexin antagonism on seizures in animal models. Conversely, clinical studies are few and propose heterogeneous results also considering the different methodological approaches to orexin levels quantification (cerebrospinal-fluid or blood samples). Because orexin system activity can be modulated by sleep, and considering the sleep impairment documented in PWE, the recently approved dual orexin receptor antagonists (DORAs) have been suggested for treating sleep impairment and insomnia in PWE. Accordingly, sleep improvement can be a therapeutic strategy for reducing seizures and better managing epilepsy. The present review analyzes the preclinical and clinical evidence linking the orexin system to epilepsy, and hypothesizes a model in which the antagonism to the orexin system by DORAs can improve epilepsy by both a direct and a sleep-mediated (indirect) effect.
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Epilepsia , Qualidade de Vida , Animais , Orexinas , Receptores de Orexina/fisiologia , Sono/fisiologia , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Antagonistas dos Receptores de Orexina/uso terapêutico , Antagonistas dos Receptores de Orexina/farmacologia , Convulsões/tratamento farmacológicoRESUMO
Narcolepsy type 1 (NT1) and type 2 (NT2), also known as narcolepsy with and without cataplexy, are sleep disorders that benefited from major scientific advances over the last two decades. NT1 is caused by the loss of hypothalamic neurons producing orexin/hypocretin, a neurotransmitter regulating sleep and wake, which can be measured in the cerebrospinal fluid (CSF). A low CSF level of hypocretin-1/orexin-A is a highly specific and sensitive biomarker, sufficient to diagnose NT1. Orexin-deficiency is responsible for the main NT1 symptoms: sleepiness, cataplexy, disrupted nocturnal sleep, sleep-related hallucinations, and sleep paralysis. In the absence of a lumbar puncture, the diagnosis is based on neurophysiological tests (nocturnal and diurnal) and the presence of the pathognomonic symptom cataplexy. In the revised version of the International Classification of sleep Disorders, 3rd edition (ICSD-3-TR), a sleep onset rapid eye movement sleep (REM) period (SOREMP) (i.e. rapid occurrence of REM sleep) during the previous polysomnography may replace the diurnal multiple sleep latency test, when clear-cut cataplexy is present. A nocturnal SOREMP is very specific but not sensitive enough, and the diagnosis of cataplexy is usually based on clinical interview. It is thus of crucial importance to define typical versus atypical cataplectic attacks, and a list of clinical features and related degrees of certainty is proposed in this paper (expert opinion). The time frame of at least three months of evolution of sleepiness to diagnose NT1 was removed in the ICSD-3-TR, when clear-cut cataplexy or orexin-deficiency are established. However, it was kept for NT2 diagnosis, a less well-characterized disorder with unknown clinical course and absence of biolo biomarkers; sleep deprivation, shift working and substances intake being major differential diagnoses. Treatment of narcolepsy is nowadays only symptomatic, but the upcoming arrival of non-peptide orexin receptor-2 agonists should be a revolution in the management of these rare sleep diseases.
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Cataplexia , Narcolepsia , Humanos , Cataplexia/diagnóstico , Orexinas , Sonolência , Narcolepsia/diagnóstico , Narcolepsia/terapia , SonoRESUMO
The orexins, also known as hypocretins, are two neuropeptides (orexin A and B or hypocretin 1 and 2) produced by a few thousand neurons located in the lateral hypothalamus that were independently discovered by two research groups in 1998. Those two peptides bind two receptors (orexin/hypocretin receptor 1 and receptor 2) that are widely distributed in the brain and involved in the central physiological regulation of sleep and wakefulness, orexin receptor 2 having the major role in the maintenance of arousal. They are also implicated in a multiplicity of other functions, such as reward seeking, energy balance, autonomic regulation and emotional behaviours. The destruction of orexin neurons is responsible for the sleep disorder narcolepsy with cataplexy (type 1) in humans, and a defect of orexin signalling also causes a narcoleptic phenotype in several animal species. Orexin discovery is unprecedented in the history of sleep research, and pharmacological manipulations of orexin may have multiple therapeutic applications. Several orexin receptor antagonists were recently developed as new drugs for insomnia, and orexin agonists may be the next-generation drugs for narcolepsy. Given the broad range of functions of the orexin system, these drugs might also be beneficial for treating various conditions other than sleep disorders in the near future.
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Cataplexia , Narcolepsia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/uso terapêutico , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/uso terapêutico , Narcolepsia/tratamento farmacológico , Orexinas/metabolismo , Sono/fisiologia , Vigília/fisiologiaRESUMO
This article addresses the clinical presentation, diagnosis, pathophysiology and management of narcolepsy type 1 and 2, with a focus on recent findings. A low level of hypocretin-1/orexin-A in the cerebrospinal fluid is sufficient to diagnose narcolepsy type 1, being a highly specific and sensitive biomarker, and the irreversible loss of hypocretin neurons is responsible for the main symptoms of the disease: sleepiness, cataplexy, sleep-related hallucinations and paralysis, and disrupted nocturnal sleep. The process responsible for the destruction of hypocretin neurons is highly suspected to be autoimmune, or dysimmune. Over the last two decades, remarkable progress has been made for the understanding of these mechanisms that were made possible with the development of new techniques. Conversely, narcolepsy type 2 is a less well-defined disorder, with a variable phenotype and evolution, and few reliable biomarkers discovered so far. There is a dearth of knowledge about this disorder, and its aetiology remains unclear and needs to be further explored. Treatment of narcolepsy is still nowadays only symptomatic, targeting sleepiness, cataplexy and disrupted nocturnal sleep. However, new psychostimulants have been recently developed, and the upcoming arrival of non-peptide hypocretin receptor-2 agonists should be a revolution in the management of this rare sleep disease, and maybe also for disorders beyond narcolepsy.
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Cataplexia , Narcolepsia , Neuropeptídeos , Cataplexia/diagnóstico , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Narcolepsia/diagnóstico , Narcolepsia/terapia , Neuropeptídeos/líquido cefalorraquidiano , Orexinas , SonolênciaRESUMO
Environmental lighting conditions play a central role in cognitive function, but the underlying mechanisms remain unclear. Utilizing a diurnal rodent model, the Nile grass rat (Arvicanthis niloticus), we previously found that daytime light intensity affects hippocampal function in this species in a manner similar to its effects in humans. Compared to animals housed in a 12:12 h bright light-dark (brLD) cycle, grass rats kept in a 12:12 h dim light-dark (dimLD) cycle showed impaired spatial memory in the Morris water maze (MWM) and reduced CA1 apical dendritic spine density. The present study explored the neural substrates mediating the effects of daylight intensity on hippocampal function focusing on the hypothalamic orexin (hypocretin) system. First, animals housed in dimLD were treated with daily intranasal administration of orexin A peptide over five training days of the MWM task. Compared to vehicle controls, this treatment led to superior spatial memory accompanied by increased phosphorylation of Ca2+ /calmodulin-dependent protein kinase II α and glutamate receptor 1 within the CA1. To assess the role of hippocampal orexinergic signaling, an adeno-associated viral vector (AAV) expressing an orexin receptor 1 (OX1R) shRNA was injected into the dorsal hippocampus targeting the CA1 of animals housed in brLD. AAV-mediated knockdown of OX1R within the hippocampus resulted in deficits in MWM performance and reduced CA1 apical dendritic spine density. These results are consistent with the view that the hypothalamic orexinergic system underlies the modulatory role of daytime illumination on hippocampal function in diurnal mammals.
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Hipocampo , Fotoperíodo , Animais , Hipocampo/metabolismo , Murinae/metabolismo , Orexinas/metabolismo , Memória EspacialRESUMO
Neuropeptides orexin A and B (OX-A/B, also called hypocretin 1 and 2) are released selectively by a population of neurons which projects widely into the entire central nervous system but is localized in a restricted area of the tuberal region of the hypothalamus, caudal to the paraventricular nucleus. The OX system prominently targets brain structures involved in the regulation of wake-sleep state switching, and also orchestrates multiple physiological functions. The degeneration and dysregulation of the OX system promotes narcoleptic phenotypes both in humans and animals. Hence, this review begins with the already proven involvement of OX in narcolepsy, but it mainly discusses the new pre-clinical and clinical insights of the role of OX in three major neurological disorders characterized by sleep impairment which have been recently associated with OX dysfunction, such as Alzheimer's disease, stroke and Prader Willi syndrome, and have been emerged over the past 10 years to be strongly associated with the OX dysfunction and should be more considered in the future. In the light of the impairment of the OX system in these neurological disorders, it is conceivable to speculate that the integrity of the OX system is necessary for a healthy functioning body.
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Narcolepsia , Neuropeptídeos , Animais , Humanos , Hipotálamo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Neuropeptídeos/metabolismo , OrexinasRESUMO
Psychiatric illnesses and cardiovascular disease (CVD) contribute to significant overall morbidity, mortality, and health care costs, and are predicted to reach epidemic proportions with the aging population. Within the Veterans Administration (VA) health care system, psychiatric illnesses such as post-traumatic stress disorder (PTSD) and CVD such as heart failure (HF), are leading causes of hospital admissions, prolonged hospital stays, and resource utilization. Numerous studies have demonstrated associations between PTSD symptoms and CVD endpoints, particularly in the Veteran population. Not only does PTSD increase the risk of HF, but this relationship is bi-directional. Accordingly, a VA-sponsored conference entitled "Cardiovascular Comorbidities in PTSD: The Brain-Heart Consortium" was convened to explore potential relationships and common biological pathways between PTSD and HF. The conference was framed around the hypothesis that specific common systems are dysregulated in both PTSD and HF, resulting in a synergistic acceleration and amplification of both disease processes. The conference was not intended to identify all independent pathways that give rise to PTSD and HF, but rather identify shared systems, pathways, and biological mediators that would be modifiable in both disease processes. The results from this conference identified specific endocrine, autonomic, immune, structural, genetic, and physiological changes that may contribute to shared PTSD-CVD pathophysiology and could represent unique opportunities to develop therapies for both PTSD and HF. Some recommendations from the group for future research opportunities are provided.
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Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Adulto , Idoso , Encéfalo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/psicologia , Estados Unidos , United States Department of Veterans Affairs , Veteranos/psicologiaRESUMO
The orexin (OX1R) and cholecystokinin A (CCK1R) receptors play opposing roles in the migration of the human colon cancer cell line HT-29, and may be involved in the pathogenesis and pathophysiology of cancer cell invasion and metastasis. OX1R and CCK1R belong to family A of the G-protein-coupled receptors (GPCRs), but the detailed mechanisms underlying their functions in solid tumor development remain unclear. In this study, we investigated whether these two receptors heterodimerize, and the results revealed novel signal transduction mechanisms. Bioluminescence and Förster resonance energy transfer, as well as proximity ligation assays, demonstrated that OX1R and CCK1R heterodimerize in HEK293 and HT-29 cells, and that peptides corresponding to transmembrane domain 5 of OX1R impaired heterodimer formation. Stimulation of OX1R and CCK1R heterodimers with both orexin-A and CCK decreased the activation of Gαq, Gαi2, Gα12, and Gα13 and the migration of HT-29 cells in comparison with stimulation with orexin-A or CCK alone, but did not alter GPCR interactions with ß-arrestins. These results suggest that OX1R and CCK1R heterodimerization plays an anti-migratory role in human colon cancer cells.
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Movimento Celular , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Receptores de Orexina/metabolismo , Multimerização Proteica , Receptor de Colecistocinina A/metabolismo , Transdução de Sinais , Células HEK293 , Células HT29 , Humanos , Receptores de Orexina/genética , Ligação Proteica , Domínios Proteicos , Receptor de Colecistocinina A/genética , beta-Arrestinas/metabolismoRESUMO
KEY POINTS: High-fat diet consumption is a major cause of obesity. Orexin neurons are known to be activated by a high-fat diet and in turn promote further consumption of a high-fat diet. Our study shows that excitatory synapses to orexin neurons become amenable to long-term depression (LTD) after 1 week of high-fat diet feeding. However, this effect reverses after 4 weeks of a high-fat diet. This LTD may be a homeostatic response to a high-fat diet to curb the activity of orexin neurons and hence caloric consumption. Adaptation seen after prolonged high-fat diet intake may contribute to the development of obesity. ABSTRACT: Overconsumption of high-fat diets is one of the strongest contributing factors to the rise of obesity rates. Orexin neurons are known to be activated by a palatable high-fat diet and mediate the activation of the mesolimbic reward pathway, resulting in further food intake. While short-term exposure to a high-fat diet is known to induce synaptic plasticity within the mesolimbic pathway, it is unknown if such changes occur in orexin neurons. To investigate this, 3-week-old male rats were fed a palatable high-fat western diet (WD) or control chow for 1 week and then in vitro patch clamp recording was performed. In the WD condition, an activity-dependent long-term depression (LTD) of excitatory synapses was observed in orexin neurons, but not in chow controls. This LTD was presynaptic and depended on postsynaptic metabotropic glutamate receptor 5 (mGluR5) and retrograde endocannabinoid signalling. WD also increased extracellular glutamate levels, suggesting that glutamate spillover and subsequent activation of perisynaptic mGluR5 may occur more readily in the WD condition. In support of this, pharmacological inhibition of glutamate uptake was sufficient to prime chow control synapses to undergo a presynaptic LTD. Interestingly, these WD effects are transient, as extracellular glutamate levels were similar to controls and LTD was no longer observed in orexin neurons after 4 weeks of WD. In summary, excitatory synapses to orexin neurons become amenable to LTD under a palatable high-fat diet, which may represent a homeostatic mechanism to prevent overactivation of these neurons and to curtail high-fat diet consumption.
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Dieta Hiperlipídica , Depressão Sináptica de Longo Prazo , Neurônios/fisiologia , Orexinas/metabolismo , Sinapses/fisiologia , Transmissão Sináptica , Animais , Masculino , Neurônios/citologia , Ratos , Ratos Sprague-DawleyRESUMO
Orexins/hypocretins (Orx/Hcrt) are hypothalamic peptides that regulate a wide range of physiological processes and have been shown to be recruited by drugs of abuse. This study was designed to test the effect of the specific Orx/Hcrt receptor-1 (Hcrt-r1) antagonist, N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea (SB334867), on reinstatement elicited by ethanol (EtOH)-associated stimuli versus stimuli associated with a conventional reinforcer [i.e. SuperSac, consisting of 3% glucose and 0.125% saccharin (w/v)]. SB334867 (1-10 mg/kg, i.p.) dose-dependently reduced reinstatement induced by the EtOH- but not SuperSac-associated stimuli. These findings support a differential role of Hcrt-r1 in mediating EtOH seeking versus natural reward seeking.
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Benzoxazóis/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/administração & dosagem , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Neuropeptídeos/fisiologia , Antagonistas dos Receptores de Orexina , Ureia/análogos & derivados , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Naftiridinas , Orexinas , Ratos , Reforço Psicológico , Recompensa , Prevenção Secundária , Autoadministração , Edulcorantes/administração & dosagem , Ureia/farmacologiaRESUMO
The deepest layer of the cortex (layer 6b [L6b]) contains relatively few neurons, but it is the only cortical layer responsive to the potent wake-promoting neuropeptide orexin/hypocretin. Can these few neurons significantly influence brain state? Here, we show that L6b-photoactivation causes a surprisingly robust enhancement of attention-associated high-gamma oscillations and population spiking while abolishing slow waves in sleep-deprived mice. To explain this powerful impact on brain state, we investigated L6b's synaptic output using optogenetics, electrophysiology, and monoCaTChR ex vivo. We found powerful output in the higher-order thalamus and apical dendrites of L5 pyramidal neurons, via L1a and L5a, as well as in superior colliculus and L6 interneurons. L6b subpopulations with distinct morphologies and short- and long-term plasticities project to these diverse targets. The L1a-targeting subpopulation triggered powerful NMDA-receptor-dependent spikes that elicited burst firing in L5. We conclude that orexin/hypocretin-activated cortical neurons form a multifaceted, fine-tuned circuit for the sustained control of the higher-order thalamocortical system.
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Dendritos , Neurônios , Camundongos , Animais , Orexinas , Dendritos/fisiologia , Neurônios/fisiologia , Tálamo/fisiologia , Células PiramidaisRESUMO
Orexin (also known as hypocretin) is a neuropeptide exclusively synthesized in the neurons of the lateral hypothalamus (LH). Initially orexin was thought to be involved in the regulation of feeding behavior. However, it is now known to also be a critical regulator of sleep/wakefulness, especially the maintenance of wakefulness. Although the somas of orexin neurons are exclusively located in the LH, these neurons send axons throughout the brain and spinal cord. Orexin neurons integrate inputs from various brain regions and project to neurons that are involved in the regulation of sleep/wakefulness. Orexin knockout mice have a fragmentation of sleep/wakefulness and cataplexy-like behavior arrest, which is similar to the sleep disorder narcolepsy. Recent progress with manipulation of neural activity of targeted neurons, using experimental tools such as optogenetics and chemogenetics, has emphasized the role of orexin neuron activity on the regulation of sleep/wakefulness. Recording of orexin neuron activity in vivo using electrophysiological and gene-encoded calcium indicator proteins revealed that these cells have specific activity patterns across sleep/wakefulness state changes. Here, we also discuss not only the role of the orexin peptide, but also the role of other co-transmitters that are synthesized and released from orexin neurons and involved in sleep/wakefulness regulation.
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Narcolepsia , Neuropeptídeos , Camundongos , Animais , Orexinas/metabolismo , Vigília/fisiologia , Sono/fisiologia , Neuropeptídeos/metabolismo , Narcolepsia/metabolismo , Neurônios/metabolismo , Camundongos Knockout , Receptores de Orexina/metabolismoRESUMO
Binge eating disorder is a debilitating disease characterized by recurrent episodes of excessive food consumption and associated with psychiatric comorbidities. Despite a growing body of research investigating the neurobiological underpinnings of eating disorders, specific treatments are lacking. Given its fundamental role in feeding behaviors, we investigated the role of the orexin (hypocretin) neuropeptide system in binge-like eating and associated phenotypes. Specifically, we submitted female and male orexin-deficient mice to a paradigm of intermittent access (once weekly for 24 h) to a Western diet (WD) to induce binge-like eating. Additionally, we measured their anxiety-like behavior and plasma corticosterone levels. All mice showed binge-like eating in response to the intermittent WD access, but females did so to a greater extent than males. While orexin deficiency did not affect binge-like eating in this paradigm, we found that female orexin-deficient mice generally weighed more, and they expressed increased hypophagia and stress levels compared to wild-type mice following binge-like eating episodes. These detrimental effects of orexin deficiency were marginal or absent in males. Moreover, male wild-type mice expressed post-binge anxiety, but orexin-deficient mice did not. In conclusion, these results extend our knowledge of orexin's role in dysregulated eating and associated negative affective states, and contribute to the growing body of evidence indicating a sexual dimorphism of the orexin system. Considering that many human disorders, and especially eating disorders, have a strong sex bias, our findings further emphasize the importance of testing both female and male subjects.
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Transtorno da Compulsão Alimentar , Neuropeptídeos , Camundongos , Masculino , Feminino , Humanos , Animais , Orexinas , Dieta Ocidental , Comportamento Alimentar/fisiologiaRESUMO
Narcolepsy type 1 (NT1) is the most common type of narcolepsy known to be caused by the loss of specific neurons responsible for producing peptide neurotransmitters (orexins/hypocretins), resulting in a sleep-wake cycle disorder. It is characterized by its association with cataplexy and abnormalities in rapid eye movement. To date, no cure has been established for this life-threatening condition. Misdiagnosis of NT1 is also quite common, although it is not exceedingly rare. Therefore, successfully identifying candidate serum biomarkers for NT1 would be a head start for accurate diagnosis and development of therapeutics for this disorder. This study aims to identify such potential serum biomarkers. A depletion protocol was employed for 27 human serum samples (16 NT1 and 11 healthy controls), followed by applying LC-MS/MS bottom-up proteomics analysis, then LC-PRM-MS for validation. The comparison of the proteome profiles of the low-abundant proteins in the samples was then investigated based on age, sex, sample groups, and the presence of the Human Leukocyte Antigen (HLA) DQB1*0602 allele. The results were tracked to gene expression studies as well as system biology to identify key proteins and understand their relationship in the pathogenesis of NT1. Our results revealed 36 proteins significantly and differentially expressed. Among the impaired pathways and bioprocesses, the complement activation pathway is impaired by six of the differentially expressed proteins (DEPs). They are coded by the genes C2, CFB, C5, C1R, C1S, and MASP1, while 11 DEPs are involved in Acute Phase Response Signaling (APRS), which are coded by the genes FN1, AMBP, APOH, CFB, CP, ITIH2, C5, C2, F2, C1, and ITIH4. The combined AUCs of the downregulated and upregulated DEPs are 0.95 and 0.76, respectively. Overall, this study reveals potential serum-protein biomarkers of NT1 and explains the possible correlation between the biomarkers and pathophysiological effects, as well as important biochemical pathways involved in NT1.
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Narcolepsia , Proteômica , Humanos , Cromatografia Líquida , Espectrometria de Massas em Tandem , Narcolepsia/etiologia , Narcolepsia/genética , Biomarcadores , OrexinasRESUMO
OBJECTIVE: Orexin-A (OX-A) is a neuropeptide produced selectively by neurons of the lateral hypothalamus. It exerts powerful control over brain function and physiology by regulating energy homeostasis and complex behaviors linked to arousal. Under conditions of chronic or acute brain leptin signaling deficiency, such as in obesity or short-term food deprivation, respectively, OX-A neurons become hyperactive and promote hyperarousal and food seeking. However, this leptin-dependent mechanism is still mostly unexplored. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) is known to be implicated in food consumption by promoting hyperphagia and obesity, and we and others demonstrated that OX-A is a strong inducer of 2-AG biosynthesis. Here, we investigated the hypothesis that, under acute (6 h fasting in wt mice) or chronic (in ob/ob mice) hypothalamic leptin signaling reduction, OX-A-induced enhancement of 2-AG levels leads to the production of the 2-AG-derived 2-arachidonoyl-sn-glycerol-3-phosphate (2-AGP), a bioactive lipid belonging to the class of lysophosphatidic acids (LPAs), which then regulates hypothalamic synaptic plasticity by disassembling α-MSH anorexigenic inputs via GSK-3ß-mediated Tau phosphorylation, ultimately affecting food intake. METHODS: We combined cell-type-specific morphological (CLEM and confocal microscopy), biochemical, pharmacological, and electrophysiological techniques to dissect the leptin- and OX-A/2-AGP-mediated molecular pathways regulating GSK-3ß-controlled pT231-Tau production at POMC neurons of obese ob/ob and wild-type (wt) lean littermate mice and in an in vitro model of POMC neurons such as mHypoN41 neurons (N41). RESULTS: 2-AGP is overproduced in the hypothalamus of obese leptin-deficient, or lean 6 h food-deprived mice, and promotes food intake by reducing α-MSH-expressing synaptic inputs to OX-A neurons via lysophosphatidic acid type-1 receptor (LPA1-R) activation, and pT231-Tau accumulation in α-MSH projections. This effect is due to the activation of the Pyk2-mediated pTyr216-GSK3ß pathway and contributes to further elevating OX-A release in obesity. Accordingly, we found a strong correlation between OX-A and 2-AGP levels in the serum of obese mice and of human subjects. CONCLUSIONS: Hypothalamic feeding pathways are endowed with 2-AGP-mediated synaptic plasticity according to their inherent functional activities and the necessity to adapt to changes in the nutritional status. These findings reveal a new molecular pathway involved in energy homeostasis regulation, which could be targeted to treat obesity and related disturbances.
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Endocanabinoides , Leptina , Camundongos , Humanos , Animais , Orexinas/metabolismo , Leptina/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Endocanabinoides/metabolismo , alfa-MSH/metabolismo , Pró-Opiomelanocortina/metabolismo , Hipotálamo/metabolismo , Obesidade/metabolismo , Lisofosfolipídeos/metabolismo , Camundongos EndogâmicosRESUMO
STUDY OBJECTIVES: To assess the performances of alternative measures of the multiple sleep latency test (MSLT) to identify hypocretin-deficiency in patients with a complaint of hypersomnolence, including patients with narcolepsy. METHODS: MSLT parameters from 374 drug-free patients with hypersomnolence, with complete clinical and polysomnographic (PSG) assessment and cerebrospinal hypocretin-1 measurement were collected. Conventional (sleep latency, number of sleep onset REM-SOREM-periods) and alternative (sleep duration, REM sleep latency and duration, sleep stage transitions) MSLT measures were compared as function of hypocretin-1 levels (≤110 vsâ >â 110 pg/mL). We performed receiver-operating characteristics analyses to determine the best thresholds of MSLT parameters to identify hypocretin-deficiency in the global population and in subgroups of patients with narcolepsy (i.e. typical cataplexy and/or positive PSG/MSLT criteria, nâ =â 223). RESULTS: Patients with hypocretin-deficiency had shorter mean sleep and REM sleep latencies, longer mean sleep and REM sleep durations and more direct REM sleep transitions during the MSLT. The current standards of MSLT/PSG criteria identified hypocretin-deficient patients with a sensitivity of 0.87 and a specificity of 0.69, and 0.81/0.99 when combined with cataplexy. A mean REM sleep durationâ ≥â 4.1 min best identified hypocretin-deficiency in patients with hypersomnolence (AUCâ =â 0.932, sensitivity 0.87, specificity 0.86) andâ ≥â 5.7 min in patients with narcolepsy (AUCâ =â 0.832, sensitivity 0.77, specificity 0.82). CONCLUSION: Compared to the current neurophysiological standard criteria, alternative MSLT parameters would better identify hypocretin-deficiency among patients with hypersomnolence and those with narcolepsy. We highlighted daytime REM sleep duration as a relevant neurophysiological biomarker of hypocretin-deficiency to be used in clinical and research settings.
Assuntos
Cataplexia , Distúrbios do Sono por Sonolência Excessiva , Narcolepsia , Humanos , Orexinas , Sono REM/fisiologia , Cataplexia/diagnóstico , Latência do Sono , Duração do Sono , Narcolepsia/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/diagnósticoRESUMO
Objective: Caffeine is a non-selective adenosine receptor antagonist with pro-arousal and pro-sympathetic nervous system excitatory effects, and these pharmacological effects fit well with the physiological functions of orexin. The purpose of this study was to investigate the role of the orexinergic nervous system in the pharmacological effects of caffeine. Methods: An animal model of sleepiness caused by adenosine accumulation was established by sleep deprivation, and caffeine's effects on the spontaneous activity and sympathetic nervous system of the model animals were evaluated by using the open-field experiment and gastrointestinal peristaltic observation, respectively, and the intervention of orexin receptor antagonists on the pharmacological effects of caffeine was also observed. Results: Mice with 8 h of sleep deprivation showed a significant decrease in spontaneous activity and a significant increase in gastrointestinal push distance. After caffeine intervention, the spontaneous activities of sleep-deprived mice significantly increased and gastrointestinal peristalsis significantly decreased dose-dependent, while orexin receptors antagonist blocked the pro-arousal and inhibitory gastrointestinal peristalsis effects of caffeine on sleep-deprived mice. Conclusions: Orexinergic nervous system mediated caffeine's excitatory effects on the pro-arousal and pro-sympathetic nervous systems. Orexin is likely to be an important performer in the pharmacological effects of caffeine.
RESUMO
Cortical layer 6b is considered by many to be a remnant of the subplate that forms during early stages of neocortical development, but its role in the adult is not well understood. Its neuronal complement has only recently become the subject of systematic studies, and its axonal projections and synaptic input structures have remained largely unexplored despite decades of research into neocortical function. In recent years, however, layer 6b (L6b) has attracted increasing attention and its functional role is beginning to be elucidated. In this review, I will attempt to provide an overview of what is currently known about the excitatory and inhibitory neurons in this layer, their pre- and postsynaptic connectivity, and their functional implications. Similarities and differences between different cortical areas will be highlighted. Finally, layer 6b neurons are highly responsive to several neuropeptides such as orexin/hypocretin, neurotensin and cholecystokinin, in some cases exclusively. They are also strongly controlled by neurotransmitters such as acetylcholine and norepinephrine. The interaction of these neuromodulators with L6b microcircuitry and its functional consequences will also be discussed.