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Emmanuel Mignot - One of the best experts on this subject based on the ideXlab platform.

  • modafinil and γ hydroxybutyrate have sleep state specific pharmacological actions on Hypocretin 1 physiology in a primate model of human sleep
    Behavioural Pharmacology, 2009
    Co-Authors: Jamie M Zeitzer, Hans-peter Landolt, Christine L Buckmaster, David M Lyons, Emmanuel Mignot
    Abstract:

    Hypocretin-1 is a hypothalamic neuropeptide that is important in the regulation of wake and the lack of which results in the sleep disorder narcolepsy. Using a monkey that has consolidated wake akin to humans, we examined pharmacological manipulation of sleep and wake and its effects on Hypocretin physiology. Monkeys were given the sleep-inducing γ-hydroxybutyrate (GHB) and the wake-inducing modafinil both in the morning and in the evening. Cerebrospinal fluid Hypocretin-1 concentrations changed significantly in response to the drugs only when accompanied by a behavioral change (GHB-induced sleep in the morning or modafinil-induced wake in the evening). We also found that there was a large (180-fold) interindividual variation in GHB pharmacokinetics that explains variability in sleep induction in response to the drug. Our data indicate that the neurochemical concomitants of sleep and wake are capable of changing the physiological output of Hypocretin neurons. Sleep independent of circadian timing is capable of decreasing cerebrospinal fluid Hypocretin-1 concentrations. Furthermore, Hypocretin neurons do not seem to respond to an 'effort' to remain awake, but rather keep track of time spent awake as a wake-promoting counterbalance to extended wakefulness.

  • decreased csf histamine in narcolepsy with and without low csf Hypocretin 1 in comparison to healthy controls
    Sleep, 2009
    Co-Authors: Seiji Nishino, Yasushi Yoshida, Eiko Sakurai, S Nevsimalova, Takehiko Watanabe, Kazuhiko Yanai, Emmanuel Mignot
    Abstract:

    Study Objective: To examine whether cerebrospinal fluid (CSF) histamine contents are altered in human narcolepsy and whether these alterations are specific to Hypocretin deficiency, as defined by low CSF Hypocretin-1.

  • csf Hypocretin 1 assessment in sleep and neurological disorders
    Lancet Neurology, 2008
    Co-Authors: Emmanuel Mignot, Jamie M Zeitzer, Patrice Bourgin
    Abstract:

    Summary Concentrations of CSF Hypocretin-1 (formerly orexin A) have been measured in many patients with sleep or neurological conditions. Low CSF Hypocretin-1 is most predictive of narcolepsy in patients positive for HLA allele DQB1*0602, most of whom have cataplexy. By contrast, the diagnostic significance of low CSF Hypocretin-1 is unclear in the presence of acute CNS inflammation or trauma. The clinical usefulness of CSF testing in hypersomnia that is symptomatic of a neurological disorder remains to be evaluated. Determination of CSF Hypocretin-1 concentration to diagnose narcolepsy might be most useful in ambulatory patients with cataplexy but with a normal multiple sleep latency test (MSLT) result, or if MSLT is not interpretable, conclusive, or feasible. Because 98% of patients with Hypocretin-1 deficiency are positive for HLA DQB1*0602, we suggest that HLA typing is a useful screen before lumbar puncture. Although Hypocretin-1 deficiency in narcolepsy might have therapeutic relevance, additional research is needed in this area.

  • reduced expression of tac1 penk and socs2 in hcrtr 2 mutated narcoleptic dog brain
    BMC Neuroscience, 2007
    Co-Authors: Julia Lindberg, Emmanuel Mignot, Seiji Nishino, Peter Saetre, Elena Jazin
    Abstract:

    Background Narcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli. Deficiencies in the Hypocretin system are well established as the origin of the condition; both from studies in humans who lack the Hypocretin ligand (HCRT) and in dogs with a mutation in Hypocretin receptor 2 (HCRTR2). However, little is known about molecular alterations downstream of the Hypocretin signals.

  • the neurobiology of Hypocretins orexins narcolepsy and related therapeutic interventions
    Trends in Pharmacological Sciences, 2006
    Co-Authors: Jamie M Zeitzer, Seiji Nishino, Emmanuel Mignot
    Abstract:

    Narcolepsy is characterized by excessive daytime sleepiness, cataplexy and other manifestations of dissociated rapid eye movement sleep. Narcolepsy is typically treated with amphetamine-like stimulants (sleepiness) and antidepressants (cataplexy). Newer compounds, such as modafinil (non-amphetamine wake-promoting compound for excessive daytime sleepiness) and sodium oxybate (short-acting sedative for fragmented nighttime sleep, cataplexy, excessive daytime sleepiness), are increasingly used. Recent discoveries indicate that the major pathophysiology of human narcolepsy is the loss of lateral hypothalamic neurons that produce the neuropeptide Hypocretin (orexin). Approximately 90% of people diagnosed as having narcolepsy with cataplexy are Hypocretin ligand deficient. This has led to the development of new diagnostic tests (cerebrospinal fluid Hypocretin-1 measurements). Hypocretin receptor agonists are likely to be ideal therapeutic options for Hypocretin-deficient narcolepsy but such compounds are still not available in humans.

Seiji Nishino - One of the best experts on this subject based on the ideXlab platform.

  • an overview of Hypocretin based therapy in narcolepsy
    Expert Opinion on Investigational Drugs, 2018
    Co-Authors: Shinichi Takenoshita, Noriaki Sakai, Yuhei Chiba, Mari Matsumura, Mai Yamaguchi, Seiji Nishino
    Abstract:

    Introduction: Narcolepsy with cataplexy is most commonly caused by a loss of Hypocretin/orexin peptide-producing neurons in the hypothalamus (i.e., Narcolepsy Type 1). Since Hypocretin deficiency i...

  • predictors of Hypocretin orexin deficiency in narcolepsy without cataplexy
    Sleep, 2012
    Co-Authors: Olivier Andlauer, Tom Rico, Takashi Kanbayashi, Michael H. Silber, Hyatt Moore, Seung Chul Hong, Seiji Nishino, Mali Einen
    Abstract:

    1247 Hypocretin Deficiency in Narcolepsy Without Cataplexy—Andlauer et al INTRODUCTION Narcolepsy without cataplexy is a complex, heterogeneous disorder.1,2 Until recently, most narcolepsy studies have focused on narcolepsy with cataplexy, an etiologically homogenous disorder tightly associated with Hypocretin deficiency and HLADQB1*06:02 positivity.3,4 Hypocretin deficiency can be tested by measuring cerebrospinal fluid (CSF) concentrations of Hypocretin-1, one third of normal values or 110 pg/ml being the most optimal cutoff based on receiver operating characteristics curve PREDICTORS OF Hypocretin DEFICIENCY IN NARCOLEPSY WITHOUT CATAPLEXY

  • predictors of Hypocretin orexin deficiency in narcolepsy without cataplexy
    Sleep, 2012
    Co-Authors: Olivier Andlauer, Takashi Kanbayashi, Michael H. Silber, Hyatt Moore, Seung Chul Hong, Seiji Nishino, Yves Dauvilliers, Fang Han, Tom Rico
    Abstract:

    Study objectives To compare clinical, electrophysiologic, and biologic data in narcolepsy without cataplexy with low (≤ 110 pg/ml), intermediate (110-200 pg/ml), and normal (> 200 pg/ml) concentrations of cerebrospinal fluid (CSF) Hypocretin-1. Setting University-based sleep clinics and laboratories. Patients Narcolepsy without cataplexy (n = 171) and control patients (n = 170), all with available CSF Hypocretin-1. Design and interventions Retrospective comparison and receiver operating characteristics curve analysis. Patients were also recontacted to evaluate if they developed cataplexy by survival curve analysis. Measurements and results The optimal cutoff of CSF Hypocretin-1 for narcolepsy without cataplexy diagnosis was 200 pg/ml rather than 110 pg/ml (sensitivity 33%, specificity 99%). Forty-one patients (24%), all HLA DQB1*06:02 positive, had low concentrations (≤ 110 pg/ml) of CSF Hypocretin-1. Patients with low concentrations of Hypocretin-1 only differed subjectively from other groups by a higher Epworth Sleepiness Scale score and more frequent sleep paralysis. Compared with patients with normal Hypocretin-1 concentration (n = 117, 68%), those with low Hypocretin-1 concentration had higher HLA DQB1*06:02 frequencies, were more frequently non-Caucasians (notably African Americans), with lower age of onset, and longer duration of illness. They also had more frequently short rapid-eye movement (REM) sleep latency (≤ 15 min) during polysomnography (64% versus 23%), and shorter sleep latencies (2.7 ± 0.3 versus 4.4 ± 0.2 min) and more sleep-onset REM periods (3.6 ± 0.1 versus 2.9 ± 0.1 min) during the Multiple Sleep Latency Test (MSLT). Patients with intermediate concentrations of CSF Hypocretin-1 (n = 13, 8%) had intermediate HLA DQB1*06:02 and polysomnography results, suggesting heterogeneity. Of the 127 patients we were able to recontact, survival analysis showed that almost half (48%) with low concentration of CSF Hypocretin-1 had developed typical cataplexy at 26 yr after onset, whereas only 2% had done so when CSF Hypocretin-1 concentration was normal. Almost all patients (87%) still complained of daytime sleepiness independent of Hypocretin status. Conclusion Objective (HLA typing, MSLT, and sleep studies) more than subjective (sleepiness and sleep paralysis) features predicted low concentration of CSF Hypocretin-1 in patients with narcolepsy without cataplexy.

  • the pathophysiologic basis of secondary narcolepsy and hypersomnia
    Current Neurology and Neuroscience Reports, 2011
    Co-Authors: Takashi Kanbayashi, Yohei Sagawa, Fumi Takemura, Ko Tsutsui, Yasuo Hishikawa, Seiji Nishino
    Abstract:

    The symptoms of narcolepsy can occur during the course of other neurologic conditions (ie, symptomatic narcolepsy). Inherited disorders, tumors, and head trauma were the three most frequent causes for symptomatic narcolepsy. Other causes include multiple sclerosis (MS), vascular disorders, and encephalitis. Cerebrospinal fluid Hypocretin-1 measures were carried out in some recent cases with symptomatic narcolepsy, and moderate decreases in Hypocretin levels were seen in a large majority of these cases. Excessive daytime sleepiness (EDS) in these symptomatic cases was sometimes reversible with an improvement of the causative neurologic disorder and with an improvement of the Hypocretin (orexin) status. Recently, we found that several symptomatic narcoleptic cases with MS show unique bilateral symmetric hypothalamic lesions associated with significant Hypocretin ligand deficiency. In addition, these patients often share the clinical characteristics of neuromyelitis optica (NMO) and the detection of NMO-IgG (or anti-aquaporin-4 [AQP4] antibodies), suggesting a new clinical entity. Further studies of the involvement of the Hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiologic mechanisms for occurrence of EDS and cataplexy.

  • decreased csf histamine in narcolepsy with and without low csf Hypocretin 1 in comparison to healthy controls
    Sleep, 2009
    Co-Authors: Seiji Nishino, Yasushi Yoshida, Eiko Sakurai, S Nevsimalova, Takehiko Watanabe, Kazuhiko Yanai, Emmanuel Mignot
    Abstract:

    Study Objective: To examine whether cerebrospinal fluid (CSF) histamine contents are altered in human narcolepsy and whether these alterations are specific to Hypocretin deficiency, as defined by low CSF Hypocretin-1.

Sebastiaan Overeem - One of the best experts on this subject based on the ideXlab platform.

  • plasma total ghrelin and leptin levels in human narcolepsy and matched healthy controls basal concentrations and response to sodium oxybate
    Journal of Clinical Sleep Medicine, 2013
    Co-Authors: Claire E H M Donjacour, Sebastiaan Overeem, Hanno Pijl, Ferdinand Roelfsema, Marijke Frolich, Daniel Pardi, N A Aziz, G J Lammers
    Abstract:

    Study Objectives:Narcolepsy is caused by a selective loss of Hypocretin neurons and is associated with obesity. Ghrelin and leptin interact with Hypocretin neurons to influence energy homeostasis. ...

  • Hypocretin orexin loss in alzheimer s disease
    Neurobiology of Aging, 2012
    Co-Authors: Sebastiaan Overeem, Rolf Fronczek, Gert Jan Lammers, Marijke Frolich, Sarita Van Geest, Freek W C Roelandse, D F Swaab
    Abstract:

    Sleep disturbances in Alzheimer's disease (AD) patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble core symptoms of narcolepsy, a sleep disorder caused by a general loss of the neurotransmitter Hypocretin. AD is a neurodegenerative disorder targeting different brain areas and types of neurons. In this study, we assessed whether the neurodegenerative process of AD also affects hypothalamic Hypocretin/orexin neurons. The total number of Hypocretin-1 immunoreactive neurons was quantified in postmortem hypothalami of AD patients (n = 10) and matched controls (n = 10). In addition, the Hypocretin-1 concentration was measured in postmortem ventricular cerebrospinal fluid of 24 AD patients and 25 controls (including the patients and controls in which the hypothalamic cell counts were performed). The number of Hypocretin-1 immunoreactive neurons was significantly decreased by 40% in AD patients (median [25th-75th percentiles]); AD 12,935 neurons (9972-19,051); controls 21,002 neurons (16,439-25,765); p = 0.049). Lower cerebrospinal fluid (CSF) Hypocretin-1 levels were found in AD patients compared with controls (AD: 275 pg/mL [197-317]; controls: 320 pg/mL [262-363]; p = 0.038). Two AD patients with documented excessive daytime sleepiness showed the lowest CSF Hypocretin-1 concentrations (55 pg/mL and 76 pg/mL). We conclude that the Hypocretin system is affected in advanced AD. This is reflected in a 40% decreased cell number, and 14% lower CSF Hypocretin-1 levels.

  • Hypocretin and melanin concentrating hormone in patients with huntington disease
    Brain Pathology, 2008
    Co-Authors: Ahmad Aziz, Sebastiaan Overeem, Rolf Fronczek, G J Lammers, Sjoerd G Van Duinen, D F Swaab, Freek W C Roelandse, Marion L C Maatschieman, Unga A Unmehopa, Raymund A C Roos
    Abstract:

    To evaluate whether Hypocretin-1 (orexin-A) and melanin-concentrating hormone (MCH) neurotransmission are affected in patients with Huntington disease (HD), we immunohistochemically stained Hypocretin and MCH neurons and estimated their total numbers in the lateral hypothalamus of both HD patients and matched controls. In addition, Hypocretin-1 levels were determined in prefrontal cortical tissue and post-mortem ventricular cerebrospinal fluid (CSF) using a radioimmunoassay. The total number of Hypocretin-1 neurons was significantly reduced by 30% in HD brains (P = 0.015), while the total number of MCH neurons was not significantly altered (P = 0.100). Levels of Hypocretin-1 were 33% lower in the prefrontal cortex of the HD patients (P = 0.025), but ventricular CSF levels were similar to the control values (P = 0.306). Neuronal intranuclear and cytoplasmic inclusions of mutant huntingtin were present in all HD hypothalami, although with a variable distribution across different hypothalamic structures. We found a specific reduction in Hypocretin signaling in patients with HD as MCH cell number was not significantly affected. It remains to be shown whether the moderate decrease in Hypocretin neurotransmission could contribute to clinical symptoms. As the number of MCH-expressing neurons was not affected, alterations in MCH signaling are unlikely to have clinical effects in HD patients.

  • increased heart rate variability but normal resting metabolic rate in Hypocretin orexin deficient human narcolepsy
    Journal of Clinical Sleep Medicine, 2008
    Co-Authors: Rolf Fronczek, Sebastiaan Overeem, Robert H A M Reijntjes, Gert Jan Lammers, Gert J Van Dijk, Hanno Pijl
    Abstract:

    Narcolepsy is a sleep disorder that affects 25–50 out of 100,000 people in Western countries.1 It is classically characterized by the tetrad of excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations.2 Obesity in narcolepsy was first described as early as the 1930s3,4 and has since been described repeatedly.5–12 The discovery of Hypocretin/orexin deficiency in human narcolepsy with cataplexy and the fact that Hypocretin peptides may be involved in metabolic control sparked renewed interest in the pathophysiology of obesity in narcolepsy. Indeed, various observations suggest that Hypocretin deficiency is involved in the pathogenesis of weight gain in narcoleptic patients. Increased bodyweight has been reported in human narcolepsy as well as in the ataxin-3 Hypocretin-deficient animal model of the disease.13,14 Moreover, patients with idiopathic hypersomnia, similarly marked by excessive daytime sleepiness but exhibiting normal cerebrospinal Hypocretin levels, are not obese.12 There is evidence that Hypocretin peptides stimulate feeding behavior:15 Injection of Hypocretins into the lateral cerebral ventricle promotes food intake in rats,16 whereas ablation of Hypocretin neurons leads to hypophagia in mice.14 Accordingly, narcoleptic humans and mice eat less than age and sex matched controls,13,18 which clearly indicates that other components of energy balance must drive weight gain in this disease. The effects of Hypocretin peptides on wakefulness and the sympathetic nervous system may be involved. Injection of Hypocretins into the lateral ventricle stimulates arousal and sympathetic activity in rats, elevating arterial blood pressure (BP), heart rate (HR), oxygen consumption, body temperature and plasma catecholamine levels.19–22 Thus, Hypocretin deficiency could promote obesity through the concerted effects of several behavioral and neuroendocrine corollaries. It may reduce sympathetic tone and thereby resting metabolic rate. Moreover, since adipose tissue is innervated by both sympathetic and parasympathetic nerves, where sympathetic inputs stimulate lipolysis and parasympathetic signals are anabolic, dominance of parasympathetic tone could promote fat storage through direct effects on adipocytes.23,24 Finally, excessive daytime sleepiness may limit physical activity, which obviously would reduce daily energy expenditure. Thus, Hypocretin deficiency may dampen sympathetic tone in narcoleptic patients, and thereby reduce resting metabolic rate and promote adipocyte lipogenesis to induce weight gain in the face of diminished food intake. We studied resting metabolic rate and HR and BP variability, as a proximate measure of autonomic balance, in Hypocretin-deficient narcoleptic patients and healthy controls matched for gender, body weight, and age. Since (lean) body mass is an important determinant of resting metabolic rate, matching for body weight was necessary to preclude confounding the data on metabolic rate by anthropometric features of our volunteers. We hypothesized that sympathetic tone and resting metabolic rate per unit of (lean) body mass would be reduced in narcoleptic subjects.

  • Hypocretin orexin loss in parkinson s disease
    Brain, 2007
    Co-Authors: Rolf Fronczek, Sebastiaan Overeem, Gert Jan Lammers, Sandy Y Y Lee, Ingrid M Hegeman, Johannes Van Pelt, Sjoerd G Van Duinen, D F Swaab
    Abstract:

    The hypothalamic Hypocretin (orexin) system plays a central role in the regulation of various functions, including sleep/wake regulation and metabolism. There is a growing interest in Hypocretin function in Parkinson's disease (PD), given the high prevalence of non-motor symptoms such as sleep disturbances in this disorder. However, studies measuring CSF Hypocretin levels have yielded contradictory results. In PD patients and matched controls, we (i) estimated the number of Hypocretin neurons in post-mortem hypothalami using immunocytochemistry and an image analysis system (ii) quantified Hypocretin levels in post-mortem ventricular CSF and (iii) prefrontal cortex using a radioimmunoassay. Furthermore, presence of Lewy bodies was verified in the hypothalamic Hypocretin cell area. Data are presented as median (25th-75th percentile). We showed a significant decrease between PD patients and controls in (i) the number of Hypocretin neurons (PD: 20 276 (13 821-31 229); controls: 36 842 (32 546-50 938); P = 0.016); (ii) the Hypocretin-1 concentration in post-mortem ventricular CSF (PD: 365.5 pg/ml (328.0-448.3); controls: 483.5 (433.5-512.3); P = 0.012) and (iii) the Hypocretin-1 concentrations in prefrontal cortex (PD: 389.6 pg/g (249.2-652.2); controls: 676.6 (467.5-883.9); P = 0.043). Hypocretin neurotransmission is affected in PD. The Hypocretin-1 concentration in the prefrontal cortex was almost 40% lower in PD patients, while ventricular CSF levels were almost 25% reduced. The total number of Hypocretin neurons was almost half compared to controls.

Anthony N Van Den Pol - One of the best experts on this subject based on the ideXlab platform.

  • differential target dependent actions of coexpressed inhibitory dynorphin and excitatory Hypocretin orexin neuropeptides
    The Journal of Neuroscience, 2006
    Co-Authors: Anthony N Van Den Pol
    Abstract:

    The Hypocretin/orexin arousal system plays a key role in maintaining an alert wake state. The Hypocretin peptide is colocalized with an opioid peptide, dynorphin. As dynorphin may be coreleased with Hypocretin, we asked what action simultaneous stimulation with the excitatory neuropeptide Hypocretin and the inhibitory peptide dynorphin might exert on cells postsynaptic to Hypocretin axons, including Hypocretin neurons. Hypocretin neurons received direct synaptic contact from other Hypocretin neurons but showed little direct response to Hypocretin. Here, we show that mouse Hypocretin neurons are acutely sensitive to dynorphin. Dynorphin inhibits the Hypocretin system by direct postsynaptic actions (hyperpolarization, decreased spike frequency, increased GIRK (G-protein-gated inwardly rectifying K+ channel) current, and attenuated calcium current, and indirectly by reducing excitatory synaptic tone. Interestingly, a selective antagonist of kappa-opioid receptors enhanced activity of the Hypocretin system, suggesting ongoing depression by endogenous hypothalamic opioids. Electrical stimulation of hypothalamic microslices that contained Hypocretin cells and their axons evoked dynorphin release. Costimulation with dynorphin and Hypocretin had three different effects on neurons postsynaptic to Hypocretin axons: direct response to only one or the other of the two peptides [Hypocretin cells respond to dynorphin, arcuate neuropeptide Y (NPY) cells respond to Hypocretin], differential desensitization causing shift from inhibitory current to excitatory current with repeated coexposure (melanin-concentrating hormone neurons), synergistic direct excitation by Hypocretin and presynaptic attenuation of inhibition by dynorphin (arcuate NPY neurons). These results suggest that Hypocretin neurons may be able to exercise a high degree of modulatory control over postsynaptic targets using multiple neuropeptides with target-dependent actions.

  • group iii metabotropic glutamate receptors maintain tonic inhibition of excitatory synaptic input to Hypocretin orexin neurons
    The Journal of Neuroscience, 2004
    Co-Authors: Claudio Acunagoycolea, Anthony N Van Den Pol
    Abstract:

    Hypocretin/orexin neurons play an important role in hypothalamic arousal. Synaptic glutamate input to Hypocretin neurons regulates cell firing. We studied the actions of group III metabotropic glutamate receptors (mGluRs) in modulating the activity of Hypocretin neurons using whole-cell voltage- and current-clamp recording in mouse whole hypothalamic slices or minislices consisting only of the lateral hypothalamus. Selective green fluorescent protein expression was used to detect live Hypocretin neurons. The mGluR agonist l-(+)-2-amino-4-phosphonobutyric acid (l-AP-4) inhibited synaptic input to Hypocretin neurons in a dose-dependent manner; both spontaneous glutamate and GABA-mediated synaptic currents were reduced in frequency. l-AP-4 also reduced the amplitude of postsynaptic potentials evoked by a stimulating electrode placed medial or lateral to the recorded cell. No postsynaptic effect of l-AP-4 was found relative to membrane potential, input resistance, or AMPA-evoked currents. l-AP-4 appeared to act by a presynaptic mechanism and reduced the frequency of both glutamate- and GABA-mediated miniature events recorded in the presence of tetrodotoxin, with no change in amplitude. (RS)-phosphonopentanoic acid (CPPG), a group III mGluR antagonist, suppressed the actions of l-AP-4. Of substantial interest, CPPG by itself increased synaptic activity recorded in Hypocretin neurons, suggesting an ongoing inhibitory tone attributable to activation of group III mGluRs. Glutamatergic interneurons have been suggested to play a role in a positive feedback recruitment of Hypocretin on Hypocretin neurons. l-AP-4 blocked Hypocretin-mediated increases in EPSCs and attenuated the Hypocretin-mediated increase in spike frequency. Together, these data suggest that tonically active inhibitory mGluRs are expressed on local Hypocretin-sensitive glutamate neurons within the lateral hypothalamus that modulate the output of the Hypocretin arousal system.

  • Hypocretin orexin excites Hypocretin neurons via a local glutamate neuron a potential mechanism for orchestrating the hypothalamic arousal system
    Neuron, 2002
    Co-Authors: Xiaobing Gao, Takeshi Sakurai, Anthony N Van Den Pol
    Abstract:

    Neurons that release Hypocretin/orexin modulate sleep, arousal, and energy homeostasis; the absence of Hypocretin results in narcolepsy. Here we present data on the physiological characteristics of these cells, identified with GFP in transgenic mouse brain slices. Hypocretin-1 and -2 depolarized Hypocretin neurons by 15mV and evoked an increase in spike frequency (+366% from a 1-3 Hz baseline). The mechanism for this appears to be Hypocretin-mediated excitation of local glutamatergic neurons that regulate Hypocretin neuron activity, in part by presynaptic facilitation of glutamate release. This represents a possible mechanism for orchestrating the output of the diffuse hypothalamic arousal system. No direct effect of Hypocretin on membrane properties of Hypocretin cells was detected. Norepinephrine and serotonin, transmitters of other arousal systems, decreased spike frequency and evoked outward currents, whereas acetylcholine and histamine had little effect.

  • distribution of Hypocretin orexin immunoreactivity in the central nervous system of syrian hamsters mesocricetus auratus
    Journal of Chemical Neuroanatomy, 2001
    Co-Authors: Eric M Mintz, Anthony N Van Den Pol, Annelise A Casano, Elliott H Albers
    Abstract:

    The Hypocretins are peptides synthesized in neurons of the hypothalamus. Recent studies have suggested a role for these peptides in the regulation of sleep, feeding, and endocrine regulation. The distribution of Hypocretin-immunoreactive cell bodies and fibers has been extensively described in rats, but not in other species. This study was designed to examine the distribution of Hypocretin immunoreactivity in Syrian hamsters, as important differences in neuropeptide distribution between rats and hamsters have previously been demonstrated. Immunoreactive cell bodies were found primarily in the lateral hypothalamic area and the perifornical area, although a few Hypocretin-positive cells were also located in the dorsomedial hypothalamus and the retrochiasmatic area. Fibers were distributed throughout the brain in a pattern similar to that seen in rats. The densest projections were found in the paraventricular nucleus of the thalamus, locus coeruleus, dorsal raphe, and lateroanterior hypothalamus. The innervation of the anterior hypothalamus may be of particular interest as similar cluster of immunoreactivity does not appear to be present in rats. Moderate levels of immunoreactivity could be seen throughout the hypothalamus, the lateral septum, bed nucleus of the stria terminalis, A5 noradrenergic area, and the midline thalamic nuclei. Hypocretin-immunoreactive fibers are present in all lamina of the spinal cord, with the greatest axon densities in lamina 1 and 10. The widespread distribution of Hypocretin suggests its involvement in a wide variety of physiological and behavioral processes. Our results in hamsters indicate that the organization of the Hypocretin system is strongly conserved across species, suggesting an important role for the peptide and its projections.

  • Hypocretin orexin activation and synaptic innervation of the locus coeruleus noradrenergic system
    The Journal of Comparative Neurology, 1999
    Co-Authors: Tamas L Horvath, Anthony N Van Den Pol, Christelle Peyron, Thomas S Kilduff, Sabrina Diano, Alexander Ivanov, Gary Astonjones
    Abstract:

    Hypocretin has been identified as a regulator of metabolic and endocrine systems. Several brain regions involved in the central regulation of autonomic and endocrine processes or attention are targets of extensive Hypocretin projections. The most dense arborization of Hypocretin axons in the brainstem was detected in the locus coeruleus (LC). Multiple labeling immunocytochemistry revealed a massive synaptic innervation of catecholaminergic LC cells by Hypocretin axon terminals in rats and monkeys. In both species, all tyrosine hydroxylaseimmunopositive cells in the LC examined by electron microscopy were found to receive asymmetrical (excitatory) synaptic contacts from multiple axons containing Hypocretin. In parallel electrophysiological studies with slices of rat brain, all LC cells showed excitatory responses to the Hypocretin-2 peptide. Hypocretin-2 uniformly increased the frequency of action potentials in these cells, even in the presence of tetrodotoxin, indicating that receptors responding to Hypocretin were expressed in LC neurons. Two mechanisms for the increased firing rate appeared to be a reduction in the slow component of the afterhyperpolarization (AHP) and a modest depolarization. Catecholamine systems in other parts of the brain, including those found in the medulla, zona incerta, substantia nigra or olfactory bulb, received significantly less Hypocretin input. Comparative analysis of lateral hypothalamic input to the LC revealed that Hypocretin-containing axon terminals were substantially more abundant than those containing melanin-concentrating hormone. The present results provide evidence for direct action of hypothalamic Hypocretin cells on the LC noradrenergic system in rats and monkeys. Our observations suggest a signaling pathway via which signals acting on the lateral hypothalamus may influence the activity of the LC and thereby a variety of CNS

Tomas Hokfelt - One of the best experts on this subject based on the ideXlab platform.

  • Hypocretin orexin and melanin concentrating hormone expressing cells form distinct populations in the rodent lateral hypothalamus relationship to the neuropeptide y and agouti gene related protein systems
    The Journal of Comparative Neurology, 1998
    Co-Authors: Christian Broberger, J G Sutcliffe, L De Lecea, Tomas Hokfelt
    Abstract:

    Cells in the lateral hypothalamus and in the arcuate nucleus play prominent roles in the central control of food intake; however, a neurochemical link connecting these potential components of a hypothalamic circuitry regulating energy metabolism remains to be established. In the present study, the topographical relationship between cells expressing mRNAs encoding melanin-concentrating hormone and the newly discovered neuropeptide family Hypocretins/orexins was studied in the rat and mouse lateral hypothalamus by using double-labeling in situ hybridization. Cells expressing the two mRNAs formed completely distinct populations, with Hypocretin/orexin cells located primarily perifornically and in the magnocellular lateral hypothalamic nucleus; melanin-concentrating hormone cells extended in a wider area both laterally and periventricularly and appeared to partly surround the Hypocretin/orexin population. In the arcuate nucleus, cells expressing neuropeptide Y and agouti gene-related protein were studied by routine fluorescence and/or confocal microscopy immunohistochemistry. Double staining demonstrated that a large proportion of the neuropeptide Y-positive cell bodies in this nucleus also contained agouti gene-related protein-like immunoreactivity. Moreover, these two peptides also coexisted in nerve terminals surrounding and in close relationship to perikarya and processes of both Hypocretin/orexin- and melanin-concentrating hormone-immunoreactive cells in the lateral hypothalamus, whereby the former appeared to receive a more dense innervation. These results thus provide evidence for an arcuate-lateral hypothalamic neuropeptide Y/agouti gene-related protein pathway. Furthermore, the results implicate Hypocretin/orexin and melanin-concentrating hormone-expressing cells as downstream targets in neuropeptide Y-induced feeding. J. Comp. Neurol. 402:460–474, 1998. © 1998 Wiley-Liss, Inc.

  • Hypocretin orexin and melanin concentrating hormone expressing cells form distinct populations in the rodent lateral hypothalamus relationship to the neuropeptide y and agouti gene related protein systems
    The Journal of Comparative Neurology, 1998
    Co-Authors: Christian Broberger, J G Sutcliffe, L De Lecea, Tomas Hokfelt
    Abstract:

    Cells in the lateral hypothalamus and in the arcuate nucleus play prominent roles in the central control of food intake; however, a neurochemical link connecting these potential components of a hypothalamic circuitry regulating energy metabolism remains to be established. In the present study, the topographical relationship between cells expressing mRNAs encoding melanin-concentrating hormone and the newly discovered neuropeptide family Hypocretins/orexins was studied in the rat and mouse lateral hypothalamus by using double-labeling in situ hybridization. Cells expressing the two mRNAs formed completely distinct populations, with Hypocretin/orexin cells located primarily perifornically and in the magnocellular lateral hypothalamic nucleus; melanin-concentrating hormone cells extended in a wider area both laterally and periventricularly and appeared to partly surround the Hypocretin/orexin population. In the arcuate nucleus, cells expressing neuropeptide Y and agouti gene-related protein were studied by routine fluorescence and/or confocal microscopy immunohistochemistry. Double staining demonstrated that a large proportion of the neuropeptide Y-positive cell bodies in this nucleus also contained agouti gene-related protein-like immunoreactivity. Moreover, these two peptides also coexisted in nerve terminals surrounding and in close relationship to perikarya and processes of both Hypocretin/orexin- and melanin-concentrating hormone-immunoreactive cells in the lateral hypothalamus, whereby the former appeared to receive a more dense innervation. These results thus provide evidence for an arcuate-lateral hypothalamic neuropeptide Y/agouti gene-related protein pathway. Furthermore, the results implicate Hypocretin/orexin and melanin-concentrating hormone-expressing cells as downstream targets in neuropeptide Y-induced feeding.