Dual orexin and MCH neuron-ablated mice display severe sleep attacks and cataplexy.
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ABSTRACT:
SUBMITTER: Hung CJ
PROVIDER: S-EPMC7173968 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Narcolepsy-cataplexy is a neurological disorder associated with the inability to maintain wakefulness and abnormal intrusions of rapid eye movement sleep-related phenomena into wakefulness such as cataplexy. The vast majority of narcoleptic-cataplectic individuals have low or undetectable levels of orexin (hypocretin) neuropeptides in the cerebrospinal fluid, likely due to specific loss of the hypothalamic orexin-producing neurons. Currently available treatments for narcolepsy are only palliative, symptom-oriented pharmacotherapies. Here, we demonstrate rescue of the narcolepsy-cataplexy phenotype of orexin neuron-ablated mice by genetic and pharmacological means. Ectopic expression of a prepro-orexin transgene in the brain completely prevented cataplectic arrests and other abnormalities of rapid eye movement sleep in the absence of endogenous orexin neurons. Central administration of orexin-A acutely suppressed cataplectic behavioral arrests and increased wakefulness for 3 h. These results indicate that orexin neuron-ablated mice retain the ability to respond to orexin neuropeptides and that a temporally regulated and spatially targeted secretion of orexins is not necessary to prevent narcoleptic symptoms. Orexin receptor agonists would be of potential value for treating human narcolepsy.
| S-EPMC384801 | biostudies-other
Project description:Cataplexy is triggered by laughter in humans and palatable food in mice. To further evaluate mice's cataplexy, we examined courtship behavior in orexin neuron-ablated mice (ORX-AB), one of the animal models of narcolepsy/cataplexy. Wild-type female mice were placed into the home cage of male ORX-AB and cataplexy-like behavior was observed along with ultrasonic vocalizations (USVs), also known as the "love song". ORX-AB with a female encounter showed cataplexy-like behavior both during the dark and light periods, whereas ORX-AB with chocolate predominantly showed it during the dark period. During the light period observation, more than 85% of cataplexy-like bouts were preceded by USVs. A strong positive correlation was observed between the number of USVs and cataplexy-like bouts. Cataplexy-like behavior in narcoleptic mice is a good behavioral measure to study the brain mechanisms behind positive emotion because they can be induced by different kinds of positive stimuli, including chocolate and female courtship.
| S-EPMC7864915 | biostudies-literature
Project description:Hypothalamic orexin (hypocretin, HCRT) deficiency causes sleep disorder narcolepsy with cataplexy in humans and murine. As another integral group of sleep/wake-regulating neurons in the same brain area, the melanin-concentrating hormone (MCH) neurons' involvement in cataplexy remains ambiguous. Here we used the live animal deep-brain calcium (Ca2+) imaging tool to record MCH neuron dynamics during cataplexy by expressing calcium sensor GCaMP6s into genetically defined MCH neurons in orexin knock-out mice, which are a model of human narcolepsy. Similar to wild-type mice, MCH neurons of the narcoleptic mice displayed significantly higher Ca2+ transient fluorescent intensity during rapid eye movement (REM) sleep and active waking (AW) episodes compared with non-REM (NREM) sleep. Moreover, MCH neurons displayed significantly lower Ca2+ signals during cataplexy. Importantly, a pre-cataplexy elevation of Ca2+ signals from MCH neurons was not a prerequisite for cataplexy initiation. Our results demonstrated the inactivation status of MCH neurons during cataplexy and suggested that MCH neurons are not involved in the initiation and maintenance of cataplexy in orexin knock-out mice.
| S-EPMC7196720 | biostudies-literature
Project description:Orexin receptor antagonists are clinically useful for treating insomnia, but thorough blockade of orexin signaling could cause narcolepsy-like symptoms. Specifically, while sleepiness is a desirable effect, an orexin antagonist could also produce cataplexy, sudden episodes of muscle weakness often triggered by strong, positive emotions. In this study, we examined the effects of dual orexin receptor antagonists (DORAs), lemborexant (E2006) and almorexant, on sleep-wake behavior and cataplexy during the dark period in wild-type (WT) mice and prepro-orexin knockout (OXKO) mice. In WT mice, lemborexant at 10 and 30 mg/kg quickly induced NREM sleep in a dose-dependent fashion. In contrast, lemborexant did not alter sleep-wake behavior in OXKO mice. Under the baseline condition, cataplexy was rare in lemborexant-treated WT mice, but when mice were given chocolate as a rewarding stimulus, lemborexant dose-dependently increased cataplexy. Almorexant produced similar results. Collectively, these results demonstrate that DORAs potently increase NREM and REM sleep in mice via blockade of orexin signaling, and higher doses can cause cataplexy when co-administered with a likely rewarding stimulus.
| S-EPMC7294412 | biostudies-literature
Project description:Mice lacking orexin/hypocretin signaling have sudden episodes of atonia and paralysis during active wakefulness. These events strongly resemble cataplexy, episodes of sudden muscle weakness triggered by strong positive emotions in people with narcolepsy, but it remains unknown whether murine cataplexy is triggered by positive emotions. To determine whether positive emotions elicit murine cataplexy, we placed orexin knockout (KO) mice on a scheduled feeding protocol with regular or highly palatable food. Baseline sleep/wake behavior was recorded with ad libitum regular chow. Mice were then placed on a scheduled feeding protocol in which they received 60% of their normal amount of chow 3 h after dark onset for the next 10 days. Wild-type and KO mice rapidly entrained to scheduled feeding with regular chow, with more wake and locomotor activity prior to the feeding time. On day 10 of scheduled feeding, orexin KO mice had slightly more cataplexy during the food-anticipation period and more cataplexy in the second half of the dark period, when they may have been foraging for residual food. To test whether more palatable food increases cataplexy, mice were then switched to scheduled feeding with an isocaloric amount of Froot Loops, a food often used as a reward in behavioral studies. With this highly palatable food, orexin KO mice had much more cataplexy during the food-anticipation period and throughout the dark period. The increase in cataplexy with scheduled feeding, especially with highly palatable food, suggests that positive emotions may trigger cataplexy in mice, just as in people with narcolepsy. Establishing this connection helps validate orexin KO mice as an excellent model of human narcolepsy and provides an opportunity to better understand the mechanisms that trigger cataplexy.
| S-EPMC2743520 | biostudies-literature
Project description:The lateral hypothalamus (LH), where wake-active orexin (Orx)-containing neurons are located, has been considered a waking center. Yet, melanin-concentrating hormone (MCH)-containing neurons are codistributed therein with Orx neurons and, in contrast to them, are active during sleep, not waking. In the present study employing juxtacellular recording and labeling of neurons with Neurobiotin (Nb) in naturally sleeping-waking head-fixed rats, we identified another population of intermingled sleep-active cells, which do not contain MCH (or Orx), but utilize gamma-aminobutyric acid (GABA) as a neurotransmitter. The 'sleep-max' active neurons represented 53% of Nb-labeled MCH-(and Orx) immunonegative (-) cells recorded in the LH. For identification of their neurotransmitter, Nb-labeled varicosities of the Nb-labeled/MCH- neurons were sought within sections adjacent to the Nb-labeled soma and immunostained for the vesicular transporter for GABA (VGAT) or for glutamate. A small proportion of sleep-max Nb+/MCH- neurons (19%) discharged maximally during slow-wave sleep (called 'S-max') in positive correlation with delta electroencephalogram activity, and from VGAT staining of Nb-labeled varicosities appeared to be GABAergic. The vast proportion of sleep-max Nb+/MCH- neurons (81%) discharged maximally during paradoxical sleep (PS, called 'P-max') in negative correlation with electromyogram amplitude, and from Nb-labeled varicosities also appeared to be predominantly GABAergic. Given their discharge profiles across the sleep-wake cycle, P-max together with S-max GABAergic neurons could thus serve to inhibit other neurons of the arousal systems, including local Orx neurons in the LH. They could accordingly dampen arousal with muscle tone and promote sleep, including PS with muscle atonia.
| S-EPMC2921479 | biostudies-literature
Project description:Narcolepsy is characterized by excessive sleepiness and cataplexy, sudden episodes of muscle weakness during waking that are thought to be an intrusion of rapid eye movement sleep muscle atonia into wakefulness. One of the most striking aspects of cataplexy is that it is often triggered by strong, generally positive emotions, but little is known about the neural pathways through which positive emotions trigger muscle atonia. We hypothesized that the amygdala is functionally important for cataplexy because the amygdala has a role in processing emotional stimuli and it contains neurons that are active during cataplexy. Using anterograde and retrograde tracing in mice, we found that GABAergic neurons in the central nucleus of the amygdala heavily innervate neurons that maintain waking muscle tone such as those in the ventrolateral periaqueductal gray, lateral pontine tegmentum, locus ceruleus, and dorsal raphe. We then found that bilateral, excitotoxic lesions of the amygdala markedly reduced cataplexy in orexin knock-out mice, a model of narcolepsy. These lesions did not alter basic sleep-wake behavior but substantially reduced the triggering of cataplexy. Lesions also reduced the cataplexy events triggered by conditions associated with high arousal and positive emotions (i.e., wheel running and chocolate). These observations demonstrate that the amygdala is a functionally important part of the circuitry underlying cataplexy and suggest that increased amygdala activity in response to emotional stimuli could directly trigger cataplexy by inhibiting brainstem regions that suppress muscle atonia.
| S-EPMC3704329 | biostudies-literature
Project description: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.University-based sleep clinics and laboratories.Narcolepsy without cataplexy (n = 171) and control patients (n = 170), all with available CSF hypocretin-1.Retrospective comparison and receiver operating characteristics curve analysis. Patients were also recontacted to evaluate if they developed cataplexy by survival curve analysis.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.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.
| S-EPMC3413802 | biostudies-other
Project description:Narcolepsy-cataplexy is a chronic neurological disorder caused by loss of orexin (hypocretin)-producing neurons, associated with excessive daytime sleepiness, sleep attacks, cataplexy, sleep paralysis, hypnagogic hallucinations, and fragmentation of nighttime sleep. Currently, human narcolepsy is treated by providing symptomatic therapies, which can be associated with an array of side effects. Although peripherally administered orexin does not efficiently penetrate the blood-brain barrier, centrally delivered orexin can effectively alleviate narcoleptic symptoms in animal models. Chronic intrathecal drug infusion through an implantable pump is a clinically available strategy to treat a number of neurological diseases. Here we demonstrate that the narcoleptic symptoms of orexin knockout mice can be reversed by lumbar-level intrathecal orexin delivery. Orexin was delivered via a chronically implanted intrathecal catheter at the upper lumbar level. The computed tomographic scan confirmed that intrathecally administered contrast agent rapidly moved from the spinal cord to the brain. Intrathecally delivered orexin was detected in the brain by radioimmunoassay at levels comparable to endogenous orexin levels. Cataplexy and sleep-onset REM sleep were significantly decreased in orexin knockout mice during and long after slow infusion of orexin (1 nmol/1 µL/h). Sleep/wake states remained unchanged both quantitatively as well as qualitatively. Intrathecal orexin failed to induce any changes in double orexin receptor-1 and -2 knockout mice. This study supports the concept of intrathecal orexin delivery as a potential therapy for narcolepsy-cataplexy to improve the well-being of patients.
| S-EPMC6003319 | biostudies-literature
Project description:BackgroundThe current standard of care for insomnia includes gamma-aminobutyric acid receptor A (GABAA) activators, which promote sleep as well as general central nervous system depression. Dual orexin receptor antagonists (DORAs) represent an alternative mechanism for insomnia treatment that induces somnolence by blocking the wake-promoting effects of orexin neuropeptides. The current study compares the role and interdependence of these two mechanisms on their ability to influence sleep architecture and quantitative electroencephalography (qEEG) spectral profiles across preclinical species.ResultsActive-phase dosing of DORA-22 induced consistent effects on sleep architecture in mice, rats, dogs, and rhesus monkeys; attenuation of active wake was accompanied by increases in both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Eszopiclone, a representative GABAA receptor modulator, promoted sleep in rats and rhesus monkeys that was marked by REM sleep suppression, but had inconsistent effects in mice and paradoxically promoted wakefulness in dogs. Active-phase treatment of rats with DORA-12 similarly promoted NREM and REM sleep to magnitudes nearly identical to those seen during normal resting-phase sleep following vehicle treatment, whereas eszopiclone suppressed REM even to levels below those seen during the active phase. The qEEG changes induced by DORA-12 in rats also resembled normal resting-phase patterns, whereas eszopiclone induced changes distinct from normal active- or inactive-phase spectra. Co-dosing experiments, as well as studies in transgenic rats lacking orexin neurons, indicated partial overlap in the mechanism of sleep promotion by orexin and GABA modulation with the exception of the REM suppression exclusive to GABAA receptor modulation. Following REM deprivation in mice, eszopiclone further suppressed REM sleep while DORA-22 facilitated recovery including increased REM sleep.ConclusionDORAs promote NREM and importantly REM sleep that is similar in proportion and magnitude to that seen during the normal resting phase across mammalian animal models. While limited overlap exists between therapeutic mechanisms, orexin signaling does not appear involved in the REM suppression exhibited by GABAA receptor modulators. The ability of DORAs to promote proportional NREM and REM sleep following sleep deprivation suggests that this mechanism may be effective in alleviating recovery from sleep disturbance.
| S-EPMC4261741 | biostudies-literature