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Michael H Chase - One of the best experts on this subject based on the ideXlab platform.
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Heart rate variability during carbachol-induced REM sleep and cataplexy
Behavioural Brain Research, 2015Co-Authors: Pablo Torterolo, Michael H Chase, Santiago Castro-zaballa, Matías Cavelli, Noelia Velásquez, Victoria Brando, Atilio Falconi, Eduardo R. MigliaroAbstract:Abstract The nucleus pontis oralis (NPO) exerts an executive control over REM sleep. Cholinergic input to the NPO is critical for REM sleep generation. In the cat, a single microinjection of carbachol (a cholinergic agonist) into the NPO produces either REM sleep (REMc) or wakefulness with Muscle Atonia (cataplexy, CA). In order to study the central control of the heart rate variability (HRV) during sleep, we conducted polysomnographic and electrocardiogram recordings from chronically prepared cats during REMc, CA as well as during sleep and wakefulness. Subsequently, we performed statistical and spectral analyses of the HRV. The heart rate was greater during CA compared to REMc, NREM or REM sleep. Spectral analysis revealed that the low frequency band (LF) power was significantly higher during REM sleep in comparison to REMc and CA. Furthermore, we found that during CA there was a decrease in coupling between the RR intervals plot (tachogram) and respiratory activity. In contrast, compared to natural behavioral states, during REMc and CA there were no significant differences in the HRV based upon the standard deviation of normal RR intervals (SDNN) and the mean squared difference of successive intervals (rMSSD). In conclusion, there were differences in the HRV during naturally-occurring REM sleep compared to REMc. In addition, in spite of the same Muscle Atonia, the HRV was different during REMc and CA. Therefore, the neuronal network that controls the HRV during REM sleep can be dissociated from the one that generates the Muscle Atonia during this state.
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Induction of active (REM) sleep and motor inhibition by hypocretin in the nucleus pontis oralis of the cat.
Journal of Neurophysiology, 2002Co-Authors: Ming-chu Xi, Jack Yamuy, Francisco R Morales, Simon J. Fung, Michael H ChaseAbstract:Hypocretin (orexin)-containing neurons in the hypothalamus, which have been implicated in the pathology of narcolepsy, project to nuclei in the brain stem reticular formation that are involved in the control of the behavioral states of sleep and wakefulness. Among these nuclei is the nucleus pontis oralis (NPO). Consequently, the present study was undertaken to determine if the hypocretinergic system provides regulatory input to neurons in the NPO with respect to the generation of the states of sleep and wakefulness. Accordingly, polygraphic recordings and behavioral observations were obtained before and after hypocretin-1 and -2 were microinjected into the NPO in chronic, unanesthetized cats. Microinjections of either hypocretin-1 or -2 elicited, with a short latency, a state of active [rapid eye movement (REM)] sleep that appeared identical to naturally occurring active sleep. The percentage of time spent in active sleep was significantly increased. Dissociated states, which are characterized by the presence of Muscle Atonia without one or more of the electrophysiological correlates of active sleep, also arose following the injection. The effect of juxtacellular application of hypocretin-1 on the electrical activity of intracellularly recorded NPO neurons was then examined in the anesthetized cat. In this preparation, the application of hypocretin-1 resulted in the depolarization of NPO neurons, an increase in the frequency of their discharge and an increase in their excitability. These latter data represent the first description of the in vivo action of hypocretin on intracellularly recorded neuronal activity and provide evidence that the active sleep-inducing effects of hypocretin are due to a direct excitatory action on NPO neurons. Therefore we suggest that hypocretinergic processes in the NPO may play a role in the generation of active sleep, particularly Muscle Atonia and therefore are likely to be involved in the pathology of narcolepsy.
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relationship between sensory stimuli elicited ipsps in motoneurons and pgo waves during cholinergically induced Muscle Atonia
Journal of Neurophysiology, 1997Co-Authors: Kristi A Kohlmeier, Faustino Lopezrodriguez, Francisco R Morales, Michael H ChaseAbstract:Kohlmeier, Kristi A., Faustino Lopez-Rodriguez, Francisco R. Morales, and Michael H. Chase. Relationship between sensory stimuli–elicited IPSPs in motoneurons and PGO waves during cholinergically ...
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State-dependent phenomena in cat masseter motoneurons.
Brain Research, 1996Co-Authors: Kristi A Kohlmeier, Francisco R Morales, Faustino Lopez-rodriguez, Michael H ChaseAbstract:Abstract In the present study we explored the mechanisms of carbachol-induced Muscle Atonia in the α-chloralose-anesthetized animal. We compared our findings to those that have been previously obtained in unanesthetized cats during Muscle Atonia occurring during natural active sleep. Accordingly, in cats anesthetized with a-chloralose, intracellular records were obtained from masseter motoneurons before and after carbachol-induced motor Atonia. Following the induction of Atonia, the membrane potential activity was dominated by high-frequency, discrete, hyperpolarizing potentials. These hyperpolarizing potentials were reversed in polarity by the intracellular injection of chloride ions and abolished by the application of strychnine. These findings indicate that they were inhibitory postsynaptic potentials (IPSPs) mediated by glycine. These IPSPs appeared exclusively during Muscle Atonia. In addition, masseter motoneurons were significantly hyperpolarized and their rheobase increased. There was a decrease in input resistance and membrane time constant. In the α-chloralose-anesthetized preparation, stimulation of the nucleus pontis oralis (NPO) induced IPSPs in masseter motoneurons following, but never prior to, the pontine injection of carbachol. Thus, this is the first demonstration that ‘reticular response-reversal’ may be elicited in an anesthetized preparation. Another state-dependent phenomenon of active sleep, the occurrence of IPSPs in motoneurons that are temporally correlated with ponto-geniculo-occipital (PGO) waves, was also observed in this preparation only after carbachol administration. Based on the data in this report, we conclude that the inhibitory system that mediates Atonia during the state of active sleep can be activated in an animal that is anesthetized with a-chloralose. Specifically, the neuronal groups that generate spontaneous IPSPs, those that mediate the phenomenon of reticular response-reversal, and those involved in the generation of PGO waves are capable of being activated and remain functional during a-chloralose-anesthesia.
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Muscle Atonia can be induced by carbachol injections into the nucleus pontis oralis in cats anesthetized with α chloralose
Brain Research, 1995Co-Authors: Faustino Lopezrodriguez, Kristi A Kohlmeier, Jack Yamuy, Francisco R Morales, Michael H ChaseAbstract:Abstract Cholinergic excitation of structures in the pontine reticular formation appears to be a key step in the generation of active sleep. For example, Muscle Atonia which occurs as a result of the postsynaptic inhibition of motoneurons during active sleep is also present after carbachol, a cholinergic agonist, is injected into the nucleus pontis oralis. In the present study, in order to obtain information regarding the mechanisms that generate Atonia during active sleep and to provide a paradigm for studying Atonia in anesthetized cats, we determined whether cholinergically induced Atonia could be generated in an animal that was anesthetized with α-chloralose. Cats which were initially anesthetized with α-chloralose (40 mg/kg, I.V.) exhibited spikes in the EEG, hippocampus and lateral geniculate nuclei. Muscle Atonia occurred after carbachol (200 mM) was injected by microiontophoresis (300–500 nA) into the nucleus pontis oralis; the spikes in the EEG, hippocampus and lateral geniculate nuclei were still present. We believe that the Atonia induced by carbachol in α-chloralose-anesthetized cats is mediated by the same mechanisms that operate during active sleep in the unanesthetized animal for the following reasons. First, in the same cats when they were not anesthetized with α-chloralose, carbachol injections in the identical brainstem sites induced active sleep with its accompanying pattern of Muscle Atonia. Second, after carbachol was injected into the same sites in α-chloralose-anesthetized cats, intracellular recordings from lumbar motoneurons revealed that inhibitory postsynaptic potentials were bombarding motoneurons; these inhibitory potentials were similar to those which are present during naturally occurring active sleep. In addition, stimulation of the nucleus reticularis gigantocellularis (NRGc) was found to induce large amplitude depolarizing potentials in lumbar motoneurons in α-chloralose-anesthetized cats prior to the administration of carbachol, whereas after its administration, accompanying Muscle Atonia there were large amplitude hyperpolarizing potentials and a reduction in the amplitude of depolarizing potentials. We therefore conclude that the cholinergically induced processes that initiate and maintain Muscle Atonia are not blocked by the actions of α-chloralose.
Jun Lu - One of the best experts on this subject based on the ideXlab platform.
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Neural Circuitry Regulating REM Sleep and Its Implication in REM Sleep Behavior Disorder
Rapid-Eye-Movement Sleep Behavior Disorder, 2018Co-Authors: Ramalingam Vetrivelan, Jun LuAbstract:Since the discovery of rapid eye movement sleep (REMs) in 1953, considerable progress has been made in deciphering the neural circuits and mechanisms involved in the generation of this stage and its cardinal signs, including cortical activation and Muscle Atonia. Research work on animal models has provided important insights on the prognosis, diagnosis, causes, and treatment of REM behavior disorder (RBD), a clinical condition in which Muscle Atonia is compromised during REMs. In this chapter, we review current knowledge in REMs circuitry and its involvement in the pathophysiology of RBD. Available evidence strongly suggests that glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD) located in the dorsolateral pons are the principal elements for the generation of REMs. These neurons may cause cortical activation and Muscle Atonia during REMs respectively through their ascending projections to the parabrachial nucleus and basal forebrain and their descending projections to the ventromedial medulla (VMM) and spinal cord. Activity of SLD neurons, and thereby REMs, is strongly under the influence of inhibitory neurons in the ventrolateral periaqueductal gray and the adjoining lateral pontine tegmentum (vlPAG/LPT). Mutual interaction between the SLD and vlPAG/LPT forms the primary REMs circuit and may determine the occurrence and duration of REMs. Many other brain regions, including medial prefrontal cortex, preoptic area, and lateral hypothalamus, may orchestrate circadian, homeostatic, and allostatic regulation of REMs by acting on this principal circuit. These data indicate that degenerative lesions of the SLD and its descending projections may underlie RBD and that assessing REMs amount and architecture, in addition to motor behavior, may be necessary to track the progression of RBD into alpha-synucleinopathy diseases such as Parkinson’s disease.
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Carbachol excites sublaterodorsal nucleus neurons projecting to the spinal cord
The Journal of Physiology, 2013Co-Authors: F. J. Weng, Thomas E Scammell, Rhîannan H. Williams, J. M. Hawryluk, Jun Lu, Clifford B. Saper, Elda ArrigoniAbstract:Key points Activation of spinally projecting sublaterodorsal nucleus (SLD) neurons inhibits motor activity, in part through spinal inhibitory interneurons, to produce Muscle Atonia during rapid-eye-movement (REM) sleep. It has long been hypothesized that acetylcholine released during REM sleep contributes to REM sleep Atonia through activation of SLD neurons. We show, using whole-cell recordings in brainstem slices, that acetylcholine directly excites spinally projecting SLD neurons via M1 and M3 muscarinic receptors, and increases afferent excitatory synaptic input to these neurons. These results suggest that acetylcholine contributes to REM sleep Muscle Atonia through excitation of spinally projecting SLD neurons. Abstract Considerable electrophysiological and pharmacological evidence has long suggested an important role for acetylcholine in the regulation of rapid-eye-movement (REM) sleep. For example, injection of the cholinergic agonist carbachol into the dorsomedial pons produces an REM sleep-like state with Muscle Atonia and cortical activation, both of which are cardinal features of REM sleep. Located within this region of the pons is the sublaterodorsal nucleus (SLD), a structure thought to be both necessary and sufficient for generating REM sleep Muscle Atonia. Subsets of glutamatergic SLD neurons potently contribute to motor inhibition during REM sleep through descending projections to motor-related glycinergic/GABAergic neurons in the spinal cord and ventromedial medulla. Prior electrophysiological and pharmacological studies examining the effects of acetylcholine on SLD neurons have, however, produced conflicting results. In the present study, we sought to clarify how acetylcholine influences the activity of spinally projecting SLD (SLDsp) neurons. We used retrograde tracing in combination with patch-clamp recordings and recorded pre- and postsynaptic effects of carbachol on SLDsp neurons. Carbachol acted presynaptically by increasing the frequency of glutamatergic miniature excitatory postsynaptic currents. We also found that carbachol directly excited SLDsp neurons by activating an Na+–Ca2+ exchanger. Both pre- and postsynaptic effects were mediated by co-activation of M1 and M3 muscarinic receptors. These observations suggest that acetylcholine produces synergistic, excitatory pre- and postsynaptic responses on SLDsp neurons that, in turn, probably serve to promote Muscle Atonia during REM sleep.
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Perspectives on the rapid eye movement sleep switch in rapid eye movement sleep behavior disorder
Sleep Medicine, 2013Co-Authors: Vetrivelan Ramaligam, Clifford B. Saper, Michael Chen, Jun LuAbstract:Rapid eye movement (REM) sleep in mammals is associated with wakelike cortical and hippocampal activation and concurrent postural Muscle Atonia. Research during the past 5 decades has revealed the details of the neural circuitry regulating REM sleep and Muscle Atonia during this state. REM-active glutamatergic neurons in the sublaterodorsal nucleus (SLD) of the dorsal pons are critical for generation for REM sleep Atonia. Descending projections from SLD glutamatergic neurons activate inhibitory premotor neurons in the ventromedial medulla (VMM) and in the spinal cord to antagonize the glutamatergic supraspinal inputs on the motor neurons during REM sleep. REM sleep behavior disorder (RBD) consists of simple behaviors (i.e., twitching, jerking) and complex behaviors (i.e., defensive behavior, talking). Animal research has lead to the hypothesis that complex behaviors in RBD are due to SLD pathology, while simple behaviors of RBD may be due to less severe SLD pathology or dysfunction of the VMM, ventral pons, or spinal cord.
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brainstem and spinal cord circuitry regulating rem sleep and Muscle Atonia
PLOS ONE, 2011Co-Authors: Ramalingam Vetrivelan, Martina Krenzer, Christelle Anaclet, Nishang Wang, Linh Vong, Bradford B Lowell, Patrick M Fuller, Jun LuAbstract:Background: Previous work has suggested, but not demonstrated directly, a critical role for both glutamatergic and GABAergic neurons of the pontine tegmentum in the regulation of rapid eye movement (REM) sleep. Methodology/Principal Findings: To determine the in vivo roles of these fast-acting neurotransmitters in putative REM pontine circuits, we injected an adeno-associated viral vector expressing Cre recombinase (AAV-Cre) into mice harboring lox-P modified alleles of either the vesicular glutamate transporter 2 (VGLUT2) or vesicular GABA-glycine transporter (VGAT) genes. Our results show that glutamatergic neurons of the sublaterodorsal nucleus (SLD) and glycinergic/GABAergic interneurons of the spinal ventral horn contribute to REM Atonia, whereas a separate population of glutamatergic neurons in the caudal laterodorsal tegmental nucleus (cLDT) and SLD are important for REM sleep generation. Our results further suggest that presynaptic GABA release in the cLDT-SLD, ventrolateral periaqueductal gray matter (vlPAG) and lateral pontine tegmentum (LPT) are not critically involved in REM sleep control. Conclusions/Significance: These findings reveal the critical and divergent in vivo role of pontine glutamate and spinal cord GABA/glycine in the regulation of REM sleep and Atonia and suggest a possible etiological basis for REM sleep behavior disorder (RBD).
Jerome M Siegel - One of the best experts on this subject based on the ideXlab platform.
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Changes in Inhibitory Amino Acid Release Linked to Pontine-Induced Atonia: An In Vivo Microdialysis Study
The Journal of Neuroscience, 2003Co-Authors: Tohro Kodama, Jerome M SiegelAbstract:We hypothesized that cessation of brainstem monoaminergic systems and an activation of brainstem inhibitory systems are both involved in pontine inhibitory area (PIA) stimulation-induced Muscle Atonia. In our previous study (Lai et al., 2001), we found a decrease in norepinephrine and serotonin release in motoneuron pools during PIA stimulation-induced Muscle tone suppression. We now demonstrate an increase in inhibitory amino acid release in motor nuclei during PIA stimulation in the decerebrate cat using in vivo microdialysis and HPLC analysis techniques. Microinjection of acetylcholine into the PIA elicited Muscle Atonia and simultaneously produced a significant increase in both glycine and GABA release in both the hypoglossal nucleus and the lumbar ventral horn. Glycine release increased by 74% in the hypoglossal nucleus and 50% in the spinal cord. GABA release increased by 31% in the hypoglossal nucleus and 64% in the spinal cord during Atonia induced by cholinergic stimulation of the PIA. As with cholinergic stimulation, 300 msec train electrical stimulation of the PIA elicited a significant increase in glycine release in the hypoglossal nucleus and ventral horn. GABA release was significantly increased in the hypoglossal nucleus but not in the spinal cord during electrical stimulation of the PIA. Glutamate release in the motor nuclei was not significantly altered during Atonia induced by electrical or acetylcholine stimulation of the PIA. We suggest that both glycine and GABA play important roles in the regulation of upper airway and postural Muscle tone. A combination of decreased monoamine and increased inhibitory amino acid release in motoneuron pools causes PIA-induced Atonia and may be involved in Atonia linked to rapid eye-movement sleep.
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Muscle Atonia is triggered by cholinergic stimulation of the basal forebrain implication for the pathophysiology of canine narcolepsy
The Journal of Neuroscience, 1995Co-Authors: Seiji Nishino, Jerome M Siegel, Mehdi Tafti, Jeff Shelton, William C Dement, Emmanuel MignotAbstract:Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep-related symptoms, such as cataplexy. The exact pathophysiology underlying the disease is unknown but may involve central cholinergic systems. It is known that the brainstem cholinergic system is activated during REM sleep. Furthermore, REM sleep and REM sleep Atonia similar to cataplexy can be triggered in normal and narcoleptic dogs by stimulating cholinergic receptors within the pontine brainstem. The pontine cholinergic system is, therefore, likely to play a role in triggering cataplexy and other REM-related abnormalities seen in narcolepsy. The other cholinergic system that could be involved in the pathophysiology of narcolepsy is located in the basal forebrain (BF). This system sends projections to the entire cerebral cortex. Since acetylcholine release in the cortex is increased both during REM and wake, the basocortical cholinergic system is believed to be involved in cortical desynchrony. In the current study, we analyzed the effect of cholinergic compounds injected into the forebrain structures of narcoleptic and control dogs. We found that carbachol (a cholinergic agonist) injected into the BF triggers cataplexy in narcoleptic dogs while it increases wakefulness in control dogs. Much higher doses of carbachol bilaterally injected in the BF were, however, shown to trigger Muscle Atonia even in control dogs. These results suggest that a cholinoceptive site in the BF is critically implicated in triggering Muscle Atonia and cataplexy. Together with similar results previously obtained in the pontine brainstem, it appears that a widespread hypersensitivity to cholinergic stimulation may be central to the pathophysiology of canine narcolepsy.
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Enhancement of acetylcholine release during REM sleep in the caudomedial medulla as measured by in vivo microdialysis
Brain Research, 1992Co-Authors: T Kodama, Jerome M SiegelAbstract:Previous studies in our laboratory have found that Muscle Atonia could be triggered by two distinct areas of the medial medulla, a caudal region, corresponding to the nucleus paramedianus (NPM) and a rostral region, corresponding to the nucleus magnocellularis (NMC). The former region is responsive to acetylcholine (ACh) and the latter region is responsive to glutamate. In this study we have measured the endogenous ACh release across the sleep-wake cycle in these two areas with the microdialysis technique in unanesthetized, freely moving cats. We found that ACh release in NPM was state-dependent and was about 30% higher ( P0.001) during rapid eye movement (REM) sleep than during slow-wave sleep and wakefulness. However, ACh release in NMC was not selectively elevated in REM sleep. The enhancement of ACh release in NPM during REM sleep supports our hypothesis that ACh release onto cholinoceptive neurons in this area mediates the Muscle Atonia of REM sleep.
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corticotropin releasing factor mediated Muscle Atonia in pons and medulla
Brain Research, 1992Co-Authors: Jerome M SiegelAbstract:Abstract The dorsolateral pontine inhibitory area (PIA) and medial medullary reticular formation (MMRF) have been found to mediate the Muscle Atonia of REM sleep. Our previous studies have shown that acetylcholine (ACh) microinjection in the PIA and in the nucleus paramedianus of the medial medulla produces Muscle Atonia. Glutamate microinjection in both PIA and nucleus magnocellularis (NMC) of the medial medulla also produces Muscle Atonia. Since immunohistochemical studies have identified corticotropin-releasing factor (CRF) as a potential dorsolateral pontine and NMC transmitter, the present study was undertaken to determine whether this transmitter could produce suppression of Muscle tone. Experiments were performed on unanesthetized, decerebrated cats. CRF was microinjected into points in the PIA and NMC at which electrical stimulation produced bilateral inhibition of Muscle tone. We found that CRF produced a dose-dependent Muscle tone suppression. At 10 nM concentration, the latency and duration of Muscle inhibition produced by CRF injection were comparable with those of l -glutamate, at 18.8 s and 4.1 min, respectively. This CRF-induced Muscle inhibition was blocked by the CRF antagonist, α-helical [Glu 27 ]corticotropin-releasing factor 9–41 (CRF 9–41). Microinjection of CRF and non-NMDA agonists, kainate and quisqualate, into the same sites in PIA and NMC produced Muscle Atonia. Pontine sites at which CRF injection induces Atonia are identical to those at which acetylcholine microinjection produces Atonia. These results indicate that CRF may interact with glutamate and acetylcholine in the generation of Muscle Atonia.
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Cardiovascular and Muscle tone changes produced by microinjection of cholinergic and glutamatergic agonists in dorsolateral pons and medial medulla.
Brain Research, 1990Co-Authors: Jerome M SiegelAbstract:Abstract Cardiovascular and Muscle responses l -glutamic acid (Glut) and cholinergic agonists injected into the dorsolateral pontine tegmentum and medial medullary reticular formation (MMRF) were examined in unanesthetized, decerebrated cats. Glut, or cholinergic agonists acetylcholine (ACh) or carbachol (Carb), were injected into pons and MMRF at sites from which electrical stimulation produced bilateral suppression of Muscle tone. Glut injection in MMRF produced hypotension without change in heart rate at doses as low as 1 mM. At higher doses (0.1–0.4 M), Glut induced hypotension with bradycardia in 23 out of 40 injections in both pons and MMRF. High concentrations of microinjected Glut decreased Muscle tone or produced complete Atonia in pons and rostral MMRF. Both N-methyl- d -aspartic acid (NMDA) and non-NMDA receptor blockers attenuated or completely blocked the cardiovascular response, while only non-NMDA antagonists blocked Muscle inhibition to Glut injection. Microinjection of cholinergic agonists produced consistent hypotension in all of the injections in pons and MMRF, however, the heart rate response was variable with increase (27/42), decrease (2/42), or no change (13/42) in rate seen. Cholinergic injection produced Muscle Atonia in pons and caudal MMRF but not in rostral MMRF. Both Muscle and cardiovascular responses were blocked by atropine but not by hexamethonium. The time course of Muscle Atonia and cardiovascular change differed in most of the experiments. We conclude that Muscle tone suppression and cardiovascular response to Glut or cholinergic agonists use different receptor mechanisms and possibly different neurons. However, the co-localization of these mechanisms suggests that neuronal networks in the medial medulla and dorsolateral pons coordinate motor and cardiovascular responses.
Pierre-hervé Luppi - One of the best experts on this subject based on the ideXlab platform.
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Neurobiology of REM sleep
Oxford Medicine Online, 2020Co-Authors: Pierre-hervé Luppi, Olivier Clement, Christelle Peyron, Patrice FortAbstract:REM (paradoxical) sleep is a state characterized by rapid eye movements, EEG activation, and Muscle Atonia. REM sleep behavior disorder (RBD) is a parasomnia characterized by loss of Muscle Atonia during REM sleep. Cataplexy, a key symptom of narcolepsy, is a striking sudden episode of Muscle weakness comparable to REM sleep Atonia triggered by emotions during wakefulness. This chapter presents recent results on the neuronal network responsible for REM sleep and explores hypotheses explaining RBD and cataplexy. RBD could be due to a specific degeneration of glutamatergic neurons responsible for Muscle Atonia, localized in the pontine sublaterodorsal tegmental nucleus (SLD) or the glycinergic/GABAergic premotoneurons localized in the ventral medullary reticular nuclei. Cataplexy in narcoleptics could be due to activation during waking of SLD neurons. In normal conditions, activation of SLD neurons would be blocked by simultaneous excitation by hypocretins of REM sleep-off GABAergic neurons localized in the ventrolateral periaqueductal gray.
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is rem sleep a paradoxical state showing Muscle Atonia and a cortical activity similar to waking
Neurophysiologie Clinique-clinical Neurophysiology, 2018Co-Authors: Pierre-hervé LuppiAbstract:Michel Jouvet renamed REM sleep paradoxical sleep (PS) after his discovery that it displays an EEG similar to waking but with a complete Muscle paralysis. To determine whether the cortical activation is similar during PS and waking, we recently identified at cellular level the populations of cortical neurons activated and displaying plasticity during waking and PS hypersomnia by means of functional neuroanatomy [3] . Our mapping clearly shows for the first time that only a small number of limbic structures are activated during PS in contrast to waking. These structures are the cortical amygdaloid nucleus, the anterior cingulate, retrosplenial and medial entorhinal cortices, the claustrum and the dentate gyrus (DG) [3] . Further, combining retrograde tracing, neurotoxic lesion and FOS immunostaining, we showed that neurons of the claustrum and from the lateral part of the supramammillary nucleus (SuML) are responsible for the activation of the cortical structures and the DG during PS [3] . We further recently showed using stimulation of the SuML/DG pathway using optogenetic induces an increase in theta power and frequency indicating that this pathway plays a role in theta. These surprising results pointed out for the first time that the claustrum and the SuML activate a subset of limbic cortical neurons specifically during PS in contrast to waking during which the aminergic, cholinergic and the hypocretin systems activate the cortex. We propose that the limbic cortical activation revealed in our study might play a key role in the previously reported beneficial effect of PS on learning and memory. Indeed, many studies clearly indicate that PS is instrumental for memory consolidation [1] . Further, it has recently been shown that PS deprivation in rats impairs consolidation of contextual fear conditioning [2] .
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REM sleep behaviour disorder
Nature reviews. Disease primers, 2018Co-Authors: Yves Dauvilliers, Pierre-hervé Luppi, Giuseppe Plazzi, Jacques Montplaisir, Carlos H. Schenck, Ronald B. Postuma, Alex Iranzo, Bradley F. BoeveAbstract:Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia that is characterized by loss of Muscle Atonia during REM sleep (known as REM sleep without Atonia, or RSWA) and abnormal behaviours occurring during REM sleep, often as dream enactments that can cause injury. RBD is categorized as either idiopathic RBD or symptomatic (also known as secondary) RBD; the latter is associated with antidepressant use or with neurological diseases, especially α-synucleinopathies (such as Parkinson disease, dementia with Lewy bodies and multiple system atrophy) but also narcolepsy type 1. A clinical history of dream enactment or complex motor behaviours together with the presence of Muscle activity during REM sleep confirmed by video polysomnography are mandatory for a definite RBD diagnosis. Management involves clonazepam and/or melatonin and counselling and aims to suppress unpleasant dreams and behaviours and improve bedpartner quality of life. RSWA and RBD are now recognized as manifestations of an α-synucleinopathy; most older adults with idiopathic RBD will eventually develop an overt neurodegenerative syndrome. In the future, studies will likely evaluate neuroprotective therapies in patients with idiopathic RBD to prevent or delay α-synucleinopathy-related motor and cognitive decline. Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterized by a loss of Muscle Atonia and abnormal behaviours during REM sleep. This Primer discusses the epidemiology, pathophysiology, diagnosis and management of RBD as well as the relationship and implications of the relationship between idiopathic RBD and neurodegenerative disease.
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Jouvet's animal model of RBD, clinical RBD, and their relationships to REM sleep mechanisms
Sleep Medicine, 2018Co-Authors: Pierre-hervé LuppiAbstract:Abstract This article focuses on the contributions made by Michel Jouvet concerning the systems responsible for the Muscle Atonia of paradoxical sleep (REM sleep). He was the first to describe the brainstem system mechanisms responsible for Muscle Atonia during paradoxical sleep using pontine cats and localized pontine lesions. Also discussed is the research going on in the eighties, when Michel Jouvet was hunting for the hypnogenetic factor. At that time, he thought that it was secreted by the hypophysis; but it finally turned out to be controlled by the hypocretin/orexin and melanin concentrating hormone neurones located in the lateral hypothalamus. Several unforgettable moments with Michel Jouvet are described which occurred between 1983 as well as his last moments with us.
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Ventromedial medulla inhibitory neuron inactivation induces REM sleep without Atonia and REM sleep behavior disorder
Nature Communications, 2018Co-Authors: Sara Valencia Garcia, Olivier Clement, Pierre-hervé Luppi, Paul-antoine Libourel, Michael Lazarus, Frédéric Brischoux, Sébastien Arthaud, Patrice FortAbstract:Despite decades of research, there is a persistent debate regarding the localization of GABA/glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical (or REM) sleep (PS), resulting in the loss of Muscle tone during this sleep state. Combining complementary neuroanatomical approaches in rats, we first show that these inhibitory neurons are localized within the ventromedial medulla (vmM) rather than within the spinal cord. We then demonstrate their functional role in PS expression through local injections of adeno-associated virus carrying specific short-hairpin RNA in order to chronically impair inhibitory neurotransmission from vmM. After such selective genetic inactivation, rats display PS without Atonia associated with abnormal and violent motor activity, concomitant with a small reduction of daily PS quantity. These symptoms closely mimic human REM sleep behavior disorder (RBD), a prodromal parasomnia of synucleinopathies. Our findings demonstrate the crucial role of GABA/glycine inhibitory vmM neurons in Muscle Atonia during PS and highlight a candidate brain region that can be susceptible to α-synuclein-dependent degeneration in RBD patients. Loss of Muscle tone is a distinguishing feature of paradoxical or REM sleep (PS) and is disrupted in REM sleep behavior disorder. Here the authors report that GABA/glycine inhibitory neurons in the ventromedial medulla are essential for producing PS Muscle Atonia without affecting PS quantity.
Patrice Fort - One of the best experts on this subject based on the ideXlab platform.
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Neurobiology of REM sleep
Oxford Medicine Online, 2020Co-Authors: Pierre-hervé Luppi, Olivier Clement, Christelle Peyron, Patrice FortAbstract:REM (paradoxical) sleep is a state characterized by rapid eye movements, EEG activation, and Muscle Atonia. REM sleep behavior disorder (RBD) is a parasomnia characterized by loss of Muscle Atonia during REM sleep. Cataplexy, a key symptom of narcolepsy, is a striking sudden episode of Muscle weakness comparable to REM sleep Atonia triggered by emotions during wakefulness. This chapter presents recent results on the neuronal network responsible for REM sleep and explores hypotheses explaining RBD and cataplexy. RBD could be due to a specific degeneration of glutamatergic neurons responsible for Muscle Atonia, localized in the pontine sublaterodorsal tegmental nucleus (SLD) or the glycinergic/GABAergic premotoneurons localized in the ventral medullary reticular nuclei. Cataplexy in narcoleptics could be due to activation during waking of SLD neurons. In normal conditions, activation of SLD neurons would be blocked by simultaneous excitation by hypocretins of REM sleep-off GABAergic neurons localized in the ventrolateral periaqueductal gray.
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Ventromedial medulla inhibitory neuron inactivation induces REM sleep without Atonia and REM sleep behavior disorder
Nature Communications, 2018Co-Authors: Sara Valencia Garcia, Olivier Clement, Pierre-hervé Luppi, Paul-antoine Libourel, Michael Lazarus, Frédéric Brischoux, Sébastien Arthaud, Patrice FortAbstract:Despite decades of research, there is a persistent debate regarding the localization of GABA/glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical (or REM) sleep (PS), resulting in the loss of Muscle tone during this sleep state. Combining complementary neuroanatomical approaches in rats, we first show that these inhibitory neurons are localized within the ventromedial medulla (vmM) rather than within the spinal cord. We then demonstrate their functional role in PS expression through local injections of adeno-associated virus carrying specific short-hairpin RNA in order to chronically impair inhibitory neurotransmission from vmM. After such selective genetic inactivation, rats display PS without Atonia associated with abnormal and violent motor activity, concomitant with a small reduction of daily PS quantity. These symptoms closely mimic human REM sleep behavior disorder (RBD), a prodromal parasomnia of synucleinopathies. Our findings demonstrate the crucial role of GABA/glycine inhibitory vmM neurons in Muscle Atonia during PS and highlight a candidate brain region that can be susceptible to α-synuclein-dependent degeneration in RBD patients. Loss of Muscle tone is a distinguishing feature of paradoxical or REM sleep (PS) and is disrupted in REM sleep behavior disorder. Here the authors report that GABA/glycine inhibitory neurons in the ventromedial medulla are essential for producing PS Muscle Atonia without affecting PS quantity.
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a particular medullary spinal inhibitory pathway is recruited for the expression of Muscle Atonia during rem sleep
Journal of Experimental Neuroscience, 2018Co-Authors: Sara Valencia Garcia, Pierre-hervé Luppi, Patrice FortAbstract:: Muscle Atonia is a major pathognomonic sign of paradoxical sleep (PS; coined REM Sleep), during which dreams mainly occur. In the 1980s, an idiopathic syndrome called REM sleep behavior disorder (RBD) was described in patients endowed with loss of PS paralysis concomitant to abnormal movements, suggesting a dysfunction of PS networks. Another major clinical RBD feature is its prevalent phenoconversion into synucleinopathies as Parkinson's disease in a delay of 10-15 years after diagnosis. Thus, we undertook experiments in rats to disentangle brainstem networks involved in PS, including Atonia. We first identified a contingent of pontine glutamate neurons recruited during PS with inputs to the ventromedial medulla (vmM) where they contact γ-aminobutyric acid (GABA)/glycine inhibitory neurons also activated during PS. Here, we further show that these vmM inhibitory neurons send efferents to somatic spinal motoneurons until lumbar levels. As reported for the pontine generator, the genetic inactivation of the vmM inhibitory neurons abolishes Atonia during PS without effects on waking locomotion and is sufficient to recapitulate major RBD symptoms. These original data suggest that RBD may reflect a severe dysfunction and/or degeneration linked to a developing synucleinopathic attack targeting specifically neurons that generate PS-specific Atonia.
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Genetic inactivation of glutamate neurons in the rat sublaterodorsal tegmental nucleus recapitulates REM sleep behaviour disorder
Brain, 2016Co-Authors: Sara Valencia Garcia, Pierre-hervé Luppi, Paul-antoine Libourel, Michael Lazarus, Daniela Grassi, Patrice FortAbstract:SEE SCHENCK AND MAHOWALD DOI101093/AWW329 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Idiopathic REM sleep behaviour disorder is characterized by the enactment of violent dreams during paradoxical (REM) sleep in the absence of normal Muscle Atonia. Accumulating clinical and experimental data suggest that REM sleep behaviour disorder might be due to the neurodegeneration of glutamate neurons involved in paradoxical sleep and located within the pontine sublaterodorsal tegmental nucleus. The purpose of the present work was thus to functionally determine first, the role of glutamate sublaterodorsal tegmental nucleus neurons in paradoxical sleep and second, whether their genetic inactivation is sufficient for recapitulating REM sleep behaviour disorder in rats. For this goal, we first injected two retrograde tracers in the intralaminar thalamus and ventral medulla to disentangle neuronal circuits in which sublaterodorsal tegmental nucleus is involved; second we infused bilaterally in sublaterodorsal tegmental nucleus adeno-associated viruses carrying short hairpin RNAs targeting Slc17a6 mRNA [which encodes vesicular glutamate transporter 2 (vGluT2)] to chronically impair glutamate synaptic transmission in sublaterodorsal tegmental nucleus neurons. At the neuroanatomical level, sublaterodorsal tegmental nucleus neurons specifically activated during paradoxical sleep hypersomnia send descending efferents to glycine/GABA neurons within the ventral medulla, but not ascending projections to the intralaminar thalamus. These data suggest a crucial role of sublaterodorsal tegmental nucleus neurons rather in Muscle Atonia than in paradoxical sleep generation. In line with this hypothesis, 30 days after adeno-associated virus injections into sublaterodorsal tegmental nucleus rats display a decrease of 30% of paradoxical sleep daily quantities, and a significant increase of Muscle tone during paradoxical sleep concomitant to a tremendous increase of abnormal motor dream-enacting behaviours. These animals display symptoms and behaviours during paradoxical sleep that closely mimic human REM sleep behaviour disorder. Altogether, our data demonstrate that glutamate sublaterodorsal tegmental nucleus neurons generate Muscle Atonia during paradoxical sleep likely through descending projections to glycine/GABA premotor neurons in the ventral medulla. Although playing a role in paradoxical sleep regulation, they are, however, not necessary for inducing the state itself. The present work further validates a potent new preclinical REM sleep behaviour disorder model that opens avenues for studying and treating this disabling sleep disorder, and advances potential regions implicated in prodromal stages of synucleinopathies such as Parkinson's disease.
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Brainstem structures involved in rapid eye movement sleep behavior disorder
Sleep and Biological Rhythms, 2013Co-Authors: Pierre-hervé Luppi, Olivier Clement, Patrice FortAbstract:Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the loss of Muscle Atonia during paradoxical (REM) sleep (PS). The neuronal dysfunctions responsible for RBD are not known. In the present review, we propose an updated integrated model of the mechanisms responsible for PS and explore different hypotheses explaining RBD. We propose that RBD appears based on a specific degeneration of PS-on glutamatergic neurons localized in the caudal pontine sublaterodorsal tegmental nucleus or the glycinergic/GABAergic premotoneurons localized in the medullary ventral gigantocellular reticular nucleus.
