An Endogenous Glutamatergic Drive onto Somatic Motoneurons Contributes to the Stereotypical Pattern of Muscle Tone across the Sleep-Wake Cycle

Department of Cell and Systems Biology, Systems Neurobiology Laboratory, University of Toronto, Toronto, Ontario, Canada M5S 3G5.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2008; 28(18):4649-60. DOI: 10.1523/JNEUROSCI.0334-08.2008
Source: PubMed


Skeletal muscle tone is modulated in a stereotypical pattern across the sleep-wake cycle. Abnormalities in this modulation contribute to most of the major sleep disorders; therefore, characterizing the neurochemical substrate responsible for transmitting a sleep-wake drive to somatic motoneurons needs to be determined. Glutamate is an excitatory neurotransmitter that modulates motoneuron excitability; however, its role in regulating motoneuron excitability and muscle tone during natural sleep-wake behaviors is unknown. Therefore, we used reverse-microdialysis, electrophysiology, pharmacological, and histological methods to determine how changes in glutamatergic neurotransmission within the trigeminal motor pool contribute to the sleep-wake pattern of masseter muscle tone in behaving rats. We found that blockade of non-NMDA and NMDA glutamate receptors (via CNQX and d-AP-5) on trigeminal motoneurons reduced waking masseter tone to sleeping levels, indicating that masseter tone is maximal during alert waking because motoneurons are activated by an endogenous glutamatergic drive. This wake-related drive is switched off in non-rapid eye movement (NREM) sleep, and this contributes to the suppression of muscle tone during this state. We also show that a functional glutamatergic drive generates the muscle twitches that characterize phasic rapid-eye movement (REM) sleep. However, loss of a waking glutamatergic drive is not sufficient for triggering the motor atonia that characterizes REM sleep because potent activation of either AMPA or NMDA receptors on trigeminal motoneurons was unable to reverse REM atonia. We conclude that an endogenous glutamatergic drive onto somatic motoneurons contributes to the stereotypical pattern of muscle tone during wakefulness, NREM sleep, and phasic REM sleep but not during tonic REM sleep.

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    • "All electrophysiological signals were digitized at 200 Hz (AcqKnowledge software; Bio PAC, Goleta, CA, USA), monitored and stored on a computer. Two behavioral states were identified and classified according to the Christian Burgess's paper [11]. Alert wake (AW) was characterized by high levels of electrophysiological activity (i.e., chewing, grooming and drinking); quiet wake (QW) was characterized by the absence of overt motor activity. "
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    ABSTRACT: Experimental and non-experimental stress significantly increase masseter muscle tone, which has been linked to the symptoms and pathogenesis of several stomatognathic system diseases. Until now, the mechanism underlying this phenomenon has remained unclear. The current study was performed to determine the mechanism of the stress-induced increase in masseter muscle tone and to investigate the effect of lamotrigine on this change. Animals challenged by repeated restraint stress received either saline as a vehicle or lamotrigine in doses of 20, 30 or 40 mg/kg body weight, whereas control animals received saline without stress treatment. Masseter muscle tone was assessed using electromyography. The activity of glutamate-related metabolic enzymes (glutaminase and glutamine synthetase) in the trigeminal motor nucleus was also investigated. Our results showed an interesting phenomenon: masseter muscle activity increased concurrently with the upregulation of the glutamate concentration after stress treatment. The activities of glutaminase and glutamine synthetase in the trigeminal motor nucleus were also upregulated and downregulated, respectively, when the rats were challenged by prolonged stress. The animals treated with lamotrigine at moderate and high doses had significantly decreased masseter muscle tone compared with stressed animals treated with vehicle. These results suggested that increased glutaminase activity and decreased glutamine synthetase activity increased glutamate production and decreased glutamate decomposition, causing an increase in glutamate levels in the trigeminal motor nucleus and eventually increasing masseter muscle tone. The administration of lamotrigine at doses of 30 or 40 mg/kg body weight effectively mitigated the adverse effects of stress on masseter muscle tone via inhibition of glutamate release.
    Physiology & Behavior 06/2014; 137. DOI:10.1016/j.physbeh.2014.06.017 · 2.98 Impact Factor
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    • "It has been shown in rats and cats that during REM sleep, in addition to a tonic GABA/glycinergic inhibition, the motoneurons receive phasic glutamate excitatory and Gly/GABA inhibitory inputs during the muscle twitches [16] [17] [56]. It has further been shown that the phasic glutamatergic inputs are responsible for the occurrence of muscle twitches, as the application of glutamate antagonists on motoneurons abolish them [17]. The localization of the neurons at the origin of these phasic glutamatergic inputs is not known. "
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    ABSTRACT: Rapid eye movement sleep behavior disorder (RBD) is a parasomnia characterized by the occurrence of intense movements during rapid eye movement (REM) sleep, also named paradoxical sleep. The neuronal dysfunctions at the origin of the loss of atonia in RBD patients are not known. One possibility is that RBD is due to the degeneration of neurons inducing the muscle atonia of REM sleep. Therefore, in our paper we review data on the populations of neurons responsible for the atonia of REM sleep before discussing their potential role in RBD. We first review evidence that motoneurons are tonically hyperpolarized by gamma-aminobutyric acid (GABA) and glycine and phasically excited by glutamate during REM sleep. Then, we review data indicating that the atonia of REM sleep is induced by glycinergic/GABAergic REM-on premotoneurons contained within the raphe magnus and the ventral and alpha gigantocellular reticular nuclei localized in the ventral medullary reticular formation. These neurons are excited during REM sleep by a direct projection from glutamatergic REM-on neurons localized in the pontine sublaterodorsal tegmental nucleus (SLD). From these results, we discuss the possibility that RBD is due to a specific degeneration of descending REM-on glutamatergic neurons localized in the caudal SLD or that of the REM-on GABA/glycinergic premotoneurons localized in the ventral medullary reticular formation. We then propose that movements of RBD are induced by descending projections of cortical motor neurons before discussing possible modes of action of clonazepam and melatonin.
    Sleep Medicine 06/2013; 14(8). DOI:10.1016/j.sleep.2013.02.004 · 3.15 Impact Factor
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    • "In addition, mixed in with the REM-off GABAergic neurons is a REM-off glutamatergic population with spinal projections that may support motor tone during NREM sleep. Inhibition of these neurons during REM may withdraw motor tone, contributing to atonia in at least some motor neuron pools (Burgess et al., 2008). Other glutamatergic REMon neurons in the parabrachial nucleus and precoeruleus area project to the forebrain and cause the EEG phenomena that characterize REM sleep (Lu et al., 2006b). "
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    ABSTRACT: We take for granted the ability to fall asleep or to snap out of sleep into wakefulness, but these changes in behavioral state require specific switching mechanisms in the brain that allow well-defined state transitions. In this review, we examine the basic circuitry underlying the regulation of sleep and wakefulness and discuss a theoretical framework wherein the interactions between reciprocal neuronal circuits enable relatively rapid and complete state transitions. We also review how homeostatic, circadian, and allostatic drives help regulate sleep state switching and discuss how breakdown of the switching mechanism may contribute to sleep disorders such as narcolepsy.
    Neuron 12/2010; 68(6):1023-42. DOI:10.1016/j.neuron.2010.11.032 · 15.05 Impact Factor
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