Luppi PH, Clement O, Sapin E, Gervasoni D, Peyron C, Leger L et al. The neuronal network responsible for paradoxical sleep and its dysfunctions causing narcolepsy and rapid eye movement (REM) behavior disorder. Sleep Med Rev 15: 153-163

UMR5167 CNRS, Institut Fédératif des Neurosciences de Lyon (IFR 19), Univ Lyon 1, Université de Lyon, Lyon, France.
Sleep Medicine Reviews (Impact Factor: 8.51). 11/2010; 15(3):153-63. DOI: 10.1016/j.smrv.2010.08.002
Source: PubMed


Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during paradoxical (REM) sleep (PS). Conversely, cataplexy, one of the key symptoms of narcolepsy, is a striking sudden episode of muscle weakness triggered by emotions during wakefulness, and comparable to REM sleep atonia. The neuronal dysfunctions responsible for RBD and cataplexy are not known. In the present review, we present the most recent results on the neuronal network responsible for PS. Based on these results, we propose an updated integrated model of the mechanisms responsible for PS and explore different hypotheses explaining RBD and cataplexy. We propose that RBD is due to a specific degeneration of a sub-population of PS-on glutamatergic neurons specifically responsible of muscle atonia, localized in the caudal pontine sublaterodorsal tegmental nucleus (SLD). Another possibility is the occurrence in RBD patients of a specific lesion of the glycinergic/GABAergic pre-motoneurons localized in the medullary ventral gigantocellular reticular nucleus. Conversely, cataplexy in narcoleptics would be due to the activation during waking of the caudal PS-on SLD neurons responsible for muscle atonia. A phasic glutamatergic excitatory pathway from the central amygdala to the SLD PS-on neurons activated during emotion would induce such activation. In normal conditions, the glutamate excitation would be blocked by the simultaneous excitation by the hypocretins of the PS-off GABAergic neurons localized in the ventrolateral periaqueductal gray and the adjacent deep mesencephalic reticular nucleus, gating the activation of the PS-on SLD neurons.

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Available from: Pierre-Hervé Luppi, Feb 06, 2015
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    • "During SWS, they would contribute to the inhibition of the noradrenergic and adrenergic neurons in conjunction with the SWS-on GABAergic neurons localized in the ventrolateral preoptic area (VLPO) [3], [60] (Figure 7). DPGi GABAergic neurons would be responsible of the inhibition of noradrenergic and adrenergic neurons during PS with a minor contribution of the GABAergic neurons of the ventrolateral periaqueductal gray [2] (Figure 7). Reciprocally, our results showing that clonidine injection in the DPGi specifically inhibit PS suggest that the noradrenergic and adrenergic neurons inhibit DPGi GABAergic neurons by means of alpha-2 adrenergic receptors at the onset of and during waking. "
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    ABSTRACT: GABAergic neurons specifically active during paradoxical sleep (PS) localized in the dorsal paragigantocellular reticular nucleus (DPGi) are known to be responsible for the cessation of activity of the noradrenergic neurons of the locus coeruleus during PS. In the present study, we therefore sought to determine the role of the DPGi in PS onset and maintenance and in the inhibition of the LC noradrenergic neurons during this state. The effect of the inactivation of DPGi neurons on the sleep-waking cycle was examined in rats by microinjection of muscimol, a GABAA agonist, or clonidine, an alpha-2 adrenergic receptor agonist. Combining immunostaining of the different populations of wake-inducing neurons with that of c-FOS, we then determined whether muscimol inhibition of the DPGi specifically induces the activation of the noradrenergic neurons of the LC. Slow wave sleep and PS were abolished during 3 and 5 h after muscimol injection in the DPGi, respectively. The application of clonidine in the DPGi specifically induced a significant decrease in PS quantities and delayed PS appearance compared to NaCl. We further surprisingly found out that more than 75% of the noradrenergic and adrenergic neurons of all adrenergic and noradrenergic cell groups are activated after muscimol treatment in contrast to the other wake active systems significantly less activated. These results suggest that, in addition to its already know inhibition of LC noradrenergic neurons during PS, the DPGi might inhibit the activity of noradrenergic and adrenergic neurons from all groups during PS, but also to a minor extent during SWS and waking.
    PLoS ONE 05/2014; 9(5):e96851. DOI:10.1371/journal.pone.0096851 · 3.23 Impact Factor
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    • "Data from animal models suggest that RBD results from brainstem dysfunction leading to a lack of muscle atonia during REM sleep [9]. Within the brainstem, degeneration of the pontine glutamatergic and medullary GABAergic neurons has been implicated in the pathophysiology of RBD [22]. "
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    ABSTRACT: Rapid eye movement (REM) sleep behavior disorder (RBD) is a sleep disturbance in which patients enact their dreams while in REM sleep. The behavior is typically violent in association with violent dream content, so serious harm can be done to the patient or the bed partner. The prevalence of RBD is well-known in Parkinson's disease, Lewy body dementia, and multiple systems atrophy. However, its prevalence and causes in stroke remained unclear. The aim of this study was to determine factors influencing the appearance of RBD in a prospective cohort of patients with acute ischemic stroke. A total of 2,024 patients with first-ever or recurrent acute ischemic stroke were admitted to the Acute Stroke Unit at the Prince of Wales Hospital between January 2010 and November 2011; 775 of them received an MRI scan. Within 2 days of admission, a research nurse collected demographic and clinical data and assessed the severity of each stroke using the National Institute of Health Stroke Scale (NIHSS). One hundred and nineteen of the 775 patients meeting study entry criteria formed the study sample. All eligible participants were invited to attend a research clinic 3 months after the onset of the index stroke. In the attendance, a research assistant administered the MMSE and the 13-item RBD questionnaire (RBDQ). Among 119 stroke patients, 10.9% were exhibited RBD, defined as an REM sleep behavior disorder questionnaire score of 19 or above. The proportion of patients with acute brainstem infarct was significantly higher in RBD patients than those without RBD. Compared with patients without RBD, RBD patients were more likely to have brainstem infarcts and had smaller infarct volumes. In a multivariate analysis, in which stroke location and infarct volume were inserted, brainstem infarcts were an independent predictor of RBD (odds ratio = 3.686; P = 0.032). The results support the notion of a predominant role of brainstem injury in the development of RBD and suggest that patients with brainstem infarcts RBD should be evaluated by a clinical neurologist.
    BMC Neurology 04/2014; 14(1):88. DOI:10.1186/1471-2377-14-88 · 2.04 Impact Factor
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    • "This region is also known as the subcoeruleus area and is likely to be the homologue of the cat peri-locus coeruleus-α (peri-LCα; Sakai et al. 2001). Considerable evidence suggests that the SLD is both necessary and sufficient for driving muscle atonia during REM sleep (Sakai et al. 2001; Boissard et al. 2002; Lu et al. 2006; Fuller et al. 2007; Luppi et al. 2011; Vetrivelan et al. 2011). "
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    ABSTRACT: Considerable electrophysiological and pharmacological evidence has long suggested an important role for acetylcholine in the regulation of REM sleep. For example, injection of the cholinergic agonist carbachol into the dorsomedial pons produces a 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 electrophysiologic and pharmacologic 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 post-synaptic effects of carbachol on SLDsp neurons. Carbachol acted presynaptically by increasing the frequency of glutamatergic miniature excitatory postsynaptic currents (mEPSCs). We also found that carbachol directly excited SLDsp neurons by activating a Na(+)/Ca(2+) 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 post-synaptic responses on SLDsp neurons that in turn likely serve to promote muscle atonia during REM sleep.
    The Journal of Physiology 12/2013; 592(7). DOI:10.1113/jphysiol.2013.261800 · 5.04 Impact Factor
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