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From bench to bed: putative animal models of REM sleep behavior disorder (RBD)

  • Neurology and Preclinical Neurological Studies - Review Article
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Abstract

REM behavior disorder (RBD) is a parasomnia characterized by REM sleep without atonia, leading to abnormal and potentially injurious behavior during REM sleep. It is considered one of the most specific predictors of neurodegenerative disorders, such as Parkinson’s disease. In this paper, we provide an overview of animal models contributing to our current understanding of REM-associated atonia, and, as a consequence, the pathophysiology of RBD. The generator of REM-associated atonia is located in glutamatergic neurons of the pontine sublaterodorsal nucleus (SLD), as shown in cats, rats and mice. These findings are supported by clinical cases of patients with lesions of the homologous structure in humans. Glutamatergic SLD neurons, presumably in conjunction with others, project to (a) the ventromedial medulla, where they either directly target inhibitory interneurons to alpha motor neurons or are relayed, and (b) the spinal cord directly. At the spinal level, alpha motor neurons are inhibited by GABAergic and glycinergic interneurons. Our current understanding is that lesions of the glutamatergic SLD are the key factor for REM sleep behavior disorder. However, open questions remain, e.g. other features of RBD (such as the typically aggressive dream content) or the frequent progression from idiopathic RBD to neurodegenerative disorders, to name only a few. In order to elucidate these questions, a constant interaction between basic and clinical researchers is required, which might, ultimately, create an early therapeutic window for neurodegenerative disorders.

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References

  • American Academy of Sleep Medicine (2005) The international classification of sleep disorders: diagnostic and coding manual, Westchester Ill. American Academy of Sleep Medicine

  • Aurora RN, Zak RS, Maganti RK, Auerbach SH, Casey KR, Chowdhuri S, Karippot A, Ramar K, Kristo DA, Morgenthaler TI (2010) Best practice guide for the treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med 6:85–95

    PubMed  Google Scholar 

  • Boeve BF (2010) REM sleep behavior disorder: updated review of the core features, the REM sleep behavior disorder–neurodegenerative disease association, evolving concepts, controversies, and future directions. Ann N Y Acad Sci 1184:15–54

    Article  PubMed  CAS  Google Scholar 

  • Boeve BF, Silber MH, Saper CB, Ferman TJ, Dickson DW, Parisi JE, Benarroch EE, Ahlskog JE, Smith GE, Caselli RC, Tippman-Peikert M, Olson EJ, Lin SC, Young T, Wszolek Z, Schenck CH, Mahowald MW, Castillo PR, del Tredici K, Braak H (2007) Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 130:2770–2788

    Article  PubMed  CAS  Google Scholar 

  • Boissard R, Gervasoni D, Schmidt MH, Barbagli B, Fort P, Luppi PH (2002) The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study. Eur J Neurosci 16:1959–1973

    Article  PubMed  Google Scholar 

  • Braak H, Ghebremedhin E, Rub U, Bratzke H, del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134

    Article  PubMed  Google Scholar 

  • Brooks PL, Peever JH (2011) Impaired GABA and glycine transmission triggers cardinal features of rapid eye movement sleep behavior disorder in mice. J Neurosci 31:7111–7121

    Article  PubMed  CAS  Google Scholar 

  • Brooks PL, Peever JH (2012) Identification of the transmitter and receptor mechanisms responsible for REM sleep paralysis. J Neurosci 32:9785–9795

    Article  PubMed  CAS  Google Scholar 

  • Chase MH (2008) Confirmation of the consensus that glycinergic postsynaptic inhibition is responsible for the atonia of REM sleep. Sleep 31:1487–1491

    PubMed  Google Scholar 

  • Chase MH, Morales FR (1990) The atonia and myoclonia of active (REM) sleep. Annu Rev Psychol 41:557–584

    Article  PubMed  CAS  Google Scholar 

  • Chase MH, Soja PJ, Morales FR (1989) Evidence that glycine mediates the postsynaptic potentials that inhibit lumbar motoneurons during the atonia of active sleep. J Neurosci 9:743–751

    PubMed  CAS  Google Scholar 

  • Clement O, Sapin E, Berod A, Fort P, Luppi PH (2011) Evidence that neurons of the sublaterodorsal tegmental nucleus triggering paradoxical (REM) sleep are glutamatergic. Sleep 34:419–423

    PubMed  Google Scholar 

  • Culebras A, Moore JT (1989) Magnetic resonance findings in REM sleep behavior disorder. Neurology 39:1519–1523

    Article  PubMed  CAS  Google Scholar 

  • Dauvilliers Y, Rompre S, Gagnon JF, Vendette M, Petit D, Montplaisir J (2007) REM sleep characteristics in narcolepsy and REM sleep behavior disorder. Sleep 30:844–849

    PubMed  Google Scholar 

  • Fort P, Bassetti CL, Luppi PH (2009) Alternating vigilance states: new insights regarding neuronal networks and mechanisms. Eur J Neurosci 29:1741–1753

    Article  PubMed  CAS  Google Scholar 

  • Gagnon JF, Postuma RB, Montplaisir J (2006) Update on the pharmacology of REM sleep behavior disorder. Neurology 67:742–747

    Article  PubMed  Google Scholar 

  • Hajnik T, Lai YY, Siegel JM (2000) Atonia-related regions in the rodent pons and medulla. J Neurophysiol 84:1942–1948

    PubMed  CAS  Google Scholar 

  • Hassani OK, Lee MG, Henny P, Jones BE (2009) Discharge profiles of identified GABAergic in comparison to cholinergic and putative glutamatergic basal forebrain neurons across the sleep-wake cycle. J Neurosci 29:11828–11840

    Article  PubMed  CAS  Google Scholar 

  • Hassani OK, Henny P, Lee MG, Jones BE (2010) GABAergic neurons intermingled with orexin and MCH neurons in the lateral hypothalamus discharge maximally during sleep. Eur J Neurosci 32:448–457

    Article  PubMed  Google Scholar 

  • Henley K, Morrison AR (1974) A re-evaluation of the effects of lesions of the pontine tegmentum and locus coeruleus on phenomena of paradoxical sleep in the cat. Acta Neurobiol Exp (Wars) 34:215–232

    CAS  Google Scholar 

  • Holmes CJ, Jones BE (1994) Importance of cholinergic, GABAergic, serotonergic and other neurons in the medial medullary reticular formation for sleep–wake states studied by cytotoxic lesions in the cat. Neuroscience 62:1179–1200

    Article  PubMed  CAS  Google Scholar 

  • Holstege JC, Bongers CM (1991) A glycinergic projection from the ventromedial lower brainstem to spinal motoneurons. An ultrastructural double labeling study in rat. Brain Res 566:308–315

    Article  PubMed  CAS  Google Scholar 

  • Iranzo A, Aparicio J (2009) A lesson from anatomy: focal brain lesions causing REM sleep behavior disorder. Sleep Med 10:9–12

    Article  PubMed  Google Scholar 

  • Jouvet M (1965) Paradoxical sleep—a study of its nature and mechanisms. Prog Brain Res 18:20–62

    Article  PubMed  CAS  Google Scholar 

  • Ju YE, Larson-Prior L, Duntley S (2012) RBD and antidepressants. Sleep Med 13:211–212

    Article  PubMed  Google Scholar 

  • Kimura K, Tachibana N, Kohyama J, Otsuka Y, Fukazawa S, Waki R (2000) A discrete pontine ischemic lesion could cause REM sleep behavior disorder. Neurology 55:894–895

    Article  PubMed  CAS  Google Scholar 

  • Kodama Y, Iwase S, Mano T, Cui J, Kitazawa H, Okada H, Takeuchi S, Sobue G (1998) Attenuation of regional differentiation of sympathetic nerve activity during sleep in humans. J Auton Nerv Syst 74:126–133

    Article  PubMed  CAS  Google Scholar 

  • Kodama T, Lai YY, Siegel JM (2003) Changes in inhibitory amino acid release linked to pontine-induced atonia: an in vivo microdialysis study. J Neurosci 23:1548–1554

    PubMed  CAS  Google Scholar 

  • Kohlmeier KA, Lopez-Rodriguez F, Liu RH, Morales FR, Chase MH (1996) State-dependent phenomena in cat masseter motoneurons. Brain Res 722:30–38

    Article  PubMed  CAS  Google Scholar 

  • Krenzer M, Anaclet C, Vetrivelan R, Wang N, Vong L, Lowell BB, Fuller PM, Lu J (2011) Brainstem and spinal cord circuitry regulating REM sleep and muscle atonia. PLoS ONE 6:e24998

    Article  PubMed  CAS  Google Scholar 

  • Lai YY, Siegel JM (1988) Medullary regions mediating atonia. J Neurosci 8:4790–4796

    PubMed  CAS  Google Scholar 

  • Lai YY, Siegel JM (1991) Pontomedullary glutamate receptors mediating locomotion and muscle tone suppression. J Neurosci 11:2931–2937

    PubMed  CAS  Google Scholar 

  • Lai YY, Siegel JM (2003) Physiological and anatomical link between Parkinson-like disease and REM sleep behavior disorder. Mol Neurobiol 27(2):137–152

    Article  PubMed  CAS  Google Scholar 

  • Lai YY, Clements JR, Wu XY, Shalita T, Wu JP, Kuo JS, Siegel JM (1999) Brainstem projections to the ventromedial medulla in cat: retrograde transport horseradish peroxidase and immunohistochemical studies. J Comp Neurol 408:419–436

    Article  PubMed  CAS  Google Scholar 

  • Lai YY, Kodama T, Siegel JM (2001) Changes in monoamine release in the ventral horn and hypoglossal nucleus linked to pontine inhibition of muscle tone: an in vivo microdialysis study. J Neurosci 21:7384–7391

    PubMed  CAS  Google Scholar 

  • Lai YY, Hsieh KC, Nguyen D, Peever J, Siegel JM (2008) Neurotoxic lesions at the ventral mesopontine junction change sleep time and muscle activity during sleep: an animal model of motor disorders in sleep. Neuroscience 154:431–443

    Article  PubMed  CAS  Google Scholar 

  • Limousin N, Dehais C, Gout O, Heran F, Oudiette D, Arnulf I (2009) A brainstem inflammatory lesion causing REM sleep behavior disorder and sleepwalking (parasomnia overlap disorder). Sleep Med 10:1059–1062

    Article  PubMed  Google Scholar 

  • Lu J, Sherman D, Devor M, Saper CB (2006) A putative flip-flop switch for control of REM sleep. Nature 441:589–594

    Article  PubMed  CAS  Google Scholar 

  • Luppi PH, Gervasoni D, Verret L, Goutagny R, Peyron C, Salvert D, Leger L, Fort P (2006) Paradoxical (REM) sleep genesis: the switch from an aminergic–cholinergic to a GABAergic–glutamatergic hypothesis. J Physiol Paris 100:271–283

    Article  PubMed  CAS  Google Scholar 

  • Luppi PH, Clement O, Sapin E, Gervasoni D, Peyron C, Leger L, Salvert D, Fort P (2011) 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

    Article  PubMed  Google Scholar 

  • Mathis J, Hess CW, Bassetti C (2007) Isolated mediotegmental lesion causing narcolepsy and rapid eye movement sleep behaviour disorder: a case evidencing a common pathway in narcolepsy and rapid eye movement sleep behaviour disorder. J Neurol Neurosurg Psychiatry 78:427–429

    Article  PubMed  CAS  Google Scholar 

  • Mileykovskiy BY, Kiyashchenko LI, Siegel JM (2002) Muscle tone facilitation and inhibition after orexin-a (hypocretin-1) microinjections into the medial medulla. J Neurophysiol 87:2480–2489

    PubMed  CAS  Google Scholar 

  • Morales FR, Sampogna S, Rampon C, Luppi PH, Chase MH (2006) Brainstem glycinergic neurons and their activation during active (rapid eye movement) sleep in the cat. Neuroscience 142:37–47

    Article  PubMed  CAS  Google Scholar 

  • Peever J (2011) Control of motoneuron function and muscle tone during REM sleep, REM sleep behavior disorder and cataplexy/narcolepsy. Arch Ital Biol 149:454–466

    PubMed  CAS  Google Scholar 

  • Postuma RB, Lang AE, Gagnon JF, Pelletier A, Montplaisir JY (2012) How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder. Brain 135:1860–1870

    Article  PubMed  CAS  Google Scholar 

  • Provini F, Vetrugno R, Pastorelli F, Lombardi C, Plazzi G, Marliani AF, Lugaresi E, Montagna P (2004) Status dissociatus after surgery for tegmental ponto-mesencephalic cavernoma: a state-dependent disorder of motor control during sleep. Mov Disord 19:719–723

    Article  PubMed  Google Scholar 

  • Sakai K, Sastre JP, Salvert D, Touret M, Tohyama M, Jouvet M (1979) Tegmentoreticular projections with special reference to the muscular atonia during paradoxical sleep in the cat: an HRP study. Brain Res 176:233–254

    Article  PubMed  CAS  Google Scholar 

  • Sapin E, Lapray D, Berod A, Goutagny R, Leger L, Ravassard P, Clement O, Hanriot L, Fort P, Luppi PH (2009) Localization of the brainstem GABAergic neurons controlling paradoxical (REM) sleep. PLoS One 4:e4272

    Article  PubMed  Google Scholar 

  • Sastre JP, Sakai K, Jouvet M (1981) Are the gigantocellular tegmental field neurons responsible for paradoxical sleep? Brain Res 229:147–161

    Article  PubMed  CAS  Google Scholar 

  • Schenck CH, Mahowald MW (1992) Motor dyscontrol in narcolepsy: rapid-eye-movement (REM) sleep without atonia and REM sleep behavior disorder. Ann Neurol 32:3–10

    Article  PubMed  CAS  Google Scholar 

  • Schenck CH, Bundlie SR, Ettinger MG, Mahowald MW (1986) Chronic behavioral disorders of human REM sleep: a new category of parasomnia. Sleep 9:293–308

    PubMed  CAS  Google Scholar 

  • Schenkel E, Siegel JM (1989) REM sleep without atonia after lesions of the medial medulla. Neurosci Lett 98:159–165

    Article  PubMed  CAS  Google Scholar 

  • Scherfler C, Frauscher B, Schocke M, Iranzo A, Gschliesser V, Seppi K, Santamaria J, Tolosa E, Hogl B, Poewe W (2011) White and gray matter abnormalities in idiopathic rapid eye movement sleep behavior disorder: a diffusion-tensor imaging and voxel-based morphometry study. Ann Neurol 69:400–407

    Article  PubMed  Google Scholar 

  • Soja PJ, Lopez-Rodriguez F, Morales FR, Chase MH (1991) The postsynaptic inhibitory control of lumbar motoneurons during the atonia of active sleep: effect of strychnine on motoneuron properties. J Neurosci 11:2804–2811

    PubMed  CAS  Google Scholar 

  • Taepavarapruk N, Taepavarapruk P, John J, Lai YY, Siegel JM, Phillips AG, McErlane SA, Soja PJ (2008) State-dependent changes in glutamate, glycine, GABA, and dopamine levels in cat lumbar spinal cord. J Neurophysiol 100:598–608

    Article  PubMed  CAS  Google Scholar 

  • Tippmann-Peikert M, Boeve BF, Keegan BM (2006) REM sleep behavior disorder initiated by acute brainstem multiple sclerosis. Neurology 66:1277–1279

    Article  PubMed  Google Scholar 

  • Unger MM, Belke M, Menzler K, Heverhagen JT, Keil B, Stiasny-Kolster K, Rosenow F, Diederich NJ, Mayer G, Moller JC, Oertel WH, Knake S (2010) Diffusion tensor imaging in idiopathic REM sleep behavior disorder reveals microstructural changes in the brainstem, substantia nigra, olfactory region, and other brain regions. Sleep 33:767–773

    PubMed  Google Scholar 

  • Verhave PS, Jongsma MJ, van den Berg RM, Vis JC, Vanwersch RA, Smit AB, van Someren EJ, Philippens IH (2011) REM sleep behavior disorder in the marmoset MPTP model of early Parkinson disease. Sleep 34:1119–1125

    PubMed  Google Scholar 

  • Vetrivelan R, Fuller PM, Tong Q, Lu J (2009) Medullary circuitry regulating rapid eye movement sleep and motor atonia. J Neurosci 29:9361–9369

    Article  PubMed  CAS  Google Scholar 

  • Webster HH, Jones BE (1988) Neurotoxic lesions of the dorsolateral pontomesencephalic tegmentum-cholinergic cell area in the cat. II. Effects upon sleep-waking states. Brain Res 458:285–302

    Article  PubMed  CAS  Google Scholar 

  • Willie JT, Sinton CM, Maratos-Flier E, Yanagisawa M (2008) Abnormal response of melanin-concentrating hormone deficient mice to fasting: hyperactivity and rapid eye movement sleep suppression. Neuroscience 156:819–829

    Article  PubMed  CAS  Google Scholar 

  • Xi Z, Luning W (2009) REM sleep behavior disorder in a patient with pontine stroke. Sleep Med 10:143–146

    Article  PubMed  Google Scholar 

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The authors declare that they have no conflict of interest with regard to this paper.

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Correspondence to Martina Krenzer.

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Krenzer, M., Lu, J., Mayer, G. et al. From bench to bed: putative animal models of REM sleep behavior disorder (RBD). J Neural Transm 120, 683–688 (2013). https://doi.org/10.1007/s00702-012-0965-x

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  • DOI: https://doi.org/10.1007/s00702-012-0965-x

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