A putative flip–flop switch for control of REM sleep


Rapid eye movement (REM) sleep consists of a dreaming state in which there is activation of the cortical and hippocampal electroencephalogram (EEG), rapid eye movements, and loss of muscle tone. Although REM sleep was discovered more than 50 years ago, the neuronal circuits responsible for switching between REM and non-REM (NREM) sleep remain poorly understood. Here we propose a brainstem flip–flop switch, consisting of mutually inhibitory REM-off and REM-on areas in the mesopontine tegmentum. Each side contains GABA (γ-aminobutyric acid)-ergic neurons that heavily innervate the other. The REM-on area also contains two populations of glutamatergic neurons. One set projects to the basal forebrain and regulates EEG components of REM sleep, whereas the other projects to the medulla and spinal cord and regulates atonia during REM sleep. The mutually inhibitory interactions of the REM-on and REM-off areas may form a flip–flop switch that sharpens state transitions and makes them vulnerable to sudden, unwanted transitions—for example, in narcolepsy.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The ventrolateral periaqueductal grey matter (vlPAG) and the lateral pontine tegmentum (LPT) constitute REM-off areas.
Figure 2: The sublaterodorsal nucleus (SLD) and precoeruleus (PC) area constitute a REM-on region.
Figure 3: The interrelationship of the two halves of the REM switch.
Figure 4: The vSLD is responsible for REM atonia.
Figure 5: PC neurons activate hippocampal theta during REM sleep.


  1. 1

    McCarley, R. W. Mechanisms and models of REM sleep control. Arch. Ital. Biol. 142, 429–467 (2004)

    CAS  PubMed  Google Scholar 

  2. 2

    Kayama, Y., Ohta, M. & Jodo, E. Firing of ‘possibly’ cholinergic neurons in the rat laterodorsal tegmental nucleus during sleep and wakefulness. Brain Res. 569, 210–220 (1992)

    CAS  Article  Google Scholar 

  3. 3

    Steriade, M., Pare, D., Datta, S., Oakson, G. & Curro Dossi, R. Different cellular types in mesopontine cholinergic nuclei related to ponto-geniculo-occipital waves. J. Neurosci. 10, 2560–2579 (1990)

    CAS  Article  Google Scholar 

  4. 4

    Wu, M. F. et al. Activity of dorsal raphe cells across the wake–sleep cycle and during cataplexy in narcoleptic dogs. J. Physiol. (Lond.) 554, 202–215 (2004)

    CAS  Article  Google Scholar 

  5. 5

    Hobson, J. A., McCarley, R. W. & Nelson, J. P. Location and spike-train characteristics of cells in anterodorsal pons having selective decreases in firing rate during desynchronized sleep. J. Neurophysiol. 50, 770–783 (1983)

    CAS  Article  Google Scholar 

  6. 6

    Aston-Jones, G. & Bloom, F. E. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep–waking cycle. J. Neurosci. 1, 876–886 (1981)

    CAS  Article  Google Scholar 

  7. 7

    Kubin, L. Carbachol models of REM sleep: recent developments and new directions. Arch. Ital. Biol. 139, 147–168 (2001)

    ADS  CAS  PubMed  Google Scholar 

  8. 8

    Coleman, C. G., Lydic, R. & Baghdoyan, H. A. M2 muscarinic receptors in pontine reticular formation of C57BL/6J mouse contribute to rapid eye movement sleep generation. Neuroscience 126, 821–830 (2004)

    CAS  Article  Google Scholar 

  9. 9

    Wilson, S. & Argyropoulos, S. Antidepressants and sleep: a qualitative review of the literature. Drugs 65, 927–947 (2005)

    CAS  Article  Google Scholar 

  10. 10

    Jones, B. E., Harper, S. T. & Halaris, A. E. Effects of locus coeruleus lesions upon cerebral monoamine content, sleep–wakefulness states and the response to amphetamine in the cat. Brain Res. 124, 473–496 (1977)

    CAS  Article  Google Scholar 

  11. 11

    Mouret, J. & Coindet, J. Polygraphic evidence against a critical role of the raphe nuclei in sleep in the rat. Brain Res. 186, 273–287 (1980)

    CAS  Article  Google Scholar 

  12. 12

    Shouse, M. N. & Siegel, J. M. Pontine regulation of REM sleep components in cats: integrity of the pedunculopontine tegmentum (PPT) is important for phasic events but unnecessary for atonia during REM sleep. Brain Res. 571, 50–63 (1992)

    CAS  Article  Google Scholar 

  13. 13

    Chemelli, R. M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451 (1999)

    CAS  Article  Google Scholar 

  14. 14

    Lee, M. G., Hassani, O. K. & Jones, B. E. Discharge of identified orexin/hypocretin neurons across the wake–sleep cycle. J. Neurosci. 25, 6716–6720 (2005)

    CAS  Article  Google Scholar 

  15. 15

    Mileykovskiy, B. Y., Kiyashchenko, L. I. & Siegel, J. M. Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46, 787–798 (2005)

    CAS  Article  Google Scholar 

  16. 16

    Thannickal, T. C. et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469–474 (2000)

    CAS  Article  Google Scholar 

  17. 17

    Lu, J. et al. Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep. J. Neurosci. 22, 4568–4576 (2002)

    CAS  Article  Google Scholar 

  18. 18

    Marcus, J. N. et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol. 435, 6–25 (2001)

    CAS  Article  Google Scholar 

  19. 19

    Sastre, J. P., Buda, C., Kitahama, K. & Jouvet, M. Importance of the ventrolateral region of the periaqueductal gray and adjacent tegmentum in the control of paradoxical sleep as studied by muscimol microinjections in the cat. Neuroscience 74, 415–426 (1996)

    CAS  Article  Google Scholar 

  20. 20

    Boissard, R. et al. 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 (2002)

    Article  Google Scholar 

  21. 21

    Sakai, K., Crochet, S. & Onoe, H. Pontine structures and mechanisms involved in the generation of paradoxical (REM) sleep. Arch. Ital. Biol. 139, 93–107 (2001)

    CAS  PubMed  Google Scholar 

  22. 22

    Onoe, H. & Sakai, K. Kainate receptors: a novel mechanism in paradoxical (REM) sleep generation. Neuroreport 6, 353–356 (1995)

    CAS  Article  Google Scholar 

  23. 23

    Boissard, R. et al. Localization of the GABAergic and non-GABAergic neurons projecting to the sublaterodorsal nucleus and potentially gating paradoxical sleep onset. Eur. J. Neurosci. 18, 1627–1639 (2003)

    Article  Google Scholar 

  24. 24

    Saper, C. B., Chou, T. C. & Scammell, T. E. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 24, 726–731 (2001)

    CAS  Article  Google Scholar 

  25. 25

    Saper, C. B., Scammell, T. E. & Lu, J. Hypothalamic regulation of sleep and circadian rhythms. Nature 437, 1257–1263 (2005)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Sastre, J. P. & Jouvet, M. Oneiric behavior in cats. Physiol. Behav. 22, 979–989 (1979)

    CAS  Article  Google Scholar 

  27. 27

    Sanford, L. D. et al. Sleep patterning and behaviour in cats with pontine lesions creating REM without atonia. J. Sleep Res. 3, 233–240 (1994)

    CAS  Article  Google Scholar 

  28. 28

    Plazzi, G. et al. Pontine lesions in idiopathic narcolepsy. Neurology 46, 1250–1254 (1996)

    CAS  Article  Google Scholar 

  29. 29

    Rye, D. B. et al. Medullary and spinal efferents of the pedunculopontine tegmental nucleus and adjacent mesopontine tegmentum in the rat. J. Comp. Neurol. 269, 315–341 (1988)

    CAS  Article  Google Scholar 

  30. 30

    Sastre, J. P., Sakai, K. & Jouvet, M. Are the gigantocellular tegmental field neurons responsible for paradoxical sleep? Brain Res. 229, 147–161 (1981)

    CAS  Article  Google Scholar 

  31. 31

    Alvarez, F. J. et al. Postnatal phenotype and localization of spinal cord V1 derived interneurons. J. Comp. Neurol. 493, 177–192 (2005)

    CAS  Article  Google Scholar 

  32. 32

    Taal, W. & Holstege, J. C. GABA and glycine frequently colocalize in terminals on cat spinal motoneurons. Neuroreport 5, 2225–2228 (1994)

    CAS  Article  Google Scholar 

  33. 33

    Chase, M. H., Soja, P. J. & Morales, F. R. Evidence that glycine mediates the postsynaptic potentials that inhibit lumbar motoneurons during the atonia of active sleep. J. Neurosci. 9, 743–751 (1989)

    CAS  Article  Google Scholar 

  34. 34

    Kapas, L. et al. The effects of immunolesions of nerve growth factor-receptive neurons by 192 IgG–saporin on sleep. Brain Res. 712, 53–59 (1996)

    CAS  Article  Google Scholar 

  35. 35

    Gerashchenko, D., Salin-Pascual, R. & Shiromani, P. J. Effects of hypocretin–saporin injections into the medial septum on sleep and hippocampal theta. Brain Res. 913, 106–115 (2001)

    CAS  Article  Google Scholar 

  36. 36

    Manford, M. & Andermann, F. Complex visual hallucinations. Clinical and neurobiological insights. Brain 21, 1819–1840 (1998)

    Article  Google Scholar 

  37. 37

    Kimura, K. et al. A discrete pontine ischemic lesion could cause REM sleep behavior disorder. Neurology 55, 894–895 (2000)

    CAS  Article  Google Scholar 

  38. 38

    Braak, H. et al. Parkinson's disease: affection of brain stem nuclei controlling premotor and motor neurons of the somatomotor system. Acta Neuropathol. (Berl.) 99, 489–495 (2000)

    CAS  Article  Google Scholar 

  39. 39

    Chou, T. C. et al. Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms. J. Neurosci. 23, 10691–10702 (2003)

    CAS  Article  Google Scholar 

Download references


We thank Q. H. Ha and M. Ha for technical expertise. This work was supported by United States Public Health Service grants.

Author information



Corresponding authors

Correspondence to Jun Lu or Clifford B. Saper.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

The REM flip-flop switch is part of a cascading pair of switches that generate forebrain vs. brainstem-spinal manifestations of REM sleep. (JPG 71 kb)

Supplementary Notes

This file contains text to accompany the above Supplementary Figure and Supplementary Methods. (DOC 45 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lu, J., Sherman, D., Devor, M. et al. A putative flip–flop switch for control of REM sleep. Nature 441, 589–594 (2006). https://doi.org/10.1038/nature04767

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing