Letter | Published:

Control of REM sleep by ventral medulla GABAergic neurons

Nature volume 526, pages 435438 (15 October 2015) | Download Citation


Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with vivid dreams1,2,3. Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation2, and the neural circuits in the pons have since been studied extensively4,5,6,7,8. The medulla also contains neurons that are active during REM sleep9,10,11,12,13, but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic (γ-aminobutyric-acid-releasing) pathway originating from the ventral medulla powerfully promotes REM sleep in mice. Optogenetic activation of ventral medulla GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. Optrode recordings from channelrhodopsin-2-tagged ventral medulla GABAergic neurons showed that they were most active during REM sleep (REMmax), and during wakefulness they were preferentially active during eating and grooming. Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate ventral medulla neuron populations. Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, which are probably mediated in part by inhibition of REM-suppressing GABAergic neurons in the ventrolateral periaqueductal grey. These results identify a key component of the pontomedullary network controlling REM sleep. The capability to induce REM sleep on command may offer a powerful tool for investigating its functions.

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  1. 1.

    & Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science 118, 273–274 (1953)

  2. 2.

    Recherches sur les structures nerveuses et les mécanismes responsables des différentes phases du sommeil physiologique. Arch. Ital. Biol. 100, 125–206 (1962)

  3. 3.

    The occurrence of low voltage, fast, electroencephalogram patterns during behavioral sleep in the cat. Electroencephalogr. Clin. Neurophysiol. 10, 291–296 (1958)

  4. 4.

    , & Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups. Science 189, 55–58 (1975)

  5. 5.

    , , , & 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)

  6. 6.

    , , , & Evidence that neurons of the sublaterodorsal tegmental nucleus triggering paradoxical (REM) sleep are glutamatergic. Sleep 34, 419–423 (2011)

  7. 7.

    , , & A putative flip-flop switch for control of REM sleep. Nature 441, 589–594 (2006)

  8. 8.

    et al. Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep. Proc. Natl Acad. Sci. USA 112, 584–589 (2015)

  9. 9.

    , & Activity of medullary reticular formation neurons in the unrestrained cat during waking and sleep. Brain Res. 179, 49–60 (1979)

  10. 10.

    , & Activités unitaires spécifiques du sommeil paradoxal dans la formation réticulée bulbaire chez le chat non-restreint. C.R. Seances Acad. Sci. D 289, 557–561 (1979)

  11. 11.

    , & c-Fos expression in GABAergic, serotonergic, and other neurons of the pontomedullary reticular formation and raphe after paradoxical sleep deprivation and recovery. J. Neurosci. 20, 4669–4679 (2000)

  12. 12.

    et al. Localization of the brainstem GABAergic neurons controlling paradoxical (REM) sleep. PLoS One 4, e4272 (2009)

  13. 13.

    , , & Role of the lateral paragigantocellular nucleus in the network of paradoxical (REM) sleep: an electrophysiological and anatomical study in the rat. PLoS One 7, e28724 (2012)

  14. 14.

    et al. Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus. Nature Neurosci. 16, 1637–1643 (2013)

  15. 15.

    , , , & Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc. Natl Acad. Sci. USA 104, 5163–5168 (2007)

  16. 16.

    c-Fos as a transcription factor: a stressful (re)view from a functional map. Neurochem. Int. 33, 287–297 (1998)

  17. 17.

    & 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 (1994)

  18. 18.

    , , , & The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network. Science 234, 734–737 (1986)

  19. 19.

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

  20. 20.

    , & Efferent connections of the ventral medulla oblongata in the rat. Brain Res. Rev. 3, 63–80 (1981)

  21. 21.

    & An inhibitory mechanism in the bulbar reticular formation. J. Neurophysiol. 9, 165–171 (1946)

  22. 22.

    & REM sleep without atonia after lesions of the medial medulla. Neurosci. Lett. 98, 159–165 (1989)

  23. 23.

    , , & Carbachol microinjections in the mediodorsal pontine tegmentum are unable to induce paradoxical sleep after caudal pontine and prebulbar transections in the cat. Neurosci. Lett. 130, 41–45 (1991)

  24. 24.

    , & Modification of paradoxical sleep following transections of the reticular formation at the pontomedullary junction. Sleep 9, 1–23 (1986)

  25. 25.

    , & Inactivation of the pons blocks medullary-induced muscle tone suppression in the decerebrate cat. Sleep 21, 695–699 (1998)

  26. 26.

    , & Rostral brainstem contributes to medullary inhibition of muscle tone. Brain Res. 268, 344–348 (1983)

  27. 27.

    et al. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nature Neurosci. 13, 1526–1533 (2010)

  28. 28.

    , & Norepinephrine effects on spinal motoneurons. Prog. Brain Res. 88, 343–350 (1991)

  29. 29.

    , & GABAergic neurons in prepositus hypoglossi regulate REM sleep by its action on locus coeruleus in freely moving rats. Synapse 42, 141–150 (2001)

  30. 30.

    , & The role of hypocretins (orexins) in sleep regulation and narcolepsy. Annu. Rev. Neurosci. 25, 283–313 (2002)

  31. 31.

    & The Mouse Brain in Stereotaxic Coordinates 3rd edn, 88 (Academic Press, 2007)

  32. 32.

    et al. Dissecting local circuits: parvalbumin interneurons underlie broad feedback control of olfactory bulb output. Neuron 80, 1232–1245 (2013)

  33. 33.

    et al. Optetrode: a multichannel readout for optogenetic control in freely moving mice. Nature Neurosci. 15, 163–170 (2012)

  34. 34.

    , , , & Quantitative measures of cluster quality for use in extracellular recordings. Neuroscience 131, 1–11 (2005)

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We thank A. Popescu for the help with in vivo physiology, M. Bikov and S. Chung for technical assistance, the University of North Carolina Virus Core for supplying AAV, and T. Kilduff and J. Cox for discussions. This work was supported by EMBO and Human Frontier Science Program postdoctoral fellowships (to F.W.).

Author information


  1. Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA

    • Franz Weber
    • , Shinjae Chung
    • , Min Xu
    •  & Yang Dan
  2. Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA

    • Kevin T. Beier
    •  & Liqun Luo


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F.W. and Y.D. conceived and designed the experiments. F.W. performed all optogenetic stimulation experiments and optrode recordings. S.C. performed a subset of pharmacogenetic experiments and fluorescence microscopy. K.T.B. and L.L. provided viral reagents for rabies-mediated trans-synaptic experiments. M.X. designed the optrodes used in this study. F.W. and Y.D. wrote the manuscript, and all authors participated in the revision of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yang Dan.

All primary histological, electrophysiological, and behavioural data have been archived in the Department of Molecular and Cell Biology, University of California, Berkeley.

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  1. 1.

    Optogenetic activation of vM GABAergic neurons induces REM sleep

    The video shows 3 laser stimulation trials, including 1 min before and after each laser stimulation period. In the first two trials the animal was in NREM sleep at laser onset, and he was awake in the third trial. The EEG spectrogram, EMG amplitude and hypnogram are shown on the right. Laser stimulation periods are depicted by the blue shading on the top right and additionally indicated as a blue square in the upper right corner of the movie frame; 10x speedup.

  2. 2.

    Firing rates of an identified vM GABAergic neuron during sleep and wakeful behaviors

    The video shows two recording periods of an identified unit. During the first period the animal was asleep, during the second period he was awake and engaged in multiple behaviors (ET – eating, GR – grooming, MV – moving, RU – running, QA – quiet awake). EEG spectrogram, EMG amplitude, hypnogram and firing rate are shown on the right. The time points of single spikes are represented as vertical lines on the bottom left. Laser stimulation periods (15 or 30 Hz) are shown as blue shadings along with the firing rate and are indicated by a blue square within the movie frame; 10x speedup.

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