Letter | Published:

Control of REM sleep by ventral medulla GABAergic neurons

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

Abstract

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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Acknowledgements

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

Affiliations

  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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Contributions

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.

Extended data

Supplementary information

Videos

  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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DOI

https://doi.org/10.1038/nature14979

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