Letter | Published:

Neural substrates of awakening probed with optogenetic control of hypocretin neurons

Nature volume 450, pages 420424 (15 November 2007) | Download Citation

Abstract

The neural underpinnings of sleep involve interactions between sleep-promoting areas such as the anterior hypothalamus, and arousal systems located in the posterior hypothalamus, the basal forebrain and the brainstem1,2. Hypocretin3 (Hcrt, also known as orexin4)-producing neurons in the lateral hypothalamus5 are important for arousal stability2, and loss of Hcrt function has been linked to narcolepsy6,7,8,9. However, it is unknown whether electrical activity arising from Hcrt neurons is sufficient to drive awakening from sleep states or is simply correlated with it. Here we directly probed the impact of Hcrt neuron activity on sleep state transitions with in vivo neural photostimulation10,11,12,13,14,15,16,17,18, genetically targeting channelrhodopsin-2 to Hcrt cells and using an optical fibre to deliver light deep in the brain, directly into the lateral hypothalamus, of freely moving mice. We found that direct, selective, optogenetic photostimulation of Hcrt neurons increased the probability of transition to wakefulness from either slow wave sleep or rapid eye movement sleep. Notably, photostimulation using 5–30 Hz light pulse trains reduced latency to wakefulness, whereas 1 Hz trains did not. This study establishes a causal relationship between frequency-dependent activity of a genetically defined neural cell type and a specific mammalian behaviour central to clinical conditions and neurobehavioural physiology.

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Acknowledgements

We thank S. Nishino and N. Fujiki for their technical support in sleep recording (Stanford University SCORE facility), and Y. Xu and C. E. Olin for critical comments. We also thank T. Sakurai and M. Yanagisawa for providing the Hcrt::EGFP transgenic and Hcrt knockout mice. A.R.A. is supported by the Belgian American Educational Foundation and the Fondation Leon Fredericq. F.Z. is supported by a fellowship from the NIH. A.M.A. is supported by the Walter and Idun Berry Foundation. K.D. is supported by NARSAD, APIRE and the Snyder, Culpeper, Coulter, Klingenstein, Whitehall, McKnight and Albert Yu and Mary Bechmann Foundations, as well as by NIMH, NIDA and the NIH Director’s Pioneer Award Program. L.dL. is supported by NIMH and NIDA.

Author Contributions All authors designed the experiments. A.R.A., F.Z. and A.M.A. collected data and performed analysis. All authors discussed the results and contributed to the text.

Author information

Author notes

    • Antoine R. Adamantidis
    •  & Feng Zhang

    These authors contributed equally to this work.

Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Stanford University, 701B Welch Road, Palo Alto, California 94304, USA

    • Antoine R. Adamantidis
    • , Karl Deisseroth
    •  & Luis de Lecea
  2. Department of Bioengineering, Stanford University, James H. Clark Center W083, Stanford, California 94305, USA

    • Feng Zhang
    • , Alexander M. Aravanis
    •  & Karl Deisseroth

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Karl Deisseroth or Luis de Lecea.

Supplementary information

PDF files

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    Supplementary Information 1

    The file contains Supplementary Figures S1-S3 and Supplementary Tables 1-2 with Legends.

Videos

  1. 1.

    Supplementary Information 2

    The file contains Supplementary Video 1 showing recording of a SWS to wake transition after a single light pulse train with simultaneous EEG/EMG recordings (in inset).

  2. 2.

    Supplementary Information 3

    The file contains Supplementary Video 2 showing recording of a REM sleep to wake transition after a single light pulse train with simultaneous EEG/EMG recordings (in inset).

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DOI

https://doi.org/10.1038/nature06310

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