Nature 450, 420-424 (15 November 2007) | doi:10.1038/nature06310; Received 2 February 2007; Accepted 1 October 2007; Published online 17 October 2007

Neural substrates of awakening probed with optogenetic control of hypocretin neurons

Antoine R. Adamantidis1,3, Feng Zhang2,3, Alexander M. Aravanis2, Karl Deisseroth1,2 & Luis de Lecea1

  1. Department of Psychiatry and Behavioral Sciences, Stanford University, 701B Welch Road, Palo Alto, California 94304, USA
  2. Department of Bioengineering, Stanford University, James H. Clark Center W083, Stanford, California 94305, USA
  3. These authors contributed equally to this work.

Correspondence to: Karl Deisseroth1,2Luis de Lecea1 Correspondence and requests for materials should be addressed to L.dL. (Email: llecea@stanford.edu) or K.D. (Email: deissero@stanford.edu).

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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