Neural substrates of awakening probed with optogenetic control of hypocretin neurons

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Abstract
A paper published in Nature in April raised the intriguing possibility that optical therapies might be developed to treat neurological disorders. That work, in tissue slices and in C. elegans roundworms, showed that brain cells can be genetically engineered to alter their activity in response to pulses of different colours of light. A follow-up study now shows that behaviour can be modified in a living mammal by similar means. Hypocretin (Hcrt)-producing neurons in the hypothalamus are active during transitions from sleep to waking states. Optical stimulation of mouse Hcrt neurons engineered to respond to light increases the likelihood of transition from sleep to wakefulness, with higher frequencies causing more abrupt awakening. As Hcrt deficiency is linked to narcolepsy, these results may provide insights into sleep disorders. 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.