This study investigates the neural substrates of awakening by optogenetically controlling hypocretin (Hcrt) neurons in the lateral hypothalamus of freely moving mice. The researchers used a lentivirus to genetically target channelrhodopsin-2 (ChR2) to Hcrt neurons and delivered light through an optical fiber to stimulate these neurons. They found that optogenetic stimulation of Hcrt neurons increased the probability of transitioning from slow wave sleep (SWS) or rapid eye movement sleep (REM) to wakefulness. The effect was frequency-dependent, with higher frequencies (5–30 Hz) significantly reducing the latency to wakefulness compared to lower frequencies (1 Hz). This study establishes a causal relationship between the activity of Hcrt neurons and the transition from sleep to wakefulness, a key aspect of arousal and sleep regulation. The researchers also tested the effects of photostimulation on the sleep-wake cycle and found that Hcrt neurons, when activated, significantly reduced the latency to wakefulness from both SWS and REM sleep. The effects were consistent across different frequencies and animals, indicating a robust and specific role of Hcrt neurons in arousal. Additionally, the study showed that the effects of photostimulation were not due to Hcrt release, as blocking Hcrt receptor 1 with an antagonist reduced the effect of photostimulation. However, the effect on wake latency was not completely blocked in Hcrt knockout animals, suggesting that other neurotransmitters may also play a role in arousal. The study demonstrates that optogenetic control of Hcrt neurons can directly influence sleep-wake transitions, providing a causal link between Hcrt neuron activity and arousal. This finding has implications for understanding sleep disorders, such as narcolepsy, which are associated with Hcrt dysfunction. The results highlight the potential of optogenetic technology in probing the neural circuits underlying complex behaviors like sleep.This study investigates the neural substrates of awakening by optogenetically controlling hypocretin (Hcrt) neurons in the lateral hypothalamus of freely moving mice. The researchers used a lentivirus to genetically target channelrhodopsin-2 (ChR2) to Hcrt neurons and delivered light through an optical fiber to stimulate these neurons. They found that optogenetic stimulation of Hcrt neurons increased the probability of transitioning from slow wave sleep (SWS) or rapid eye movement sleep (REM) to wakefulness. The effect was frequency-dependent, with higher frequencies (5–30 Hz) significantly reducing the latency to wakefulness compared to lower frequencies (1 Hz). This study establishes a causal relationship between the activity of Hcrt neurons and the transition from sleep to wakefulness, a key aspect of arousal and sleep regulation. The researchers also tested the effects of photostimulation on the sleep-wake cycle and found that Hcrt neurons, when activated, significantly reduced the latency to wakefulness from both SWS and REM sleep. The effects were consistent across different frequencies and animals, indicating a robust and specific role of Hcrt neurons in arousal. Additionally, the study showed that the effects of photostimulation were not due to Hcrt release, as blocking Hcrt receptor 1 with an antagonist reduced the effect of photostimulation. However, the effect on wake latency was not completely blocked in Hcrt knockout animals, suggesting that other neurotransmitters may also play a role in arousal. The study demonstrates that optogenetic control of Hcrt neurons can directly influence sleep-wake transitions, providing a causal link between Hcrt neuron activity and arousal. This finding has implications for understanding sleep disorders, such as narcolepsy, which are associated with Hcrt dysfunction. The results highlight the potential of optogenetic technology in probing the neural circuits underlying complex behaviors like sleep.