This study investigates the neural substrates of awakening by optogenetically controlling hypocretin (Hcrt) neurons in freely moving mice. Hcrt neurons, which are crucial for arousal stability, were genetically targeted with channelrhodopsin-2 (ChR2) using a lentivirus. The authors found that optogenetic stimulation of Hcrt neurons at frequencies between 5 and 30 Hz significantly reduced the latency to wakefulness from slow wave sleep (SWS) or rapid eye movement sleep (REM sleep), compared to 1 Hz stimulation, which did not show a significant effect. This suggests a frequency-dependent causal relationship between Hcrt neuron activity and sleep-to-wake transitions. The study also demonstrates that the behavioral effects of Hcrt neuron stimulation are mediated by hypocretin receptor 1 (Hert1) and are not fully blocked in hypocretin knockout mice, indicating the involvement of other neurotransmitters. These findings provide insights into the neural mechanisms underlying sleep and arousal, and open up possibilities for exploring similar mechanisms in other neuropsychiatric disorders.This study investigates the neural substrates of awakening by optogenetically controlling hypocretin (Hcrt) neurons in freely moving mice. Hcrt neurons, which are crucial for arousal stability, were genetically targeted with channelrhodopsin-2 (ChR2) using a lentivirus. The authors found that optogenetic stimulation of Hcrt neurons at frequencies between 5 and 30 Hz significantly reduced the latency to wakefulness from slow wave sleep (SWS) or rapid eye movement sleep (REM sleep), compared to 1 Hz stimulation, which did not show a significant effect. This suggests a frequency-dependent causal relationship between Hcrt neuron activity and sleep-to-wake transitions. The study also demonstrates that the behavioral effects of Hcrt neuron stimulation are mediated by hypocretin receptor 1 (Hert1) and are not fully blocked in hypocretin knockout mice, indicating the involvement of other neurotransmitters. These findings provide insights into the neural mechanisms underlying sleep and arousal, and open up possibilities for exploring similar mechanisms in other neuropsychiatric disorders.