Vasopressin neurons in the paraventricular hypothalamus promote wakefulness via lateral hypothalamic orexin neurons.

The sleep-wakefulness cycle is regulated by complicated neural networks that include many different populations of neurons throughout the brain. Arginine vasopressin neurons in the paraventricular nucleus of the hypothalamus (PVH) regulate various physiological events and behaviors, such as body-fluid homeostasis, blood pressure, stress response, social interaction, and feeding. Changes in arousal level often accompany these PVH-mediated adaptive responses. However, the contribution of PVH neurons to sleep-wakefulness regulation has remained unknown. Here, we report the involvement of PVH neurons in arousal promotion. Optogenetic stimulation of PVH neurons rapidly induced transitions to wakefulness from both NREM and REM sleep. This arousal effect was dependent on AVP expression in these neurons. Similarly, chemogenetic activation of PVH neurons increased wakefulness and reduced NREM and REM sleep, whereas chemogenetic inhibition of these neurons significantly reduced wakefulness and increased NREM sleep. We observed dense projections of PVH neurons in the lateral hypothalamus with potential connections to orexin/hypocretin (LH) neurons. Optogenetic stimulation of PVH neuronal fibers in the LH immediately induced wakefulness, whereas blocking orexin receptors attenuated the arousal effect of PVH neuronal activation drastically. Monosynaptic rabies-virus tracing revealed that PVH neurons receive inputs from multiple brain regions involved in sleep-wakefulness regulation, as well as those involved in stress response and energy metabolism. Moreover, PVH neurons mediated the arousal induced by novelty stress and a melanocortin receptor agonist melanotan-II. Thus, our data suggested that PVH neurons promote wakefulness via LH neurons in the basal sleep-wakefulness and some stressful conditions.