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

Abstract

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^AVP) 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^AVP-mediated adaptive responses. However, the contribution of PVH^AVP neurons to sleep-wakefulness regulation has remained unknown. Here, we report the involvement of PVH^AVP neurons in arousal promotion. Optogenetic stimulation of PVH^AVP 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^AVP 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^AVP neurons in the lateral hypothalamus with potential connections to orexin/hypocretin (LH^Orx) neurons. Optogenetic stimulation of PVH^AVP neuronal fibers in the LH immediately induced wakefulness, whereas blocking orexin receptors attenuated the arousal effect of PVH^AVP neuronal activation drastically. Monosynaptic rabies-virus tracing revealed that PVH^AVP 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^AVP neurons mediated the arousal induced by novelty stress and a melanocortin receptor agonist melanotan-II. Thus, our data suggested that PVH^AVP neurons promote wakefulness via LH^Orx neurons in the basal sleep-wakefulness and some stressful conditions.

Keywords: DREADD; channelrhodopsin; hypothalamus; melanocortin; mouse; orexin; paraventricular nucleus; sleep-wakefulness; stress; vasopressin.