Lateralized vagal oxytocin receptor signaling separately controls feeding and socioemotional functions via hypothalamic oxytocin neurons.

Abstract

Oxytocin neurons in the paraventricular hypothalamus (PVH^Oxt) regulate feeding, anxiety, and social behaviors. Activation of Oxt receptor (Oxtr)-expressing vagal sensory neurons engages these PVH^Oxt neurons and improves hyperphagic obesity; however, their roles in anxiety and sociability remain unclear. Here, we activated vagal Oxtr-expressing neurons in male mice using a single intraperitoneal (IP) Oxt injection or chemogenetics. IP Oxt reduced anxiety-like behavior, enhanced social interaction, and suppressed feeding while activating both vagal sensory neurons and PVH^Oxt neurons. These effects were abolished by chemogenetic inhibition of PVH^Oxt neurons or central Oxtr blockade. Subdiaphragmatic vagotomy revealed lateralized functions: right-side vagotomy eliminated anxiolytic and prosocial effects, whereas left-side vagotomy blocked feeding suppression. Consistently, chemogenetic activation of left-sided neurons suppressed feeding, while right-sided activation reduced anxiety and increased sociability. These findings identify Oxtr-expressing vagal sensory neurons as a major peripheral pathway in which left- and right-sided inputs differentially control feeding and socioemotional behaviors.