Hypothalamic representation of the imminence of predator threat detected by the vomeronasal organ in mice

Animals have the innate ability to select optimal defensive behaviors with appropriate intensity within specific contexts. The vomeronasal organ (VNO) serves as a primary sensory channel for detecting predator cues by relaying signals to the medial hypothalamic nuclei, particularly the ventromedial hypothalamus (VMH), which directly controls defensive behavioral outputs. Here, we demonstrate that cat saliva contains predator cues that signal the imminence of predator threat and modulate the intensity of freezing behavior through the VNO in mice. Cat saliva activates VNO neurons expressing the V2R-A4 subfamily of sensory receptors, and the number of VNO neurons activated in response to saliva correlates with both the freshness of saliva and the intensity of freezing behavior. Moreover, the number of VMH neurons activated by fresh, but not old, saliva positively correlates with the intensity of freezing behavior. Detailed analyses of the spatial distribution of activated neurons, as well as their overlap within the same individual mice, revealed that fresh and old saliva predominantly activate distinct neuronal populations within the VMH. Collectively, this study suggests that there is an accessory olfactory circuit in mice that is specifically tuned to time-sensitive components of cat saliva, which optimizes their defensive behavior to maximize their chance of survival according to the imminence of threat.