A parabrachial to hypothalamic pathway mediates defensive behavior

Defensive behaviors are critical for animal's survival. Both the paraventricular nucleus of the hypothalamus (PVN) and the parabrachial nucleus (PBN) have been shown to be involved in defensive behaviors. However, whether there are direct connections between them to mediate defensive behaviors remains unclear. Here, by retrograde and anterograde tracing, we uncover that cholecystokinin (CCK)-expressing neurons in the lateral PBN (LPB^CCK) directly project to the PVN. By in vivo fiber photometry recording, we find that LPB^CCK neurons actively respond to various threat stimuli. Selective photoactivation of LPB^CCK neurons promotes aversion and defensive behaviors. Conversely, photoinhibition of LPB^CCK neurons attenuates rat or looming stimuli-induced flight responses. Optogenetic activation of LPB^CCK axon terminals within the PVN or PVN glutamatergic neurons promotes defensive behaviors. Whereas chemogenetic and pharmacological inhibition of local PVN neurons prevent LPB^CCK-PVN pathway activation-driven flight responses. These data suggest that LPB^CCK neurons recruit downstream PVN neurons to actively engage in flight responses. Our study identifies a previously unrecognized role for the LPB^CCK-PVN pathway in controlling defensive behaviors.