Endocannabinoids disinhibit the ventral tegmental nucleus of Gudden to dorsal premammillary nucleus pathway to enhance escape behavior following learned threat experience.

Innate escape behaviors, while not requiring prior learning, are shaped by an animal's learned experiences, such as previous exposure. Here, we found that learned threat experience in mice enhances flight behaviors, which is linked to increased activation of cholecystokinin-expressing neurons in the dorsal premammillary nucleus (PMd(CCK) neurons), a population that controls circa-strike escape responses. This heightened activity coincides with reduced inhibition from parvalbumin-expressing GABAergic neurons in the ventral tegmental nucleus of Gudden (VTg(PV)), which typically suppress PMd(CCK) activity and escape behaviors. Furthermore, threat memory prompts a prefrontal projection to stimulate the release of endocannabinoids, inhibiting the axon terminals of VTg(PV) neurons. The necessity of this endocannabinoid-mediated disinhibition for the observed enhancement in flight behaviors is confirmed through genetic deletion or pharmacological blockade of endocannabinoid receptors on VTg(PV) neurons. Thus, our study uncovers a neural mechanism by which experience amplifies innate escape behaviors, highlighting the crucial role of endocannabinoids.