UCLA

Naturalistic escape requires versatile context-specific flight with rapid evaluation of local geometry to identify and use efficient escape routes. It is unknown how spatial navigation and escape circuits are recruited to produce context-specific flight. Using mice, we show activity in cholecystokinin-expressing hypothalamic dorsal premammillary cells (PMd-cck) is sufficient and necessary for context-specific escape that adapts to each environment’s layout. Contrastingly, numerous other nuclei implicated in flight only induced stereotyped panic-related escape. We reasoned the PMd can induce context-specific escape because it projects to both escape and spatial navigation nuclei. Indeed, activity in PMd-cck projections to thalamic spatial navigation circuits are only necessary for context-specific escape induced by moderate threats, but not panic-related stereotyped escape caused by perceived asphyxiation. Conversely, the PMd projection to the escape-inducing dorsal periaqueductal gray projection is necessary for all escapes tested. Thus, PMd-cck controls versatile flight, engaging spatial navigation and escape circuits.

It is additionally unknown if a single circuit controls escape vigor from innate and conditioned threats. We further demonstrate that PMd-cck cells are activated during escape, but not other defensive behaviors. PMd-cck ensemble activity can also predict future escape. Furthermore, PMd inhibition decreases escape speed from both innate and conditioned threats. Inhibition of the PMd-cck projection to the dlPAG also decreased escape speed. Intriguingly, PMd- cck and dlPAG activity in mice showed higher mutual information during exposure to innate and conditioned threats. In parallel, human fMRI data show that a posterior hypothalamic-to-dlPAG pathway increased activity during exposure to aversive images, indicating that a similar pathway may possibly have a related role in humans. Our data identify the PMd-dlPAG circuit as a central node, controlling escape vigor elicited by both innate and conditioned threats.