Hypothalamic Control of Learned Flight Induced by Threat Imminence

Flexible experience-dependent learned escape has paramount survival value. However, flight is generally investigated in the presence of innate threats. To study conditioned escape, we developed a paradigm in which mice learn to escape a moving shock grid, which simulates a naturalistic situation of being chased by a threat. In a single session, mice learn to escape from the shock-delivering moving grid, displaying a "flight upon grid approach" (FUGA). Importantly, this learned flight is also displayed the next day during fear retrieval, in the absence of shock. We reasoned that circuits implicated in escape and learned fear control this behavior. Fittingly, cholecystokinin (cck)-expressing cells in the hypothalamic dorsal premammillary nucleus (PMd-cck neurons) are necessary for escape from innate threats, and PMd activity modulates learned defense, suggesting it may participate in the maintenance of learned FUGA escapes. Here, we show in male and female mice that inhibiting PMd-cck activity during FUGA acquisition impairs learned flight during fear retrieval. Furthermore, these results were specific to a paradigm with a moving threat, as PMd-cck inhibition during fear acquisition did not alter behavior during fear retrieval in contextual or auditory-cued fear conditioning. Lastly, PMd-cck cells encoded distance to the moving grid and FUGA escape speed, but were not activated by fear-conditioned tones or conditioned freezing. These data show that the PMd is critical for the maintenance of the memory of the threat associated with the grid and underscore recent views demonstrating that the hypothalamus has key contributions for learning flexible experience-dependent survival actions.