Dorsal premammillary projection to periaqueductal gray controls escape vigor from innate and conditioned threats

• Published in: eLife 2021-09, Vol.10
• Main Authors: Wang, Weisheng, Schuette, Peter J, La-Vu, Mimi Q, Torossian, Anita, Tobias, Brooke C, Ceko, Marta, Kragel, Philip A, Reis, Fernando McV, Ji, Shiyu, Sehgal, Megha, Maesta-Pereira, Sandra, Chakerian, Meghmik, Silva, Alcino J, Canteras, Newton S, Wager, Tor, Kao, Jonathan C, Adhikari, Avishek
• Format: Article
• Language: English
• Subjects: Adult; Animals; Behavior; Behavior, Animal; Brain Mapping; Cholecystokinin; Cholecystokinin - genetics; Cholecystokinin - metabolism; Conditioning, Psychological; Defensive behavior; dorsal premammillary nucleus; escape; Escape Reaction; Fear; Female; Functional magnetic resonance imaging; Humans; Hypothalamus; Hypothalamus, Posterior - diagnostic imaging; Hypothalamus, Posterior - metabolism; Hypothalamus, Posterior - physiology; Magnetic Resonance Imaging; Male; Males; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neural Pathways - physiology; Neuroscience; Optogenetics; panic; periaqueductal gray; Periaqueductal Gray - diagnostic imaging; Periaqueductal Gray - metabolism; Periaqueductal Gray - physiology; Periaqueductal gray area; Photic Stimulation; predator; Rats; Rats, Long-Evans; Threats; Time Factors; Velocity; Vigor; Visual Perception; Young Adult
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.69178

Escape from threats has paramount importance for survival. However, it is unknown if a single circuit controls escape vigor from innate and conditioned threats. Cholecystokinin (cck)-expressing cells in the hypothalamic dorsal premammillary nucleus (PMd) are necessary for initiating escape from innate threats via a projection to the dorsolateral periaqueductal gray (dlPAG). We now show that in mice 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 functional magnetic resonance imaging 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.