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

Ruikai Chai, Nawen Wang, Jinlu Nie, Zongyi Xu, Shuqian Zhang, Suixin Deng, Rongxin Wang, Mu Li, Xinyi Gao, Ruijie Geng, Haibin Li, Lei Li, Hebi Wu, Zhiming Li, Tian-Lin Cheng, Xiao-Hong Xu, Yousheng Shu (), Huilin Hong (), Xiao Huang () and Weisheng Wang ()
Additional contact information
Ruikai Chai: Fudan University
Nawen Wang: Fudan University
Jinlu Nie: Fudan University
Zongyi Xu: Fudan University
Shuqian Zhang: Fudan University
Suixin Deng: Fudan University
Rongxin Wang: Fudan University
Mu Li: Fudan University
Xinyi Gao: Fudan University
Ruijie Geng: Fudan University
Haibin Li: Fudan University
Lei Li: Fudan University
Hebi Wu: Fudan University
Zhiming Li: Fudan University
Tian-Lin Cheng: Fudan University
Xiao-Hong Xu: Fudan University
Yousheng Shu: Fudan University
Huilin Hong: Fudan University
Xiao Huang: Fudan University
Weisheng Wang: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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 (PMdCCK 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 (VTgPV), which typically suppress PMdCCK activity and escape behaviors. Furthermore, threat memory prompts a prefrontal projection to stimulate the release of endocannabinoids, inhibiting the axon terminals of VTgPV 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 VTgPV neurons. Thus, our study uncovers a neural mechanism by which experience amplifies innate escape behaviors, highlighting the crucial role of endocannabinoids.

Date: 2025
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DOI: 10.1038/s41467-025-60080-1

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