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<sup>CCK</sup> 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<sup>PV</sup>), which typically suppress PMd<sup>CCK</sup> activity and escape behaviors. Furthermore, threat memory prompts a prefrontal projection to stimulate the release of endocannabinoids, inhibiting the axon terminals of VTg<sup>PV</sup> 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<sup>PV</sup> neurons. Thus, our study uncovers a neural mechanism by which experience amplifies innate escape behaviors, highlighting the crucial role of endocannabinoids.

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Publication Details

Journal
Nature Communications
Published
2025-05-26
DOI
https://doi.org/10.1038/s41467-025-60080-1
Citations
1
Primary Topic
Cannabis and Cannabinoid Research
Type
article
Field-Weighted Citation Impact
1.39

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article

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

Shuqian Zhang, Nawen Wang, Xiao Huang, Suixin Deng et al.
1 citations
Nature Communications
Cannabis and Cannabinoid Research
1.39
article

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

Shuqian Zhang, Nawen Wang, Xiao Huang, Suixin Deng, Huilin Hong, Renjie Chai, Mu Li, Tian‐Lin Cheng, Weisheng Wang, Zongyi Xu, Ruijie Geng, Huiling Wu, Jiawei Nie, Lei Li, Xinyi Gao, Zhiming Li, Xiaohong Xu, Rongxin Wang, Haibin Li, Yousheng Shu
article en
1 citations

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 (PMd<sup>CCK</sup> 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<sup>PV</sup>), which typically suppress PMd<sup>CCK</sup> activity and escape behaviors. Furthermore, threat memory prompts a prefrontal projection to stimulate the release of endocannabinoids, inhibiting the axon terminals of VTg<sup>PV</sup> 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<sup>PV</sup> neurons. Thus, our study uncovers a neural mechanism by which experience amplifies innate escape behaviors, highlighting the crucial role of endocannabinoids.

Nature CommunicationsVol. 16(1)
Allen Institute for Brain Science (US), Fudan University (CN), Chinese Institute for Brain Research (CN), Zhongshan Hospital (CN), Children's Hospital of Fudan University (CN)
National Natural Science Foundation of China, Fudan University, Zhejiang University
Climate action
Openalex Percentile: Top 20%
Cannabis and Cannabinoid Research
1.39
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