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Induction of Anxiety-Like Phenotypes by Knockdown of Cannabinoid Type-1 Receptors in the Amygdala of Marmosets

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Abstract

The amygdala is an important hub for regulating emotions and is involved in the pathophysiology of many mental diseases, such as depression and anxiety. Meanwhile, the endocannabinoid system plays a crucial role in regulating emotions and mainly functions through the cannabinoid type-1 receptor (CB1R), which is strongly expressed in the amygdala of non-human primates (NHPs). However, it remains largely unknown how the CB1Rs in the amygdala of NHPs regulate mental diseases. Here, we investigated the role of CB1R by knocking down the cannabinoid receptor 1 (CNR1) gene encoding CB1R in the amygdala of adult marmosets through regional delivery of AAV-SaCas9-gRNA. We found that CB1R knockdown in the amygdala induced anxiety-like behaviors, including disrupted night sleep, agitated psychomotor activity in new environments, and reduced social desire. Moreover, marmosets with CB1R-knockdown had up-regulated plasma cortisol levels. These results indicate that the knockdown of CB1Rs in the amygdala induces anxiety-like behaviors in marmosets, and this may be the mechanism underlying the regulation of anxiety by CB1Rs in the amygdala of NHPs.

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Acknowledgements

We thank Dr. Zilong Qiu for providing the AAV-SaCas9 vector. We are grateful to Research Assistant Shuangshuang Liu from the Core Facilities of Zhejiang University School of Medicine, as well as Dr. Sanhua Fang and Research Assistant Li Liu from the Core Facilities of Zhejiang University Institute of Neuroscience. This work was supported by the Zhejiang Province Natural Science Foundation of China (LD22H090003), Key-Area Research and Development Program of Guangdong Province (2019B030335001 and 2018B030334001), the National Natural Science Foundation of China (31871070, 82090031, 32071097, 31871056, and 32170991), the Key R&D Program of Zhejiang Province (2020C03009), Fundamental Research Funds for the Central Universities (2021FZZX001-37), and the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-057).

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  1. Lin Zhu, Di Zheng, and Rui Li contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Lin Zhu, Di Zheng, Rui Li, Ruolan Cai, Chenfei Lyu, Hao Sun, Xiaohui Wang, Yu Ding, Guoqiang Jia, Xinjian Li, Lixia Gao & Xiao-Ming Li

  2. NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brian Medicine, Zhejiang University, Hangzhou, 310058, China

    Lin Zhu, Di Zheng, Rui Li, Chen-Jie Shen, Ruolan Cai, Chenfei Lyu, Hao Sun, Xiaohui Wang, Yu Ding, Guoqiang Jia, Xinjian Li, Lixia Gao & Xiao-Ming Li

  3. Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, Hangzhou, 310029, China

    Lin Zhu, Rui Li, Ruolan Cai, Chenfei Lyu, Binliang Tang, Hao Sun, Xiaohui Wang, Bin Xu, Guoqiang Jia, Xinjian Li & Lixia Gao

  4. Center for Brain Science and Brain-Inspired Intelligence, Research Units for Emotion and Emotion Disorders, Chinese Academy of Medical Sciences, China/Guangdong-Hong Kong-Macao Greater Bay Area, Joint Institute for Genetics and Genome Medicine Between Zhejiang University and University of Toronto, Hangzhou, 310058, China

    Xiao-Ming Li

  5. Rehabilitation Medicine Center, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 311399, China

    Binliang Tang

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  1. Lin Zhu
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  2. Di Zheng
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Zhu, L., Zheng, D., Li, R. et al. Induction of Anxiety-Like Phenotypes by Knockdown of Cannabinoid Type-1 Receptors in the Amygdala of Marmosets. Neurosci. Bull. 39, 1669–1682 (2023). https://doi.org/10.1007/s12264-023-01081-2

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