Induction of Anxiety-Like Phenotypes by Knockdown of Cannabinoid Type-1 Receptors in the Amygdala of Marmosets
Lin Zhu1,2,3 · Di Zheng1,2 · Rui Li1,2,3 · Chen‑Jie Shen2 · Ruolan Cai1,2,3 · Chenfei Lyu1,2,3 · Binliang Tang3,5 · Hao Sun1,2,3 · Xiaohui Wang1,2,3 · Yu Ding1,2 · Bin Xu3 · Guoqiang Jia1,2,3 · Xinjian Li1,2,3 · Lixia Gao1,2,3 · Xiao‑Ming Li1,2,41 Department of Neurobiology and Department of Neurology of Second Afliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
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
3 Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, Hangzhou 310029, China
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
5 Rehabilitation Medicine Center, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People’s Hospital, Afliated People’s Hospital, Hangzhou Medical College, Hangzhou 311399, China
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.
Keywords
Cannabinoid type-1 receptor; Amygdala; Marmoset; Anxiety; CRISPR/Cas9
