1. Academic Validation
  2. Cannabinoid CB1 receptors in the amygdalar cholecystokinin glutamatergic afferents to nucleus accumbens modulate depressive-like behavior

Cannabinoid CB1 receptors in the amygdalar cholecystokinin glutamatergic afferents to nucleus accumbens modulate depressive-like behavior

  • Nat Med. 2019 Feb;25(2):337-349. doi: 10.1038/s41591-018-0299-9.
Chen-Jie Shen 1 Di Zheng 1 Ke-Xin Li 1 Jian-Ming Yang 1 Hao-Qi Pan 1 Xiao-Dan Yu 1 Jia-Yu Fu 1 Yi Zhu 1 Qi-Xin Sun 1 Meng-Yu Tang 1 Ying Zhang 1 Peng Sun 1 Yi Xie 1 Shumin Duan 1 Hailan Hu 1 Xiao-Ming Li 2
Affiliations

Affiliations

  • 1 Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Joint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Joint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
Abstract

Major depressive disorder is a devastating psychiatric disease that afflicts up to 17% of the world's population. Postmortem brain analyses and imaging studies of patients with depression have implicated basal lateral amygdala (BLA) dysfunction in the pathophysiology of depression. However, the circuit and molecular mechanisms through which BLA neurons modulate depressive behavior are largely uncharacterized. Here, in mice, we identified that BLA cholecystokinin (CCK) glutamatergic neurons mediated negative reinforcement via D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and that chronic social defeat selectively potentiated excitatory transmission of the CCKBLA-D2NAc circuit in susceptible mice via reduction of presynaptic cannabinoid type-1 receptor (CB1R). Knockdown of CB1R in the CCKBLA-D2NAc circuit elevated synaptic activity and promoted stress susceptibility. Notably, selective inhibition of the CCKBLA-D2NAc circuit or administration of synthetic cannabinoids in the NAc was sufficient to produce antidepressant-like effects. Overall, our studies reveal the circuit and molecular mechanisms of depression.

Figures
Products