Cre-on or Cre-out optogenetic viruses were used to activate CCK
BLA-NAcc and non-CCK
BLA-NAcc glutamatergic neurons. Rabies virus was used for monosynaptic viral tracing. hM3Dq-mCherry and hM4Di-mCherry were used for chemogenetic manipulation.
The viruses used in this article are in the table below
Optogenetic |
AAV2/9-CaMKIIα-Cre-on-ChR2(H134R)-mCherry
AAV2/9-CaMKIIα-Cre-on-Arch3.0-eYFP
AAV2/9-CaMKIIα-Cre-on-oCHIEF-mCherry
AAV2/9-CaMKIIα-Cre-out-ChR2(H134R)-eYFP
AAV2/9-CaMKIIα-Cre-out-Arch3.0-eYFP |
Chemogenetics |
AAV2/9-CaMKIIα-Cre-on-hM3Dq-mCherry
AAV2/9-CaMKIIα-Cre-on-hM4Di-mCherry |
Custom-Made AAVs |
AAV8-CaMKIIα-Cre-on-miR30-shCB1R-eGFP |
Tracing Helper |
AAV-CAG-DIO-TVA-eGFP
AAV-CAG-DIO-RG |
RV |
RV-EvnA-DsRed |
Chen-Jie Shen, Di Zheng, Ke-Xin Li, Jian-Ming Yang, Hao-Qi Pan, Xiao-Dan Yu, Jia-Yu Fu, Yi Zhu, Qi-Xin Sun, Meng-Yu Tang, Ying Zhang, Peng Sun, Yi Xie, Shumin Duan, Hailan Hu and Xiao-Ming Li
Pub Date: 2019-01-14,
DOI: 10.1038/s41591-018-0299-9,
Email: [email protected]
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 CCK
BLA–D2
NAc circuit in susceptible mice via reduction of presynaptic cannabinoid type-1 receptor (CB1R). Knockdown of CB1R in the CCK
BLA–D2
NAc circuit elevated synaptic activity and promoted stress susceptibility. Notably, selective inhibition of the CCK
BLA–D2
NAc 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.
Figure. 1 BLa CCK and non-CCK glutamatergic neurons differentially form synaptic connections with D2 and D1 MSNs, respectively, in Nacc.
Through the use of immunohistochemistry, viral tracing and ex vivo electrophysiology, the authors show that BLA cholecystokinin (CCK)-expressing excitatory input to the NAc core (NAcc) D2 medium spiny neurons (MSNs) transmitted negative valence and that social defeat stress selectively potentiated excitatory transmission of the CCK
BLA–D2
NAcc circuit via downregulation of presynaptic CB1R in susceptible mice. These results suggest, for the first time, that downregulation of CB1R in a CCK
BLA–D2
NAcc circuit represents an endophenotype for stress-induced depression and points to an essential role of CB1R within this circuit in promoting stress resilience.
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