한빛사 논문
Jeongseop Kim1,2,∗, Shinwoo Kang3,4,5,6,∗, Tae-Yong Choi1, Keun-A Chang3,4,5,¶, Ja Wook Koo1,2,¶
1Emotion, Cognition & Behavior research group, Korea Brain Research Institute (KBRI), Dong-gu, Daegu 41062, Republic of Korea
2Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Dalseong-gun, Daegu 42988, Republic of Korea
3Department of Pharmacology, College of Medicine, Gachon University, Yeonsu-gu, Incheon 21936, Republic of Korea
4Neuroscience Research Institute, Gachon University, Namdong-gu, Incheon 21565, Republic of Korea
5Department of Health Sciences and Technology, GAIHST, Gachon University, Yeonsu-gu, Incheon 21999, Republic of Korea
6Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA
∗These authors contributed equally to this work.
¶These authors contributed equally to this work.
Abstract
Background
The metabotropic glutamate receptor 5 (mGluR5) has been implicated in stress-related psychiatric disorders, particularly major depressive disorders. Although growing evidence supports the pro-resilient role of mGluR5 in corticolimbic circuitry in the depressive-like behaviors following chronic stress exposure, the underlying neural mechanisms, including circuits and molecules, remain unknown.
Methods
We measured the c-fos+ expression and probability of neurotransmitter release in and from the basolateral amygdala (BLA) neurons projecting to the medial prefrontal cortex (BLA→mPFC), and ventral hippocampus (BLA→vHPC) after chronic social defeat stress (CSDS). The role of the BLA projections in depressive-like behaviors was assessed using optogenetic manipulations, and the underlying molecular mechanisms of mGluR5 and downstream signaling were investigated by Western blotting, viral-mediated gene transfer, and pharmacological manipulations.
Results
CSDS disrupted the neural activity and glutamatergic transmission in both BLA→mPFC and BLA→vHPC projections. Optogenetic activation of the BLA projections reversed the detrimental CSDS effects on depressive-like behaviors and mGluR5 expression in mPFC and vHPC. Conversely, inhibition of the BLA projections of mice undergoing subthreshold social defeat stress-induced a susceptible phenotype and mGluR5 reduction. These two BLA circuits appeared to act in an independent way. Importantly, we demonstrate that mGluR5 overexpression in mPFC or vHPC was pro-resilient, while the mGluR5 knockdown was pro-susceptible and that the pro-resilient effects of mGluR5 are mediated through distinctive downstream signaling pathways in the mPFC and vHPC.
Conclusions
These findings identify mGluR5 in the mPFC and vHPC that receive BLA inputs as a critical mediator of stress-resilience, highlighting circuit-specific signaling for depressive-like behaviors.
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