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A Chronic Immobilization Stress Protocol for Inducing Depression-Like Behavior in Mice
Published on: May 15, 2019
Neuronal-microglial liver X receptor β activating decrease neuroinflammation and chronic stress-induced
Chunhui Li1, Huanghui Wu2, Ha Sen Ta Na3
1Department of Anesthesiology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, PR China; Department of Anesthesiology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215000, PR China.
Abstract:
Depression is accompanied by excessive neuroinflammation. Liver X receptor β (LXRβ) has been reported as a newly emerging target that exerts systemic and organic inflammation modulation. However, the modulatory mechanism in alleviating neuroinflammation are far from being revealed. In the current study, depression-related behaviors in mice were induced by chronic unpredictable mild stress (CUMS) and corticosterone (CORT) drinking. Mice received either TO901317, PLX-5622 and intra- bilateral basolateral amygdale (BLA) injection of rAAV9-hSyn-hM3D(Gq)-eGFP to activate LXRβ, eliminate microglia and pharmacogenetic activate neurons in BLA, respectively, followed by behavioral tests. Microglial pro-inflammatory and pro-phagocytic activation, as well as nuclear factor-κB (NF-κB) signaling pathway, NLRP3 inflammasome activation and interleukin-1β (IL-1β) release in BLA were investigated. Moreover, pro-inflammatory activation of BV2 cells-induced by CORT with or without TO901317 was detected. Neuroinflammation indicated by IL-1β release was measured in a co-culture system of HT22-primary microglia with or without TO901317. Our results indicated that chronic stress induced depression-related behaviors, which were accompanied with microglial pro-inflammatory and pro-phagocytic activation, as well as NF-κB signaling pathway and NLRP3 inflammasome activation in BLA. Accordingly, pharmacological activation of LXRβ inhibited microglial pro-inflammatory and pro-phagocytic activation, as well as NF-κB signaling pathway and NLRP3 inflammasome activation, and IL-1β release both in vivo and in vitro. Finally, both elimination of microglia and pharmacogenetic activation of neurons in BLA protected mice from chronic stress-induced depression-related behavior. Collectively, pharmacological activation of neuronal-microglial LXRβ alleviates depression-related behavior by modulating excessive neuroinflammation via inhibiting NF-κB signaling pathway and NLRP3 inflammasome activation.
Insights
Activating Liver X receptor beta (LXRβ) in neurons and microglia alleviates depression by reducing neuroinflammation. This involves inhibiting the NF-κB signaling pathway and NLRP3 inflammasome activation, crucial for treating stress-induced depression.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Depression is linked to excessive neuroinflammation.
- Liver X receptor beta (LXRβ) shows potential in modulating inflammation.
- The precise mechanisms of LXRβ in alleviating neuroinflammation in depression are not fully understood.
Purpose of the Study:
- To investigate the role of LXRβ in modulating neuroinflammation and depression-related behaviors.
- To elucidate the underlying molecular mechanisms involving microglial activation and inflammatory pathways.
- To assess the therapeutic potential of LXRβ activation in depression.
Main Methods:
- Depression models in mice using chronic unpredictable mild stress (CUMS) and corticosterone (CORT).
- Pharmacological activation of LXRβ using TO901317 and manipulation of microglia/neurons in the basolateral amygdala (BLA).
- Assessment of behavioral tests, microglial activation, NF-κB signaling, NLRP3 inflammasome, and IL-1β release in vivo and in vitro.
Main Results:
- CUMS and CORT induced depression-like behaviors with increased microglial activation, NF-κB and NLRP3 inflammasome activation, and IL-1β release in the BLA.
- LXRβ activation significantly inhibited these inflammatory markers and behaviors.
- Eliminating microglia or activating neurons in the BLA protected against depression-like behaviors.
Conclusions:
- Pharmacological activation of neuronal-microglial LXRβ effectively alleviates depression-related behaviors.
- This therapeutic effect is mediated by the modulation of neuroinflammation through the inhibition of NF-κB signaling and NLRP3 inflammasome activation.
- LXRβ represents a promising therapeutic target for depression treatment by addressing neuroinflammation.
