Effect of Toll‐like receptor 4 on depressive‐like behaviors induced by chronic social defeat stress

Abstract

Introduction A growing body of evidence suggests that stress is an important factor in depression, and pro‐inflammatory cytokines contribute to the occurrence and development of depression in both animal models and human patients. Toll‐like receptor 4 (TLR4) has been shown to be a key innate immune pattern recognition receptor involved in the regulation of stress responses and inflammation. However, the exact effects of TLR4 on depressive‐like behaviors induced by chronic social defeat stress (CSDS) are not known. Methods In this study, the effects of TLR4 on depressive‐like behaviors were investigated in an animal model of depression induced by CSDS. The depressive‐like behaviors were assessed by forced swimming test (FST), social interaction test (SIT), and light–dark box test (LDT). The protein expressions of TLR4 and tumor necrosis factor‐α (TNF‐α) in the hippocampus were measured using Western blotting. Results We found that CSDS increased TLR4 protein levels in the hippocampus and induced behavioral despair in FST, social avoidance in SIT, and anxiety‐like behavior in LDT. Fluoxetine normalized the increased expression of TLR4 and reversed behavioral despair, social avoidance, as well as anxiety‐like behavior induced by CSDS. However, directly blocking TLR4, by using either TLR4 inhibitor TAK‐242 or knockout of TLR4, only inhibited behavioral despair, but not social avoidance or anxiety‐like behavior induced by CSDS. Conclusions These results demonstrate a specific modulating role of TLR4 in behavioral despair induced by CSDS and suggest that TAK‐242 may be a beneficial treatment for patients with behavioral despair.

Differentially Expressed Genes in the Brain of Aging Mice With Cognitive Alteration and Depression- and Anxiety-Like Behaviors

“…This conclusion is strongly supported by the previous studies that showed that knockout of Cnr2 in the brain could attenuate psychomotor, depression- and anxiety-like behaviors in mice ( Liu Q.R. et al, 2017 ) and that blocking Tlr4 could reduce the anxiety- and depression-like behaviors ( Strekalova et al, 2015 ; Zhang et al, 2020 ). In addition, we also found that the other two neuroinflammation-related genes Fgf2 and Cbln1 were differentially expressed in the hippocampus of aging mice, both of which have been demonstrated to affect fear conditioning and spatial memory processes in aged animals ( Hirai et al, 2005 ).…”

Alleviation of depression-like behavior in a cystic fibrosis mouse model by Hdac6 depletion

“…Another potential mechanism of action is the anti-inflammatory effect of HDAC6 inhibition 23 . Inflammation has been correlated with depression in a number of studies 35 – 38 , therefore, alleviating inflammatory signaling may be a mode of action of Hdac6 depletion. We have shown specifically in CF mouse models that depletion of Hdac6 results in reduced inflammation and better clearance of bacteria in airways from infected mice 23 .…”

Salidroside Improves Chronic Stress Induced Depressive Symptoms Through Microglial Activation Suppression

“…And a certain number of studies also revealed both chronic stress and LPS challenges induced distinct molecular and behavioral changes in mice ( Espinosa-Oliva et al, 2011 ; Couch et al, 2016 ). For instance, Toll-like receptors (TLRs) play an important role in this depressive behavioral changes ( Habib et al, 2015 ; Zhang.W., et al, 2020 ). Further studies are needed to address whether antidepressant effects of SLDS also affects TLRs pathway.…”

“…OFT was conducted the day after FST as described ( Sevastre-Berghian et al, 2020 ). OFT has been reported as a scientifically valid method to evaluate the general locomotivity and anxiety levels in animal experiments ( Sevastre-Berghian et al, 2020 ; Zhang et al, 2020 ). Briefly, the open field (Techman software, China) 36 cm × 36 cm was surrounded by walls.…”