The Innate Immune Receptors TLR2/4 Mediate Repeated Social Defeat Stress-Induced Social Avoidance through Prefrontal Microglial Activation

Nie, Xiang; Kitaoka, Shiho; Tanaka, Kohei; Segi-Nishida, Eri; Imoto, Yuki; Ogawa, Atsubumi; Nakano, Fumitake; Tomohiro, Ayaka; Nakayama, Kazuki; Taniguchi, Masayuki; Mimori-Kiyosue, Yuko; Kakizuka, Akira; Narumiya, Shuh; Furuyashiki, Tomoyuki

doi:10.1016/j.neuron.2018.06.035

Cited by 238 publications

(195 citation statements)

References 46 publications

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“…It has been reported that only mice lacking TLR2 and TLR4 in combination (TLR2/4 double knockout) abolished CSDS‐induced social avoidance. Neither TLR2 knockout nor TLR4 knockout alone could abolish CSDS‐induced social avoidance (Nie et al, ). Combined with our results, TLR4, in combination with TLR2, may participate in modulation of social avoidance, while TLR4 alone only modulates behavioral despair.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…One recent study has found that voluntary exercise increases resilience to CSDS in mice (Mul et al, ), which indicates that voluntary exercise may be an effective and useful intervention to increase resilience to social defeat stress in humans. Gut microbiota, diet, and the immune system have also been implicated in resilience to CSDS in mice (Ambree, Ruland, Scheu, Arolt, & Alferink, ; Aubry et al, ; Kingston et al, ; McKim et al, ; Nie et al, ; Szyszkowicz, Wong, Anisman, Merali, & Audet, ). Improvement in eating habits may help change the immune system through alterations of microbiota, which may in turn increase resilience to social defeat stress in humans, especially given the strong correlations between the immune system and resilience to CSDS (Ambree et al, ; Aubry et al, ; McKim et al, ; Nie et al, ; Szyszkowicz et al, ).…”

Section: Social Status and Mtdmentioning

confidence: 99%

“…Gut microbiota, diet, and the immune system have also been implicated in resilience to CSDS in mice (Ambree, Ruland, Scheu, Arolt, & Alferink, ; Aubry et al, ; Kingston et al, ; McKim et al, ; Nie et al, ; Szyszkowicz, Wong, Anisman, Merali, & Audet, ). Improvement in eating habits may help change the immune system through alterations of microbiota, which may in turn increase resilience to social defeat stress in humans, especially given the strong correlations between the immune system and resilience to CSDS (Ambree et al, ; Aubry et al, ; McKim et al, ; Nie et al, ; Szyszkowicz et al, ). tDCS is a noninvasive intervention that has already been applied for the treatment of depression in clinical practice (Fregni et al, ; Nitsche, Boggio, Fregni, & Pascual‐Leone, ).…”

Section: Social Status and Mtdmentioning

confidence: 99%

Social status and modern‐type depression: A review

2019

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BackgroundsSocial hierarchy is one of the most influential social structures employed by social species. While dominants in such hierarchies can preferentially access rich resources, subordinates are forced into lower social statuses and lifestyles with inferior resources. Previous studies have indicated that the social rank regulates social behaviors and emotion in a variety of species, whereby individual organisms live within the framework of their ranks. However, in human societies, people, particularly young men, who cannot accept their own social status may show social withdrawal behaviors such as hikikomori to avoid confronting their circumstances.MethodsThis article reviews the neural mechanisms underlying social status identified in animal studies with rodents and primates, and assesses how social rank affects animal's social behaviors and emotion which may be relevant to modern type depression.ResultsSeveral brain regions such as medial prefrontal cortex are implicated in the formation of animal's social status, which leads to the differences in vulnerability and resilience to social stress.ConclusionOn the basis of these findings, we propose that physical interventions such as voluntary exercise, diet, transcranial direct current stimulation, and psychotherapy, rather than psychotropic drugs, may be useful therapeutic approaches for modern type depression, which is a typical example of social status conflict and a phenotype of adjustment disorder to the traditional hierarchical social order.

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“…1 Animal studies using a variety of stress models such as social defeat stress, chronic mild stress, and restraint stress in rodents have revealed that exposure to environmental stress induces inflammatory responses in the brain and systemic circulation, thereby contributing to emotional alternations. [2][3][4][5][6] For example, social defeat stress activates microglia in several brain areas including the medial prefrontal cortex, and this activation is indispensable for dendritic atrophy in the medial prefrontal cortex and the induction of social avoidance. 2 Social defeat stress also induces the production of interleukin-6 in bone marrow-derived leukocytes.…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4][5][6] For example, social defeat stress activates microglia in several brain areas including the medial prefrontal cortex, and this activation is indispensable for dendritic atrophy in the medial prefrontal cortex and the induction of social avoidance. 2 Social defeat stress also induces the production of interleukin-6 in bone marrow-derived leukocytes. 7 The circulating IL-6 has been shown to enter the brain parenchyma due to concomitant disruption of the blood-brain barrier for the induction of social avoidance.…”

Section: Introductionmentioning

confidence: 99%

Social defeat stress induces phosphorylation of extracellular signal‐regulated kinase in the leptomeninges in mice

Okamura

Nagai

Numa

et al. 2019

Neuropsychopharm Rep

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Aims Animal studies using various stress models have shown that excessive environmental stress induces depression? and anxiety?like behaviors through inflammatory responses in the brain and periphery. Although the leptomeningeal cells have multiple functions related to inflammatory responses in the brain, whether environmental stress influences the leptomeninges remains unknown. In this study, we aimed to examine phosphorylation of the extracellular signal‐regulated kinase (ERK) in the leptomeninges. Methods We subjected C57BL/6 male mice to a single episode of social defeat stress and analyzed the expression of phosphorylated ERK in the leptomeninges by immunohistochemistry. Results Social defeat stress in mice induced phosphorylation of ERK in the leptomeninges, adjacent to vascular endothelial cells and the glia limitans. This ERK phosphorylation was maintained for at least one hour after the stress. Conclusions This study shows the effect of environmental stress on the leptomeninges for the first time and paves the way for elucidating its functional role in stress‐induced changes in neural functions.

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The Innate Immune Receptors TLR2/4 Mediate Repeated Social Defeat Stress-Induced Social Avoidance through Prefrontal Microglial Activation

Cited by 238 publications

References 46 publications

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

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

Social status and modern‐type depression: A review

Social defeat stress induces phosphorylation of extracellular signal‐regulated kinase in the leptomeninges in mice

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