Microglial production of TNF-alpha is a key element of sustained fear memory

Yu, Zhiqian; Fukushima, Hotaka; Ono, Chiaki; Sakai, Mai; Kasahara, Yoshiyuki; Kikuchi, Yoku; Gunawansa, Nicole; Takahashi, Yuta; Matsuoka, Hiroo; Kida, Satoshi; Tomita, Hiroaki

doi:10.1016/j.bbi.2016.08.011

Cited by 52 publications

(41 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, future studies on whether kososan extract improves general depressive and anxious states in socially defeated mice are necessary to conclude antidepressant- and anxiolytic-like activities of kososan extract in the CSDS model. Intriguingly, it has also been reported that CSDS enhances hippocampal-dependent fear memory in the contextual fear conditioning paradigm [74] and that the fear memory is closely linked to microglia-mediated neuroinflammation [75–77]. Moreover, CSDS-induced social avoidant behavior can be a possible learned fear against conspecific [78].…”

Section: Discussionmentioning

confidence: 99%

Kososan, a Kampo medicine, prevents a social avoidance behavior and attenuates neuroinflammation in socially defeated mice

Ito

Hirose

Ishida

et al. 2017

J Neuroinflammation

View full text Add to dashboard Cite

BackgroundKososan, a Kampo (traditional Japanese herbal) medicine, has been used for the therapy of depressive mood in humans. However, evidence for the antidepressant efficacy of kososan and potential mechanisms are lacking. Recently, it has been recognized that stress triggers neuroinflammation and suppresses adult neurogenesis, leading to depression and anxiety. Here, we examined whether kososan extract affected social behavior in mice exposed to chronic social defeat stress (CSDS), an animal model of prolonged psychosocial stress, and neuroinflammation induced by CSDS.MethodsIn the CSDS paradigm, C57BL/6J mice were exposed to 10 min of social defeat stress from an aggressive CD-1 mouse for 10 consecutive days (days 1–10). Kososan extract (1.0 g/kg) was administered orally once daily for 12 days (days 1–12). On day 11, the social avoidance test was performed to examine depressive- and anxious-like behaviors. To characterize the impacts of kososan on neuroinflammation and adult neurogenesis, immunochemical analyses and ex vivo microglial stimulation assay with lipopolysaccharide (LPS) were performed on days 13–15.ResultsOral administration of kososan extract alleviated social avoidance, depression- and anxiety-like behaviors, caused by CSDS exposure. CSDS exposure resulted in neuroinflammation, as indicated by the increased accumulation of microglia, the resident immune cells of the brain, and their activation in the hippocampus, which was reversed to normal levels by treatment with kososan extract. Additionally, in ex vivo studies, CSDS exposure potentiated the microglial pro-inflammatory response to a subsequent LPS challenge, an effect that was also blunted by kososan extract treatment. Indeed, the modulatory effect of kososan extract on neuroinflammation appears to be due to a hippocampal increase in an anti-inflammatory phenotype of microglia while sparing an increased pro-inflammatory phenotype of microglia caused by CSDS. Moreover, reduced adult hippocampal neurogenesis in defeated mice was recovered by kososan extract treatment.ConclusionsOur findings suggest that kososan extract prevents a social avoidant behavior in socially defeated mice that is partially mediated by the downregulation of hippocampal neuroinflammation, presumably by the relative increased anti-inflammatory microglia and regulation of adult hippocampal neurogenesis. Our present study also provides novel evidence for the beneficial effects of kososan on depression/anxiety and the possible underlying mechanisms.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0876-8) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Kososan, a Kampo medicine, prevents a social avoidance behavior and attenuates neuroinflammation in socially defeated mice

Ito

Hirose

Ishida

et al. 2017

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…Importantly, several lines of work suggest that inflammation may be causally involved in the emergence and maintenance of these psychobehavioral symptoms of PTSD. In particular, a number of animal studies have shown that heightened inflammation impairs extinction of fear memory . In humans, increased inflammation is shown to be related to enhanced amygdala activation in response to threatening stimuli .…”

Section: Mechanisms Underlying the Link Between Inflammation And Ptsdmentioning

confidence: 99%

“…For example, the association of autoimmune disorders with PTSD is shown to be even stronger than that with other psychiatric disorders . Furthermore, animal studies of PTSD have shown that behavioral alterations mimicking the fear memory‐related symptoms (e.g., conditioned fear responses) are associated with immune dysfunction and inflammation . Taken together, it can be said that elevated proinflammatory markers may be useful in classifying (stress‐related) psychiatric disorders in general, with PTSD possibly representing a model case in which heightened inflammation lies at the intersection where psychopathology meets pathoetiology.…”

Section: Future Directionsmentioning

confidence: 99%

Inflammation and post‐traumatic stress disorder

Hori

Kim

2019

Psychiatry Clin Neurosci

280

176

View full text Add to dashboard Cite

While post‐traumatic stress disorder (PTSD) is currently diagnosed based solely on classic psychological and behavioral symptoms, a growing body of evidence has highlighted a link between this disorder and alterations in the immune and inflammatory systems. Epidemiological studies have demonstrated that PTSD is associated with significantly increased rates of physical comorbidities in which immune dysregulation is involved, such as metabolic syndrome, atherosclerotic cardiovascular disease, and autoimmune diseases. In line with this, a number of blood biomarker studies have reported that compared to healthy controls, individuals with PTSD exhibit significantly elevated levels of proinflammatory markers, such as interleukin‐1β, interleukin‐6, tumor necrosis factor‐α, and C‐reactive protein. Moreover, various lines of animal and human research have suggested that inflammation is not only associated with PTSD but also can play an important role in its pathogenesis and pathophysiology. In this review, we first summarize evidence suggestive of increased inflammation in PTSD. We then examine findings that suggest possible mechanisms of inflammation in this disorder in terms of two different but interrelated perspectives: putative causes of increased proinflammatory activities and potential consequences that inflammation generates. Given that there is currently a dearth of treatment options for PTSD, possibilities of new therapeutic approaches using pharmacological and non‐pharmacological treatments/interventions that have anti‐inflammatory effects are also discussed. Despite the increasing attention given to the inflammatory pathology of PTSD, there remains much to be elucidated, including more detailed mechanisms of inflammation, potential usefulness of inflammatory biomarkers as diagnostic and prognostic markers, and efficacy of novel treatment strategies targeting inflammation.

show abstract

“…The membrane-bound TNFα can also be cleaved from cells to form soluble sTNFα, which function is still considered controversial (Wajant et al, 2003;Croft and Siegel, 2017). Macrophages are the primary source of TNFα, but other cell-types such as lymphocytes, mast cells, endothelial cells and CNS microglia also produce TNFα (Wajant et al, 2003;Yu et al, 2017). TNFα binds to two membrane-bound receptors: The TNFα receptor type 1 and 2 (TNFαR1/2).…”

Section: Tnfα-signaling In Motivation and Affective Statementioning

confidence: 99%

Molecular Mechanisms of Reward and Aversion

Klawonn¹

2018

Linköping University Medical Dissertations

View full text Add to dashboard Cite

Microglial production of TNF-alpha is a key element of sustained fear memory

Cited by 52 publications

References 47 publications

Kososan, a Kampo medicine, prevents a social avoidance behavior and attenuates neuroinflammation in socially defeated mice

Kososan, a Kampo medicine, prevents a social avoidance behavior and attenuates neuroinflammation in socially defeated mice

Inflammation and post‐traumatic stress disorder

Molecular Mechanisms of Reward and Aversion

Contact Info

Product

Resources

About