Microglia as Central Protagonists in the Chronic Stress Response

Schramm, Eva; Waisman, Ari

doi:10.1212/nxi.0000000000200023

Cited by 43 publications

(24 citation statements)

References 61 publications

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“…Interestingly, according to previous studies, the effects of chronic stress on microglial activation are heterogeneous (Yirmiya et al, 2015). In addition to the proliferation of microglia, which is peaked at 2-4 days after stress, chronic stress also induces the apoptosis of microglia (Kreisel et al, 2014;Tong et al, 2017;Schramm and Waisman, 2022). After exposure to stress for several weeks, the microglia density even decreases in some specific brain region (e.g., DG of hippocampus) (Tong et al, 2017;Schramm and Waisman, 2022).…”

Section: Discussionmentioning

confidence: 96%

“…In addition to the proliferation of microglia, which is peaked at 2-4 days after stress, chronic stress also induces the apoptosis of microglia (Kreisel et al, 2014;Tong et al, 2017;Schramm and Waisman, 2022). After exposure to stress for several weeks, the microglia density even decreases in some specific brain region (e.g., DG of hippocampus) (Tong et al, 2017;Schramm and Waisman, 2022). In the present study, we sacrificed the mice after performing behavioral tests, and that was 10 days after mice were stressed, while animals were euthanized 24 h after the final stress session in Tynan et al (2010)'s study.…”

Section: Discussionmentioning

confidence: 99%

“…The delicate ramified processes and highly motile identity allow microglia to sense and react to the local environment (Umpierre and Wu, 2021). During stress exposure, microglia response to these neuronal changes as well as neurotransmitters and hormone alterations, subsequently contribute to stress-induced neuroinflammation, thus shaping neuronal function and associated behavior (Wohleb et al, 2016;Schramm and Waisman, 2022). However, the complexity of stress conditions and communication between microglia and other cells make the exact mechanism of microglial activation remains mostly unclear.…”

Section: Introductionmentioning

confidence: 99%

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Dlg1 deletion in microglia ameliorates chronic restraint stress induced mice depression-like behavior

Peng

Jiang

et al. 2023

Front. Pharmacol.

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Background: Major depression is one of the most common psychiatric disorders worldwide, inflicting suffering, significant reduction in life span, and financial burdens on families and society. Mounting evidence implicates that exposure to chronic stress can induce the dysregulation of the immune system, and the activation of brain-resident innate immune cells, microglia, leading to depression-like symptoms. However, the specific mechanisms need to be further elucidated.Method: Animal models of depression were established by chronic restraint stress (CRS), and depression-like behavior was assessed by sucrose preference test (SPT), open field test (OFT), tail suspension test (TST) and forced swimming test (FST). Microglial activation was visualized by immunofluorescent and immunohistochemical staining, and microglial morphological changes were further analyzed by skeleton analysis. The levels of inflammatory cytokines were detected by western blotting and qPCR.Result: Microglial Dlg1 knockout ameliorates CRS-induced mice depression-like behavior. In contrast to the effect of Dlg1 in the LPS-induced mouse model, Dlg1 knockout had little effect on microglial density, but significantly decreased the number of activated microglia and reversed microglia morphological changes in mice challenged with CRS. Moreover, the upregulation of inflammatory cytokines following CRS exposure was partially reversed by Dlg1 deletion.Conclusion: Our study provides the evidence that Dlg1 ablation in microglia remarkedly reverses microglial activation and depression-like behavior in mice exposed to CRS, implicating a potential target for the treatment of clinical depression.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dlg1 deletion in microglia ameliorates chronic restraint stress induced mice depression-like behavior

Peng

Jiang

et al. 2023

Front. Pharmacol.

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“…Chronic stress has been largely shown to induce an increased expression of pro‐inflammatory mediators in activated microglia. [ 29 ] For example, HMGB1 can be actively secreted from activated microglia or passively released from necrotic cells to initiate inflammatory responses under stress conditions. [ 30 ] Extracellular HMGB1 interacts with several pathogen recognition receptors such as the RAGE, to promote the local generation of pro‐inflammatory cytokines including tumor‐necrosis factor and IL‐6 in brain.…”

Section: Discussionmentioning

confidence: 99%

The Bioactive Dietary Polyphenol Preparation Alleviates Depression and Anxiety‐Like Behaviors by Modulating the Regional Heterogeneity of Microglia Morphology

Yang

Frolinger

Iqbal

et al. 2023

Molecular Nutrition Food Res

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ScopeThe goal of this study is to investigate the effects of a bioactive dietary polyphenol preparation (BDPP), which is made up of grape‐derived polyphenols, on microglial responses, as well as the underlying molecular mechanisms in depression and anxiety‐like behaviors.Methods and resultsThe study finds that treatment with BDPP significantly decreases depression‐like and anxiety‐like behaviors induced by chronic stress in mice, while leaving their locomotor activity unaffected. The study also finds that BDPP treatment reverses microglia activation in the amygdala and hippocampal formation, regions of the brain involved in emotional regulation, from an amoeboid shape to ramified shape. Additionally, BDPP treatment modulates the release of pro‐inflammatory cytokines such as interleukin‐6 via high mobility box 1 protein and the receptor for advanced glycation end products (HMGB1‐RAGE) signaling pathway in activated microglia induced by chronic stress.ConclusionThe findings suggest regional heterogeneity in microglial responses following chronic stress in subregions of the corticolimbic circuit. Specifically, activation of the immune‐inflammatory HMGB1‐RAGE pathway may provide a new avenue for preventing the manifestation of psychiatric impairments including stress‐induced anxiety‐ and depression‐like behavior, using bioactive and bioavailable polyphenols.

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“…During neuroinflammation, MIF has been identified as an upstream regulator of IL-1β and IL-6 production from microglia. Chronic stress activates microglia in multiple brain regions, thereby altering the cerebral microenvironment through the production of proinflammatory cytokines, the induction of ROS, and phagocytosis ( Schramm and Waisman, 2022 ). An excessive production of ROS by microglia can create a self-reinforcing cycle of microglial activation and potentiate HPA axis stimulation through the release of IL-1β within the hypothalamus ( Ramirez et al, 2017 ).…”

Section: Low-grade Inflammation As a Common Feature Underlying The Cr...mentioning

confidence: 99%

Interplay between stress and cancer—A focus on inflammation

Petrinović

Milošević²,

Marković³

et al. 2023

Front. Physiol.

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Stress is an integral part of life. While acute responses to stress are generally regarded as beneficial in dealing with immediate threats, chronic exposure to threatening stimuli exerts deleterious effects and can be either a contributing or an aggravating factor for many chronic diseases including cancer. Chronic psychological stress has been identified as a significant factor contributing to the development and progression of cancer, but the mechanisms that link chronic stress to cancer remain incompletely understood. Psychological stressors initiate multiple physiological responses that result in the activation of the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system, and the subsequent changes in immune function. Chronic stress exposure disrupts the homeostatic communication between the neuroendocrine and immune systems, shifting immune signaling toward a proinflammatory state. Stress-induced chronic low-grade inflammation and a decline in immune surveillance are both implicated in cancer development and progression. Conversely, tumor-induced inflammatory cytokines, apart from driving a tumor-supportive inflammatory microenvironment, can also exert their biological actions distantly via circulation and therefore adversely affect the stress response. In this minireview, we summarize the current findings on the relationship between stress and cancer, focusing on the role of inflammation in stress-induced neuroendocrine-immune crosstalk. We also discuss the underlying mechanisms and their potential for cancer treatment and prevention.

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Microglia as Central Protagonists in the Chronic Stress Response

Cited by 43 publications

References 61 publications

Dlg1 deletion in microglia ameliorates chronic restraint stress induced mice depression-like behavior

Dlg1 deletion in microglia ameliorates chronic restraint stress induced mice depression-like behavior

The Bioactive Dietary Polyphenol Preparation Alleviates Depression and Anxiety‐Like Behaviors by Modulating the Regional Heterogeneity of Microglia Morphology

Interplay between stress and cancer—A focus on inflammation

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