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Journal ArticleDOI

Chronic Stress Induced Remodeling of the Prefrontal Cortex: Structural Re-Organization of Microglia and the Inhibitory Effect of Minocycline

01 Aug 2013-Cerebral Cortex (Oxford University Press)-Vol. 23, Iss: 8, pp 1784-1797
TL;DR: Stress increased the internal complexity of microglia, enhancing ramification without altering the overall area occupied by the cell and that this effect was more pronounced in larger cells, highlighting that increased ramification ofmicroglia may represent an important neurobiological mechanism through which microglial mediate the behavioral effects of chronic psychological stress.
Abstract: Recently, it has been discovered that the working memory deficits induced by exposure to chronic stress can be prevented by treating stressed animals with minocycline, a putative inhibitor of microglial activity. One of the pressing issues that now requires clarification is exactly how exposure to chronic stress modifies microglial morphology, this being a significant issue as microglial morphology is tightly coupled with their function. To examine how chronic stress alters microglial morphology, we digitally reconstructed microglia within the rat medial prefrontal cortex. Our analysis revealed that stress increased the internal complexity of microglia, enhancing ramification (i.e. branching) without altering the overall area occupied by the cell and that this effect was more pronounced in larger cells. We subsequently determined that minocycline treatment largely abolished the pro-ramifying effects of stress. With respect to mechanisms, we could not find any evidence of increased inflammation or neurodegeneration (interleukin-1β, MHC-II, CD68, terminal deoxynucleotidyl transferase dUTP nick end labeling, and activated caspase-3). We did, however, find that chronic stress markedly increased the expression of β1-integrin (CD29), a protein previously implicated in microglial ramification. Together, these findings highlight that increased ramification of microglia may represent an important neurobiological mechanism through which microglia mediate the behavioral effects of chronic psychological stress.
Citations
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Journal ArticleDOI
TL;DR: Some forms of depression can be considered as a microglia disease (microgliopathy), which should be treated by a personalized medical approach using microglial inhibitors or stimulators depending on the microglian status of the depressed patient.

591 citations


Cites background or methods from "Chronic Stress Induced Remodeling o..."

  • ..., branching) of processes, and expression of the activation marker IBA1 (ionized calcium-binding adapter molecule 1, also known as allograft inflammatory factor 1, AIF1), but not of type II major histocompatibility complex molecules (MHC-II), in many stress-responsive brain areas [57–60]....

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  • ...Chronic restraint stress 6 h daily restraint for 21 days Rats/SD IHC of activation markers, bintegrin (a marker of microglial ramification), and P2X7 (a purinergic receptor) Reconstruction of Iba-1-labeled microglia followed by morphometric and Scholl analyses " Iba-1 IR $ MHC-II, CD68 IR " b-integrin IR # P2X7 IR " Branch points (nodes), intersections, and process length in large microglia (top 25%) PFC [57,58,60]...

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Journal ArticleDOI
TL;DR: Findings provide direct causal evidence that disturbances in microglial functioning has an etiological role in chronic stress-induced depression, suggesting that microglia stimulators could serve as fast-acting anti-depressants in some forms of depressive and stress-related conditions.
Abstract: The limited success in understanding the pathophysiology of major depression may result from excessive focus on the dysfunctioning of neurons, as compared with other types of brain cells. Therefore, we examined the role of dynamic alterations in microglia activation status in the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We report that following an initial period (2-3 days) of stress-induced microglial proliferation and activation, some microglia underwent apoptosis, leading to reductions in their numbers within the hippocampus, but not in other brain regions, following 5 weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. Blockade of the initial stress-induced microglial activation by minocycline or by transgenic interleukin-1 receptor antagonist overexpression rescued the subsequent microglial apoptosis and decline, as well as the CUS-induced depressive-like behavior and suppressed neurogenesis. Similarly, the antidepressant drug imipramine blocked the initial stress-induced microglial activation as well as the CUS-induced microglial decline and depressive-like behavior. Treatment of CUS-exposed mice with either endotoxin, macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, all of which stimulated hippocampal microglial proliferation, partially or completely reversed the depressive-like behavior and dramatically increased hippocampal neurogenesis, whereas treatment with imipramine or minocycline had minimal or no anti-depressive effects, respectively, in these mice. These findings provide direct causal evidence that disturbances in microglial functioning has an etiological role in chronic stress-induced depression, suggesting that microglia stimulators could serve as fast-acting anti-depressants in some forms of depressive and stress-related conditions.

500 citations

Journal ArticleDOI
TL;DR: There is consistent evidence that a range of psychosocial stressors lead to elevated microglial activity in the hippocampus and good evidence that this is also the case in other brain regions, which is considered in terms of the two-hit hypothesis.
Abstract: Rationale Psychosocial stressors are a well-documented risk factor for mental illness. Neuroinflammation, in particular elevated microglial activity, has been proposed to mediate this association. A number of preclinical studies have investigated the effect of stress on microglial activity. However, these have not been systematically reviewed before.

433 citations


Cites background or result from "Chronic Stress Induced Remodeling o..."

  • ...…al. 2010) and/or changes in the percentage area occupied by Iba-1 signal per region (Kreisel et al. 2014; Couch et al. 2013; Diz-Chaves et al. 2013; Hinwood et al. 2013, 2012; Kopp et al. 2013; Bian et al. 2012; Diz-Chaves et al. 2012; Park et al. 2011; Yoo et al. 2011; Brevet et al. 2010; Tynan…...

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  • ...It is difficult then to separate the effects of chronic restraint from the effects of social isolation, which were described by Schiavone et al. (2009)....

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  • ...Analysis of Iba-1 staining consisted of region-specific cell counting (Giovanoli et al. 2013; Hinwood et al. 2013; Kopp et al. 2013; Hinwood et al. 2012; Wohleb et al. 2012, 2011; Kojo et al. 2010; Tynan et al. 2010) and/or changes in the percentage area occupied by Iba-1 signal per region (Kreisel…...

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  • ...Further analysis by Hinwood et al. (2013) found that chronic restraint led to distinct morphological changes, with increased ramification of the microglia....

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  • ...Control animals were handled each day and returned to their home cage Tynan et al. (2010), Park et al. (2011), Yoo et al. (2011), Hinwood et al. (2012, 2013), Kopp et al. (2013) Occlusal disharmony ddY mice 1–5 days Surgical placement of resin on the upper molars increased the vertical dimension of…...

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Journal ArticleDOI
TL;DR: Current trends and methods of fractal analysis are reviewed, focusing on box counting analysis, including lacunarity and multifractal analysis, as applied to microglial morphology.
Abstract: It is well established that microglial form and function are inextricably linked. In recent years, the traditional view that microglial form ranges between "ramified resting" and "activated amoeboid" has been emphasized through advancing imaging techniques that point to microglial form being highly dynamic even within the currently accepted morphological categories. Moreover, microglia adopt meaningful intermediate forms between categories, with considerable crossover in function and varying morphologies as they cycle, migrate, wave, phagocytose, and extend and retract fine and gross processes. From a quantitative perspective, it is problematic to measure such variability using traditional methods, but one way of quantitating such detail is through fractal analysis. The techniques of fractal analysis have been used for quantitating microglial morphology, to categorize gross differences but also to differentiate subtle differences (e.g., amongst ramified cells). Multifractal analysis in particular is one technique of fractal analysis that may be useful for identifying intermediate forms. Here we review current trends and methods of fractal analysis, focusing on box counting analysis, including lacunarity and multifractal analysis, as applied to microglial morphology.

390 citations


Cites background from "Chronic Stress Induced Remodeling o..."

  • ...In some cases, significant differences in various features have been noted even between strains of one species (Humphrey and Moore, 1995; Klyushnenkova and Vanguri, 1997)....

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Journal ArticleDOI
TL;DR: The mechanisms by which commensal gut microbiota can regulate neuroinflammation are focused on and the understanding of their role in stress-related disorders as a consequence of neuroinflammatory processes is exploited.

354 citations


Cites background from "Chronic Stress Induced Remodeling o..."

  • ...The release of cytokines following microglia activation have been reported to have a causal role in behavioural phenotype in stress models (Blandino et al., 2013; Hinwood et al., 2012, 2013; Kreisel et al., 2014; Wohleb et al., 2013)....

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Journal ArticleDOI
15 Oct 2008-Nature
TL;DR: Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits and show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.
Abstract: Unravelling the pathophysiology of depression is a unique challenge. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are impossible to reproduce in animal models. Nevertheless, other symptoms have been accurately modelled, and these, together with clinical data, are providing insight into the neurobiology of depression. Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.

2,535 citations

Journal ArticleDOI
TL;DR: In this article, the effects of stress on the immune system and brain are discussed and two new terms, allostasis and allostatic load, are introduced to supplement and clarify the meanings of stress and homeostasis.

1,661 citations