Social stress during adolescence activates long-term microglia inflammation insult in reward processing nuclei

Rodrı́guez-Arias, Marta; Montagud‐Romero, Sandra; Carrión, Ana María Guardia; Ferrer-Pérez, Carmen; Pérez-Villalba, Ana; Marco, Eva M.; Gallardo, Meritxell López; Viveros, María-Paz; Miñarro, José

doi:10.1371/journal.pone.0206421

Cited by 27 publications

(12 citation statements)

References 105 publications

(123 reference statements)

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“…With the aim of identifying features of activated microglial cells, some studies showed that activated cells exhibit morphological changes compared to the typical surveillant morphotype of resting microglia (Boche et al, 2013; Walker et al, 2014). Those studies were accomplished by either subjective (Kloss et al, 2001; Cho et al, 2006; Diz-Chaves et al, 2012; Rodríguez-Arias et al, 2018) or objective (Karperien et al, 2013; York et al, 2018) approaches, the latter employing quantitative morphological analysis. However, the existence of different cellular morphotypes within the population of activated microglial cells has not been previously addressed.…”

Section: Discussionmentioning

confidence: 99%

Microglial Morphometric Parameters Correlate With the Expression Level of IL-1β, and Allow Identifying Different Activated Morphotypes

Fernández‐Arjona

Grondona

Fernández-Llébrez

et al. 2019

Front. Cell. Neurosci.

106

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Microglia are the resident macrophages in the brain. Traditionally, two forms of microglia have been described: one considered as a resting/surveillant state in which cells have a highly branched morphology, and another considered as an activated state in which they acquire a de-ramified or amoeboid form. However, many studies describe intermediate microglial morphologies which emerge during pathological processes. Since microglial form and function are closely related, it is of interest to correlate microglial morphology with the extent of its activation. To address this issue, we used a rat model of neuroinflammation consisting in a single injection of the enzyme neuraminidase (NA) within the lateral ventricle. Sections from NA-injected animals were co-immunolabeled with the microglial marker IBA1 and the cytokine IL-1β, which highlight features of the cell’s shape and inflammatory activation, respectively. Activated (IL-1β positive) microglial cells were sampled from the dorsal hypothalamus nearby the third ventricle. Images of single microglial cells were processed in two different ways to obtain (1) an accurate measure of the level of expression of IL-1β (indicating the degree of activation), and (2) a set of 15 morphological parameters to quantitatively and objectively describe the cell’s shape. A simple regression analysis revealed a dependence of most of the morphometric parameters on IL-1β expression, demonstrating that the morphology of microglial cells changes progressively with the degree of activation. Moreover, a hierarchical cluster analysis pointed out four different morphotypes of activated microglia, which are characterized not only by morphological parameters values, but also by specific IL-1β expression levels. Thus, these results demonstrate in an objective manner that the activation of microglial cells is a gradual process, and correlates with their morphological change. Even so, it is still possible to categorize activated cells according to their morphometric parameters, each category presenting a different activation degree. The physiological relevance of those activated morphotypes is an issue worth to be assessed in the future.

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Section: Discussionmentioning

confidence: 99%

Microglial Morphometric Parameters Correlate With the Expression Level of IL-1β, and Allow Identifying Different Activated Morphotypes

Fernández‐Arjona

Grondona

Fernández-Llébrez

et al. 2019

Front. Cell. Neurosci.

106

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“…Broad spectrum effects of social defeat stress on microglial activation have been observed, such as increased or reduced cell number, enlarged or decreased cell size and altered ramify state. [50][51][52] Our data show that the number of Iba-1 positive microglia in the mPFC is not changed in stressed mice when examined 3 weeks after the last stress episode. Previous studies have shown dynamic changes in microglial activation in stressed mice, and the initial activation is required for later behavioral and neuropathological alterations induced by stress exposure.…”

Section: Discussionmentioning

confidence: 64%

<p>The Long-Term Effects of Adolescent Social Defeat Stress on Oligodendrocyte Lineage Cells and Neuroinflammatory Mediators in Mice</p>

Zeman

et al. 2020

NDT

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Objective: Adverse childhood and adolescent experiences are associated with the emergences of psychopathology later in life and have negative consequences on white matter integrity. However, this adversity-induced white matter impairment remains not fully investigated. Methods: Adolescent Balb/c mice were subjected to intermittent social defeat stress once a day during postnatal days 25 to 40. Then, the subjects were allowed to recover for three weeks before sacrifice. At the end, oligodendrocyte (OL) lineage cells, cell proliferation, and microglia activation, as well as myelin basic protein (MBP) levels in frontal cortex and hippocampus were evaluated. The levels of interleukin (IL)-1β and IL-6 in the brain regions were assessed. Results: MBP protein level in frontal cortex, but not in the hippocampus of defeated mice, decreased significantly compared to controls. The numeral densities of mature OLs, oligodendrocyte progenitor cells, and proliferating cells in medial prefrontal cortex were comparable between the defeated mice and controls. The defeated mice, however, showed significantly higher IL-1β level, although IL-6 level and numeral density of microglia in frontal cortex did not change relative to controls. Conclusion: These results indicate that effects of intermittent social defeat stress on the white matter integrity and OL lineage cells in mouse brain are region-and developmental stage-specific. Upregulated IL-1β may contribute to this negative consequence though the underlying mechanism remains to be investigated.

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“…Our protocol of social stress, which consists of four social defeat episodes at intervals of 48 h during which the intruder animals are undisturbed in their home cages, is less intense than the chronic stress models that are usually employed to study resilience to social stress. With our less intense protocol, the OF1 strain of mice showed a profound increase in the rewarding effects of cocaine, measured with the CPP and SA procedures (Montagud-Romero et al, 2016, 2018Ferrer-Pérez et al, 2018), as well as a clear increase in inflammatory parameters (Ferrer-Pérez et al, 2019;Rodríguez-Arias et al, 2018;Montagud-Romero et al, 2020). Several reports have suggested that the C57BL/6 strain is less susceptible to stress than other strains (Dadomo et al, 2011;Razzoli et al, 2011a and2011b).…”

Section: Susceptibility or Resilience To Depressive-like Behaviors Anmentioning

confidence: 86%

“…As a result of the blood brain barrier's increased permeability due to SD, immune cells can easily penetrate the CNS (Rodríguez-Arias et al, 2017). A long-term increase in the number of macrophages, activation of microglia (Rodríguez-Arias et al, 2018;Stankiewicz et al, 2015), increase in pro-inflammatory cytokines such as IL-1β or IL-6 (Ferrer-Pérez et al, 2018;Wohleb et al, 2011Wohleb et al, , 2012Wohleb et al, , 2014, and decreases in chemokines such as CX3CL1 (Montagud-Romero et al, 2019) have been described in rodents after exposure to SD stress.…”

Section: Susceptible Mice Showed Increased Levels Of Il-6mentioning

confidence: 99%

Neuroinflammatory and behavioral susceptibility profile of mice exposed to social stress towards cocaine effects

Ballestín

Alegre-Zurano

Ferrer-Pérez

et al. 2021

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Using the social defeat (SD) model, numerous studies have shown that stressed mice display an enhanced response to the motivational effects of cocaine in the self-administration (SA) and conditioned-place preference (CPP) paradigms. However, not all subjects exposed to stress express its harmful effects. Some are particularly susceptible to the deleterious effects of repeated SD, while resilient mice successfully cope with stressful experiences and display adjusted psychological functioning after stress. Vulnerability to develop stress-related disorders, such as depression, has been linked to coping strategies and more recently to individual differences in the immune system. However, no studies have evaluated if coping strategies and immune system reactivity to social stress experiences can also predict susceptibility to stress-induced enhancement of the cocaine response. We evaluated cocaine response in socially defeated mice in the CPP and SA paradigms. To evaluate neuroimmune reactivity to stress the pro-inflammatory cytokine IL-6 and the chemokine CX3CL1 were measured in the striatum and hippocampus. Behavioral phenotype during and after SD episodes was also evaluated. Our results showed that susceptible mice to the depressive-like behaviors effects of stress showed increased conditioned rewarding effects of cocaine in the CPP. In addition, susceptible mice displayed passive-reactive coping behavior during social stress episodes and more pronounced changes in neuroinflammatory markers after the last SD episode, which lasted for one month. Although the complex mechanisms underlying susceptibility or resilience to social stress are still unclear, our results point to multiple adaptive stress responses expressed at different phenotypic levels.

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Social stress during adolescence activates long-term microglia inflammation insult in reward processing nuclei

Cited by 27 publications

References 105 publications

Microglial Morphometric Parameters Correlate With the Expression Level of IL-1β, and Allow Identifying Different Activated Morphotypes

Microglial Morphometric Parameters Correlate With the Expression Level of IL-1β, and Allow Identifying Different Activated Morphotypes

<p>The Long-Term Effects of Adolescent Social Defeat Stress on Oligodendrocyte Lineage Cells and Neuroinflammatory Mediators in Mice</p>

Neuroinflammatory and behavioral susceptibility profile of mice exposed to social stress towards cocaine effects

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