Synergistic effects of early life mild adversity and chronic social defeat on rat brain microglia and cytokines

Ferle, Vasiliki; Repouskou, Anastasia; Aspiotis, George; Raftogianni, Androniki; Chrousos, George P.; Stylianopoulou, Fotini; Stamatakis, Antonios

doi:10.1016/j.physbeh.2019.112791

Cited by 28 publications

(19 citation statements)

References 72 publications

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“…Glial cells in the PFC are highly important for inducing depressive behavior which was supported by the finding that glial loss alone may cause depressive like behavior [150]. In addition, numerous studies have demonstrated that chronic stress can alter the number of glial cells and impair their functions [105,[151][152][153][154][155][156][157][158]. Furthermore, Rajkowska and co-workers reported a significant decrease in neuronal and glial cell densities in the PFC of depressed patients [159,160].…”

Section: Prefrontal Cortex (Pfc)mentioning

confidence: 91%

“…Several CMS studies reported on a robust decrease in the number of GFAP-expressing astroglia in the dentate gyrus [102,103], whereas microglial activation was detected both in vivo (with PET) and postmortem (with immunofluorescence staining, and western blotting) [104]. Furthermore, CMS exposure results in an increased number of activated microglial cells (Iba-1+) [105]. These findings have led to "gliocentric theories of depression," in which glial cells account for the pathophysiology of depression [106][107][108][109].…”

Section: Hippocampal Formationmentioning

confidence: 99%

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Stress-Induced Morphological, Cellular and Molecular Changes in the Brain—Lessons Learned from the Chronic Mild Stress Model of Depression

Khan

Geiger

Wiborg

et al. 2020

Cells

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Major depressive disorder (MDD) is a severe illness imposing an increasing social and economic burden worldwide. Numerous rodent models have been developed to investigate the pathophysiology of MDD. One of the best characterized and most widely used models is the chronic mild stress (CMS) model which was developed more than 30 years ago by Paul Willner. More than 2000 published studies used this model, mainly to assess novel compounds with potential antidepressant efficacy. Most of these studies examined the behavioral consequences of stress and concomitant drug intervention. Much fewer studies focused on the CMS-induced neurobiological changes. However, the stress-induced cellular and molecular changes are important as they may serve as potential translational biomarkers and increase our understanding of the pathophysiology of MDD. Here, we summarize current knowledge on the structural and molecular alterations in the brain that have been described using the CMS model. We discuss the latest neuroimaging and postmortem histopathological data as well as molecular changes including recent findings on microRNA levels. Different chronic stress paradigms occasionally deliver dissimilar findings, but the available experimental data provide convincing evidence that the CMS model has a high translational value. Future studies examining the neurobiological changes in the CMS model in combination with clinically effective antidepressant drug intervention will likely deliver further valuable information on the pathophysiology of MDD.

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Section: Prefrontal Cortex (Pfc)mentioning

confidence: 91%

Section: Hippocampal Formationmentioning

confidence: 99%

Stress-Induced Morphological, Cellular and Molecular Changes in the Brain—Lessons Learned from the Chronic Mild Stress Model of Depression

Khan

Geiger

Wiborg

et al. 2020

Cells

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“…In fact, as evident in Table 1, at least 16 animal studies have shown that in the prefrontal cortex, exposure to different psychosocial stressors gives rise to increases in ionized calcium-binding adaptor molecule 1 (Iba-1) immunoreactivity, a specific marker for the morphological changes and expansion of microglia. These psychosocial stressors involve repeated social defeat (SD), varying unpredictable stress, prenatal stress, social isolation, and chronic restraint (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). Similar effects from psychosocial stressors were also evident in other areas of the brain, including the amygdala (25,26), hippocampus (25-28, 30, 36, 38, 39, 41-47), nucleus accumbens (36,37) and paraventricular nucleus (25,26).…”

Section: Psychosocial Stress Microglia and Depressive-like Behavior mentioning

confidence: 99%

Microglial Dysregulation and Suicidality: A Stress-Diathesis Perspective

Baharikhoob

Kolla

2020

Front. Psychiatry

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According to the stress-diathesis model of suicidal behavior, completed suicide depends on the interaction between psychosocial stressors and a trait-like susceptibility. While there are likely multiple biological processes at play in suicidal behavior, recent findings point to overactivation of microglia, the resident macrophages of the central nervous system, as implicated in stress-induced suicidal behavior. However, it remains unclear how microglial dysregulation can be integrated into a clinical model of suicidal behavior. Therefore, this narrative review aims to (1) examine the findings from human post-mortem and neuroimaging studies that report a relationship between microglial activation and suicidal behavior, and (2) update the clinical model of suicidal behavior to integrate the role of microglia. A systematic search of SCOPUS, PubMed, PsycINFO, and Embase databases revealed evidence of morphological alterations in microglia and increased translocator protein density in the brains of individuals with suicidality, pointing to a positive relationship between microglial dysregulation and suicidal behavior. The studies also suggested several pathological mechanisms leading to suicidal behavior that may involve microglial dysregulation, namely (1) enhanced metabolism of tryptophan to quinolinic acid through the kynurenine pathway and associated serotonin depletion; (2) increased quinolinic acid leading to excessive Nmethyl-D-aspartate-signaling, resulting in potential disruption of the blood brain barrier; (3) increased quinolinic acid resulting in higher neurotoxicity, and; (4) elevated interleukin 6 contributing to loss of inhibition of glutamatergic neurons, causing heightened glutamate release and excitotoxicity. Based on these pathways, we reconceptualized the stressdiathesis theory of suicidal behavior to incorporate the role of microglial activity.

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“…Furthermore, after exposure to ELA laterlife stressors induced a clear inflammatory response in the prefrontal cortex and hippocampus. This suggests a clear role for the immune system in the programming of the long-term effects of ELA on the brain (Ferle et al, 2020). This link is reinforced by the association of differential methylation of neuronal development genes in PBMCs after ELA (Esposito et al, 2016), and the epidemiological link between sepsis in new-borns and long term brain development (Alshaikh et al, 2013).…”

Section: Biological Components and Consequences Of Elamentioning

confidence: 99%

Is Early Life Adversity a Trigger towards Inflammageing?

Merz¹,

Turner²

2021

Preprint

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There are many ‘faces’ of early life adversity (ELA), such as childhood trauma, institutionalization, abuse or exposure to environmental toxins. These have been implicated in the onset and severity of a wide range of chronic non-communicable diseases later in life. The later-life disease risk has a well-established immunological component. This raises the question as to whether accelerated immune-ageing mechanistically links early-life adversity to the lifelong health trajectory resulting in either ‘poor’ or ‘healthy’ ageing. Here we examine observational and mechanistic studies of ELA and inflammageing, highlighting common and distinct features in these two life stages. Many biological processes appear in common including reduction in telomere length, increased immuno-senescence, metabolic distortions and chronic (viral) infections. We propose that ELA shapes the developing immune, endocrine and nervous system in a non-reversible way, creating a distinct phenotype with accelerated immuno-senescence and systemic inflammation. We believe that ELA acts as an accelerator for inflammageing and age-related diseases. Furthermore, we now have the tools and cohorts to be able to dissect the interaction between early life adversity and later life phenotype. This should, in the near future, allow us to identify the ecological and mechanistic processes that are involved in ‘healthy’ or accelerated immune-ageing.

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Synergistic effects of early life mild adversity and chronic social defeat on rat brain microglia and cytokines

Cited by 28 publications

References 72 publications

Stress-Induced Morphological, Cellular and Molecular Changes in the Brain—Lessons Learned from the Chronic Mild Stress Model of Depression

Stress-Induced Morphological, Cellular and Molecular Changes in the Brain—Lessons Learned from the Chronic Mild Stress Model of Depression

Microglial Dysregulation and Suicidality: A Stress-Diathesis Perspective

Is Early Life Adversity a Trigger towards Inflammageing?

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