Elsevier

International Immunopharmacology

Volume 66, January 2019, Pages 242-250
International Immunopharmacology

On the role of corticosterone in behavioral disorders, microbiota composition alteration and neuroimmune response in adult male mice subjected to maternal separation stress

https://doi.org/10.1016/j.intimp.2018.11.037Get rights and content

Highlights

  • MS provoked negative behaviors, inflammatory responses in the hippocampus and colon tissues of adult male mice

  • MS led to overactivation of the HPA axis and overproduction of the corticosterone

  • MS altered composition of the gut microbiota

  • Corticosterone, likely, mediated negative effects of MS on behavior and inflammatory responses

  • Adrenalectomy restored, in part, microbiota composition in the gut and mitigated negative effects of MS

Abstract

Experiencing psychosocial adversities in early life such as maternal separation (MS) increases the risk of psychiatric disorders. Immune-inflammatory responses have imperative roles in the pathophysiology of psychiatric disorders. MS relatively changes the composition of intestinal microbiota leading to an overactivation of the hypothalamic–pituitary–adrenal (HPA) axis, and subsequently increases the corticosterone level. In this study, we aimed to evaluate the role of corticosterone in behavioral changes and microbiota modifications in a mouse model of MS afflicted neuroinflammatory response in the hippocampus. For this purpose, 180 min of MS stress was applied to mice at postnatal day (PND) 2–14 followed by behavioral tests including forced swimming test (FST), splash test, open field test (OFT) and elevated plus maze (EPM) at PND 50–52. For evaluating the role of corticosterone, mice were subjected to adrenalectomy. Using real-time RT-PCR, the expression of inflammatory genes was determined in the hippocampus and colon tissues. We found that MS provoked depressive- and anxiety-like behaviors in adult male mice. In addition, MS was able to active a neuroimmune response in the hippocampus, motivate inflammation and histopathologic changes in the colon tissue and modify the composition of gut microbiota as well. Interestingly, our findings showed that adrenalectomy (decline in the corticosterone level), could modulate the above-mentioned negative effects of MS. In conclusion, our results demonstrated that overactivation of HPA axis and the subsequent increased level of corticosterone could act, possibly, as the deleterious effects of MS on behavior, microbiota composition changes and activation of neuroimmune response.

Introduction

Social ties, principally mother-infant relationship during the infantile period, have a critical role in the development of the brain and behavior in adulthood [1]. It is shown that neonate exposure into psychosocial adversities, like maternal separation (MS) stress, dramatically interrupt brain development and augments the risk of neuropsychiatric diseases including anxiety and depression [2].

Activation of hypothalamic–pituitary–adrenal (HPA) axis followed by stress adapts body function has the potential to modulate physiological responses to upcoming tensions through over-release of glucocorticoids [3]. Previous studies have demonstrated that experiencing adversities in early life contributed to overactivation of the HPA axis, and consequently increased corticosterone levels resulting in psychological disorders in later life [3]. In other words, experiencing early life stress like MS leads to persistent and life-long changes in the HPA axis which means that the stress center (HPA axes) sets in a higher point [4,5].

The gut contains a diverse microbial biota, which are mainly anaerobes bacteria, in addition to fungi and viruses [6]. Microflora has an approved central role in the regulation of emotion and behaviors [7]. Alterations in the composition of the intestinal microbiota are associated with changes in the inflammatory, neuroendocrine and behavioral responses of the host [8]. Early life adversity such as MS disturbs development and composition of the intestinal microbiota [9]. Alterations in the composition of the microbiota, along with increasing gut permeability following stress, could lead to the over-production of pro-inflammatory cytokines in the bowel. It is coupled with the fact that there are noticable interactions between stress, the immune system and the gut microbiota [10].

It has been suggested that oxidative and nitrosative stress (O&NS), as well as immune-inflammatory responses, have an imperative role in the pathophysiology of psychiatric disorders [11]. Moreover, chronic exposure to glucocorticosteroids could initiate inflammatory immune responses in the brain and arise depressive-like behaviors [12].

Considering 1) the relationship between stress and immune-inflammatory responses following early life tensions, 2) Alterations in microbiota following chronic stress, 3) over-activation of the HPA axis in stressful condition, 4) potential role of neuroinflammation in the pathophysiology of psychiatric disorders; in the present study, we aimed to evaluate the role of corticosterone on microbial composition, neuroinflammation and behavioral changes following maternal separation stress. In addition, we intended to examine whether adrenalectomy can modulate the negative effects of MS.

Section snippets

Animals and housing conditions

Forty-five pregnant NMRI mice on gestation day of 1 were bought from Pasteur Institute of Iran. Animals were kept under standard laboratory environment of 12-h light/dark cycle, temperature 22 ± 1 °C and free access to food and water. The day of birth was considered as postnatal day (PND) 0. Pups at PND 2 were subjected to maternal separation (MS) paradigm. In this model, offsprings were daily separated from their mothers during PND 2–14 for 3 h (09:00–12:00 a.m.) and then returned to their

Adrenalectomy could modulate depressive -like behaviors in adult male mice

Two-way ANOVA analysis showed that there are significant differences between experimental groups. Bonferroni post-test showed that the duration of immobility time in the FST (Fig. 1A) significantly increased in MS mice in comparison with the control group (P < 0.01). Moreover, following adrenalectomy duration of immobility time significantly decreased in MS mice (P < 0.05). In the splash test (Fig. 1B), results showed that MS provoked a significant decrease in grooming activity time in

Discussion

Findings of the present study showed that maternal separation (MS) stress provoked anxiogenic- and depressive-like effects in adult male mice revealed by behavioral tests including FST, OFT, EPM and splash test. We observed that the expression of inflammatory genes related to neuro-immune response increased in the hippocampus of MS mice. Evaluation of the bowel (colon) tissue determined that MS led to the histopathologic changes in the colon and also increased the expression of inflammatory

Conclusion

In conclusion, results of the present study demonstrated that 1) MS provoked depressive- and anxiety-like behaviors in adult male mice 2) MS modified gut microbiota composition 3) MS activated neuro-immune response in the hippocampus 4) MS led to the damage in colon tissue 5) MS led to overproduction of corticosterone 6) adrenalectomy inverted, at least in part, negative effects of MS on the behavior and also mitigated neuroinflammatory response in the hippocampus 7) adrenalectomy reset, may be

Conflict of interest

The authors declare that there is no conflict of interest.

Compliance with ethical standards

All applicable international and institutional guidelines for the care and use of animals were followed.

Acknowledgment

This work was supported by a grant from Shahrekord University of Medical Sciences (SKUMS) with grant number of “1395-01-75-3254”.

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