Dataset Information

Differential GR Expression and Translocation in the Hippocampus Mediates Susceptibility vs. Resilience to Chronic Social Defeat Stress.

ABSTRACT: While social stress exposure is a common risk factor for affective disorders, most individuals exposed to it can maintain normal physical and psychological functioning. However, factors that determine susceptibility vs. resilience to social stress remain unclear. Here, the resident-intruder model of social defeat was used as a social stressor in male C57BL/6J mice to investigate the difference between susceptibility and resilience. As depression is often characterized by hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, we conducted the present study to further investigate the individual differences in the HPA axis response and glucocorticoid receptor (GR) protein expression and translocation between susceptible mice and resilient mice. We found that hypercortisolemia, induced by social defeat stress occurred in susceptible mice, but not in resilient mice. Moreover, susceptible mice exhibited significantly less GR protein expression and nuclear translocation in the hippocampus than resilient mice. Treatment with escitalopram could decrease the serum corticosterone (CORT), increase GR protein expression as well as nuclear translocation in the hippocampus and ultimately reverse social withdrawal behaviors in susceptible mice. These results indicate that the up-regulation of GR and the enhancement of GR nuclear translocation in the hippocampus play an important role in resilience to chronic social defeat stress.

SUBMITTER: Han QQ

PROVIDER: S-EPMC5440566 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Differential GR Expression and Translocation in the Hippocampus Mediates Susceptibility vs. Resilience to Chronic Social Defeat Stress.

Han Qiu-Qin QQ Yang Liu L Huang Hui-Jie HJ Wang Ya-Lin YL Yu Rui R Wang Jing J Pilot Adam A Wu Gen-Cheng GC Liu Qiong Q Yu Jin J

Frontiers in neuroscience 20170523

While social stress exposure is a common risk factor for affective disorders, most individuals exposed to it can maintain normal physical and psychological functioning. However, factors that determine susceptibility vs. resilience to social stress remain unclear. Here, the resident-intruder model of social defeat was used as a social stressor in male C57BL/6J mice to investigate the difference between susceptibility and resilience. As depression is often characterized by hyperactivity of the hyp ...[more]

PMID: 28588443

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Project description:Dysregulation of innate immune responses has frequently been reported in stress-associated psychiatric disorders such as major depression. In mice, enhanced circulating cytokine levels as well as altered innate immune cell numbers have been found after stress exposure. In addition, stress-induced recruitment of peripheral monocytes to the brain has been shown to promote anxiety-like behavior. However, it is yet unclear whether specific differences in the innate immune system are associated with stress susceptibility or resilience in mice. Utilizing chronic social defeat, a model of depression and stress vulnerability, we characterized peripheral and brain-invading myeloid cells in stress-susceptible and resilient animals. In all defeated animals, we found reduced percentages of CD11c+ dendritic cells (DCs) by flow cytometry in the spleen when compared to non-defeated controls. Exclusively in susceptible mice conventional DCs of the spleen showed up-regulated expression of MHC class II and co-stimulatory CD80 molecules pointing toward an enhanced maturation phenotype of these cells. Susceptible, but not resilient animals further exhibited an increase in inflammatory Ly6Chi monocytes and higher numbers of spleen-derived CD11b+ cells that produced the proinflammatory cytokine tumor necrosis factor (TNF) upon lipopolysaccharide (LPS) stimulation. Increased percentages of peripheral CD45hi CD11b+ cells immigrated into the brain of defeated mice, regardless of resilience or susceptibility. However, cellular infiltrates in the brain of susceptible mice contained higher percentages of CC chemokine receptor 2 (CCR2+) Ly6Chi monocytes representing an inflammatory phenotype. Thus, we defined specific stress-related immune signatures involving conventional DCs and inflammatory Ly6Chi monocytes in susceptible and resilient mice. Together, our findings suggest an impact of the innate immune system in vulnerability to stress-related disorders such as major depression.

Project description:Background: Microstructural alterations in the hippocampus may underlie stress-related disorders and stress susceptibility. However, whether these alterations are pre-existing stress vulnerability biomarkers or accumulative results of chronic stress remain unclear. Moreover, examining the whole hippocampus as one unit and ignoring the possibility of a lateralized effect of stress may mask some stress effects and contribute to the heterogeneity of previous findings. Methods: After C57BL/6 mice were exposed to a 10-day chronic social defeat stress (CSDS) paradigm, different stress phenotypes, i.e., susceptible (n = 10) and resilient (n = 7) mice, were discriminated by the behavior of the mice in a social interaction test. With in vivo diffusion tensor imaging (DTI) scans that were conducted both before and after the stress paradigm, we evaluated diffusion properties in the left and right, dorsal (dHi) and ventral hippocampus (vHi) of experimental mice. Results: A significantly lower fractional anisotropy (FA) was found in the right vHi of the susceptible mice prior to the CSDS paradigm than that found in the resilient mice, suggesting that pre-existing microstructural abnormalities may result in stress susceptibility. However, no significant group differences were found in the post-stress FA values of any of the hippocampal regions of interest (ROIs). In addition, mean diffusivity (MD) and radial diffusivity (RD) values were found to be significantly greater only in the right dHi of the resilient group compared to those of the susceptible mice. Furthermore, a significant longitudinal decrease was only observed in the right dHi RD value of the susceptible mice. Moreover, the social interaction (SI) ratio was positively related to post-stress left MD, right dHi MD, and right dHi RD values and the longitudinal right dHi MD percent change. Meanwhile, a negative relationship was detected between the SI ratio and bilateral mean of the post-stress left relative to right vHi FA value, highlighting the important role of right hippocampus in stress-resilience phenotype. Conclusion: Our findings demonstrated different longitudinal microstructural alterations in the bilateral dHi and vHi between stress-susceptible and resilient subgroups and indicated a right-sided lateralized stress effect, which may be useful in the diagnosis and prevention of stress-related disorders as well as their intervention.

Project description:BackgroundPost-traumatic stress disorder (PTSD) is a trauma-related disorder that is associated with pro-inflammatory activation and neurobiological impairments in the brain and leads to a series of affective-like behaviors. Electroacupuncture (EA) has been proposed as a clinically useful therapy for several brain diseases. However, the potential role of EA treatment in PTSD and its molecular and cellular mechanisms has rarely been investigated.MethodsWe used an established preclinical social defeat stress mouse model to study whether EA treatment modulates PTSD-like symptoms and understand its underlying mechanisms. To this end, male C57BL/6 mice were subjected to repeated social defeat stress (RSDS) for 6 consecutive days to induce symptoms of PTSD and treated with EA at Baihui (GV 20) and Dazhui (GV 14) acupoints.ResultsThe stimulation of EA, but not needle insertion at Baihui (GV 20) and Dazhui (GV 14) acupoints effectively improved PTSD-like behaviors such as, social avoidance and anxiety-like behaviors. However, EA stimulation at the bilateral Tianzong (SI11) acupoints did not affect the PTSD-like behaviors obtained by RSDS. EA stimulation also markedly inhibited astrocyte activation in both the dorsal and ventral hippocampi of RSDS-treated mice. Using next-generation sequencing analysis, our results showed that EA stimulation attenuated RSDS-enhanced lipocalin 2 expression in the hippocampus. Importantly, using double-staining immunofluorescence, we observed that the increased lipocalin 2 expression in astrocytes by RSDS was also reduced by EA stimulation. In addition, intracerebroventricular injection of mouse recombinant lipocalin 2 protein in the lateral ventricles provoked social avoidance, anxiety-like behaviors, and the activation of astrocytes in the hippocampus. Interestingly, the overexpression of lipocalin 2 in the brain also altered the expression of stress-related genes, including monoamine oxidase A, monoamine oxidase B, mineralocorticoid receptor, and glucocorticoid receptor in the hippocampus.ConclusionsThis study suggests that the treatment of EA at Baihui (GV 20) and Dazhui (GV 14) acupoints improves RSDS-induced social avoidance, anxiety-like behaviors, astrocyte activation, and lipocalin 2 expression. Furthermore, our findings also indicate that lipocalin 2 expression in the brain may be an important biomarker for the development of PTSD-related symptoms.

Dataset Information

Differential GR Expression and Translocation in the Hippocampus Mediates Susceptibility vs. Resilience to Chronic Social Defeat Stress.

Publications

Differential GR Expression and Translocation in the Hippocampus Mediates Susceptibility vs. Resilience to Chronic Social Defeat Stress.

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