scholarly journals Transcriptome-Wide Identification of G-to-A RNA Editing in Chronic Social Defeat Stress Mouse Models

2021 ◽  
Vol 12 ◽  
Author(s):  
Ji Tao ◽  
Chun-Yan Ren ◽  
Zhi-Yuan Wei ◽  
Fuquan Zhang ◽  
Jinyu Xu ◽  
...  
Keyword(s):  
Rna Editing ◽  
Mouse Models ◽  
Physiological Stress ◽  
Neurological Diseases ◽  
Social Defeat ◽  
Social Defeat Stress ◽  
Chronic Social Defeat Stress ◽  
Solute Carrier ◽  
The Brain

Emerging evidence suggests that RNA editing is associated with stress, neurological diseases, and psychiatric disorders. However, the role of G-to-A RNA editing in chronic social defeat stress (CSDS) remains unclear. We herein identified G-to-A RNA editing and its changes in the ventral tegmental area (VTA), a key region of the brain reward system, in CSDS mouse models under emotional stress (ES) and physiological stress (PS) conditions. Our results revealed 3812 high-confidence G-to-A editing events. Among them, 56 events were significantly downregulated while 23 significantly upregulated in CSDS compared to controls. Moreover, divergent editing patterns were observed between CSDS mice under ES and PS conditions, with 42 and 21 events significantly upregulated in PS and ES, respectively. Interestingly, differential RNA editing was enriched in genes with multiple editing events. Genes differentially edited in CSDS included those genetically associated with mental or neurodevelopmental disorders, especially mood disorders, such as FAT atypical cadherin 1 and solute carrier family 6 member 1. Notably, changes of G-to-A RNA editing were also implicated in ionotropic glutamate receptors, a group of well-known targets of adenosine-to-inosine RNA editing. Such results demonstrate dynamic G-to-A RNA editing changes in the brain of CSDS mouse models, underlining its role as a potential molecular mechanism of CSDS and stress-related diseases.

scholarly journals Splenic NKG2D confers resilience versus susceptibility in mice after chronic social defeat stress: beneficial effects of (R)-ketamine

2019 ◽  
Author(s):  
Kai Zhang ◽  
Akemi Sakamoto ◽  
Lijia Chang ◽  
Youge Qu ◽  
Siming Wang ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Molecular Mechanisms ◽  
Social Defeat ◽  
Social Defeat Stress ◽  
Beneficial Effects ◽  
Nkg2d Expression ◽  
Chronic Social Defeat Stress ◽  
Group 2 ◽  
Stress Susceptibility

AbstractThe spleen is a large immune organ that plays a key role in the immune system. The precise molecular mechanisms underlying the relationship between the spleen and stress-related psychiatric disorders are unknown. Here we investigated the role of spleen in stress-related psychiatric disorders. FACS analysis was applied to determine the contribution of the spleen to susceptibility and resilience in mice that were subjected to chronic social defeat stress (CSDS). We found a notable increase in splenic volume and weight in CSDS-susceptible mice compared to control (no CSDS) mice and CSDS-resilient mice. The number of granulocytes, but not of T cells and B cells, in the spleen of susceptible mice was higher than in the spleen of both control and resilient mice. Interestingly, NKG2D (natural killer group 2, member D) expression in the spleen of CSDS-susceptible mice was higher than that in control mice and CSDS-resilient mice. In addition, NKG2D expression in the spleen of patients with depression was higher than that in controls. Both increased splenic weight and increased splenic NKG2D expression in CSDS-susceptible mice were ameliorated after a subsequent administration of (R)-ketamine. The present findings indicate a novel role of splenic NKG2D in stress susceptibility versus resilience in mice subjected to CSDS. Furthermore, abnormalities in splenic functions in CSDS-susceptible mice were ameliorated after subsequent injection of (R)-ketamine. Thus, the brain–spleen axis might, at least in part, contribute to the pathogenesis of stress-related psychiatric disorders such as depression.

scholarly journals The protective role of Neuregulin1-ErbB4 signaling in a chronic social defeat stress model

Neuroreport ◽  
2020 ◽  
Vol 31 (9) ◽  
pp. 678-685
Author(s):  
Wenjuan Wang ◽  
Yong Qiao ◽  
Huiying Qu ◽  
Lin Zhu ◽  
Linlin Mu ◽  
...  
Keyword(s):  
Social Defeat ◽  
Protective Role ◽  
Stress Model ◽  
Social Defeat Stress ◽  
Chronic Social Defeat Stress

scholarly journals Cannabinoid receptor 1 signalling modulates stress susceptibility and microglial responses to chronic social defeat stress

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eva C. Beins ◽  
Thomas Beiert ◽  
Imke Jenniches ◽  
Jan N. Hansen ◽  
Este Leidmaa ◽  
...  
Keyword(s):  
Stress Responses ◽  
Cannabinoid Receptor ◽  
Inflammatory Responses ◽  
Myeloid Cells ◽  
Social Defeat ◽  
Social Defeat Stress ◽  
Cannabinoid Receptor 1 ◽  
Behavioural Phenotype ◽  
Chronic Social Defeat Stress ◽  
The Brain

AbstractPsychosocial stress is one of the main environmental factors contributing to the development of psychiatric disorders. In humans and rodents, chronic stress is associated with elevated inflammatory responses, indicated by increased numbers of circulating myeloid cells and activation of microglia, the brain-resident immune cells. The endocannabinoid system (ECS) regulates neuronal and endocrine stress responses via the cannabinoid receptor 1 (CB1). CB1-deficient mice (Cnr1−/−) are highly sensitive to stress, but if this involves altered inflammatory responses is not known. To test this, we exposed Cnr1+/+ and Cnr1−/− mice to chronic social defeat stress (CSDS). Cnr1−/− mice were extremely sensitive to a standard protocol of CSDS, indicated by an increased mortality rate. Therefore, a mild CSDS protocol was established, which still induced a behavioural phenotype in susceptible Cnr1−/− mice. These mice also showed altered glucocorticoid levels after mild CSDS, suggesting dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. Mild CSDS induced weak myelopoiesis in the periphery, but no recruitment of myeloid cells to the brain. In contrast, mild CSDS altered microglial activation marker expression and morphology in Cnr1−/− mice. These microglial changes correlated with the severity of the behavioural phenotype. Furthermore, microglia of Cnr1−/− mice showed increased expression of Fkbp5, an important regulator of glucocorticoid signalling. Overall, the results confirm that CB1 signalling protects the organism from the physical and emotional harm of social stress and implicate endocannabinoid-mediated modulation of microglia in the development of stress-related pathologies.

scholarly journals Histone Lysine Demethylase JMJD2D/KDM4D and Family Members Mediate Effects of Chronic Social Defeat Stress on Mouse Hippocampal Neurogenesis and Mood Disorders

2020 ◽  
Vol 10 (11) ◽  
pp. 833
Author(s):  
Swati Maitra ◽  
Nitin Khandelwal ◽  
Scherazad Kootar ◽  
Pooja Sant ◽  
Salil S. Pathak ◽  
...  
Keyword(s):  
Mood Disorders ◽  
Chronic Stress ◽  
Social Defeat ◽  
Social Defeat Stress ◽  
Histone Lysine ◽  
Chronic Social Defeat Stress ◽  
Proliferation And Differentiation ◽  
Lysine Residues ◽  
Induced Changes

Depression, anxiety and related mood disorders are major psychiatric illnesses worldwide, and chronic stress appears to be one of the primary underlying causes. Therapeutics to treat these debilitating disorders without a relapse are limited due to the incomplete molecular understanding of their etiopathology. In addition to the well-studied genetic component, research in the past two decades has implicated diverse epigenetic mechanisms in mediating the negative effects of chronic stressful events on neural circuits. This includes the cognitive circuitry, where the dynamic hippocampal dentate gyrus (DG) neurogenesis gets affected in depression and related affective disorders. Most of these epigenetic studies have focused on the impact of acetylation/deacetylation and methylation of several histone lysine residues on neural gene expression. However, there is a dearth of investigation into the role of demethylation of these lysine residues in chronic stress-induced changes in neurogenesis that results in altered behaviour. Here, using the chronic social defeat stress (CSDS) paradigm to induce depression and anxiety in C57BL/6 mice and ex vivo DG neural stem/progenitor cell (NSCs/NPCs) culture we show the role of the members of the JMJD2/KDM4 family of histone lysine demethylases (KDMs) in mediating stress-induced changes in DG neurogenesis and mood disorders. The study suggests a critical role of JMJD2D in DG neurogenesis. Altered enrichment of JMJD2D on the promoters of Id2 (inhibitor of differentiation 2) and Sox2 (SRY-Box Transcription Factor 2) was observed during proliferation and differentiation of NSCs/NPCs obtained from the DG. This would affect the demethylation of repressive epigenetic mark H3K9, thus activating or repressing these and possibly other genes involved in regulating proliferation and differentiation of DG NSCs/NPCs. Treatment of the NSCs/NPCs culture with Dimethyloxallyl Glycine (DMOG), an inhibitor of JMJDs, led to attenuation in their proliferation capacity. Additionally, systemic administration of DMOG in mice for 10 days induced depression-like and anxiety-like phenotype without any stress exposure.

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