scholarly journals Sexually divergent effects of social dominance on chronic stress outcomes in mice

2020 ◽  
Author(s):  
Stoyo Karamihalev ◽  
Elena Brivio ◽  
Cornelia Flachskamm ◽  
Rainer Stoffel ◽  
Mathias V. Schmidt ◽  
...  
Keyword(s):  
Social Context ◽  
Chronic Stress ◽  
Social Dominance ◽  
Tracking System ◽  
Group Living ◽  
Chronic Mild Stress ◽  
Outcome Data ◽  
Mild Stress ◽  
Dominance Status ◽  
Dominant Female

AbstractBackgroundSex and social context are two major factors in the development of depression and other stress-related disorders. However, few studies of the effects of stress on rodent behavior and physiology have investigated social context and fewer still have assessed the possibility of sex-specific effects of social context.MethodsWe assessed social dominance of group-living mice during several days of monitoring using a high-throughput automated behavioral tracking system. We then exposed groups from each sex to a three-week chronic mild stress (CMS) procedure, followed by a behavioral test battery. Finally, we used principle component analysis and post-hoc tests to explore the sources of variance in the behavioral outcome data.ResultsWe found stable hierarchies in both sexes, however social dominance in males exhibited several additional associations with behaviors related to locomotion and exploration that were not seen in females. Crucially, pre-stress social dominance status was associated with opposing outcomes on multiple behavioral readouts between the two sexes following CMS. In particular, subordinate male mice and dominant female mice appeared more responsive to the environmental challenge, as observed in anxiety-like and locomotor behaviors.ConclusionsThis work demonstrates that sex differences interact with preexisting social dominance status to alter the effects of chronic stress. It highlights the importance of understanding the interplay between sex and social context and its contribution to individual differences in stress response.

scholarly journals Stress Modifies the Expression of Glucocorticoid-Responsive Genes by Acting at Epigenetic Levels in the Rat Prefrontal Cortex: Modulatory Activity of Lurasidone

2021 ◽  
Vol 22 (12) ◽  
pp. 6197
Author(s):  
Paola Brivio ◽  
Giulia Sbrini ◽  
Letizia Tarantini ◽  
Chiara Parravicini ◽  
Piotr Gruca ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Chronic Stress ◽  
Chronic Mild Stress ◽  
Male Rats ◽  
Mild Stress ◽  
Experimental Conditions ◽  
Glucocorticoid Responsive Element ◽  
Responsive Element

Epigenetics is one of the mechanisms by which environmental factors can alter brain function and may contribute to central nervous system disorders. Alterations of DNA methylation and miRNA expression can induce long-lasting changes in neurobiological processes. Hence, we investigated the effect of chronic stress, by employing the chronic mild stress (CMS) and the chronic restraint stress protocol, in adult male rats, on the glucocorticoid receptor (GR) function. We focused on DNA methylation specifically in the proximity of the glucocorticoid responsive element (GRE) of the GR responsive genes Gadd45β, Sgk1, and Gilz and on selected miRNA targeting these genes. Moreover, we assessed the role of the antipsychotic lurasidone in modulating these alterations. Chronic stress downregulated Gadd45β and Gilz gene expression and lurasidone normalized the Gadd45β modification. At the epigenetic level, CMS induced hypermethylation of the GRE of Gadd45β gene, an effect prevented by lurasidone treatment. These stress-induced alterations were still present even after a period of rest from stress, indicating the enduring nature of such changes. However, the contribution of miRNA to the alterations in gene expression was moderate in our experimental conditions. Our results demonstrated that chronic stress mainly affects Gadd45β expression and methylation, effects that are prolonged over time, suggesting that stress leads to changes in DNA methylation that last also after the cessation of stress procedure, and that lurasidone is a modifier of such mechanisms.

scholarly journals Social dominance mediates behavioral adaptation to chronic stress in a sex-specific manner

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Stoyo Karamihalev ◽  
Elena Brivio ◽  
Cornelia Flachskamm ◽  
Rainer Stoffel ◽  
Mathias V Schmidt ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Social Dominance ◽  
Behavioral Outcomes ◽  
Group Living ◽  
Social Hierarchy ◽  
Behavioral Adaptation ◽  
The Social ◽  
Specific Manner ◽  
Behavioral Monitoring ◽  
Influence Behavior

Sex differences and social context independently contribute to the development of stress-related disorders. However, less is known about how their interplay might influence behavior and physiology. Here we focused on social hierarchy status, a major component of the social environment in mice, and whether it influences behavioral adaptation to chronic stress in a sex-specific manner. We used a high-throughput automated behavioral monitoring system to assess social dominance in same-sex, group-living mice. We found that position in the social hierarchy at baseline was a significant predictor of multiple behavioral outcomes following exposure to chronic stress. Crucially, this association carried opposite consequences for the two sexes. This work demonstrates the importance of recognizing the interplay between sex and social factors and enhances our understating of how individual differences shape the stress response.

scholarly journals Depressive behavior and vascular dysfunction: a link between clinical depression and vascular disease?

2010 ◽  
Vol 108 (5) ◽  
pp. 1041-1051 ◽  
Author(s):  
Alexandre C. d'Audiffret ◽  
Stephanie J. Frisbee ◽  
Phoebe A. Stapleton ◽  
Adam G. Goodwill ◽  
Elsa Isingrini ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Vascular Disease ◽  
Chronic Stress ◽  
Vascular Dysfunction ◽  
Significant Risk ◽  
Chronic Mild Stress ◽  
Prior History ◽  
No Production ◽  
Mild Stress ◽  
Depressive Behavior

As chronic stress and depression have become recognized as significant risk factors for peripheral vascular disease in patients with no prior history of vasculopathy, we interrogated this relationship utilizing an established mouse model of chronic stress/depressive symptoms from behavioral research. Male mice were exposed to 8 wk of unpredictable chronic mild stress (UCMS; e.g., wet bedding, predator sound/smell, random disruption of light/dark cycle), with indexes of depressive behavior (coat status, grooming, and mobility) becoming exacerbated vs. controls. In vascular rings, constrictor (phenylephrine) and endothelium-independent dilator (sodium nitroprusside) responses were not different between groups, although endothelium-dependent dilation (methacholine) was attenuated with UCMS. Nitric oxide synthase (NOS) inhibition was without effect in UCMS but nearly abolished reactivity in controls, while cyclooxygenase inhibition blunted dilation in both. Combined blockade abolished reactivity in controls, although a significant dilation remained in UCMS that was abolished by catalase. Arterial NO production was attenuated by UCMS, although H2O2 production was increased. UCMS mice demonstrated an increased, although variable, insulin resistance and inflammation. However, while UCMS-induced vascular impairments were consistent, the predictive power of aggregate plasma levels of insulin, TNF-α, IL-1β, and C-reactive peptide were limited. However, when separated into tertiles with regard to vascular outcomes, insulin resistance and hypertension were predictive of the most severe vascular impairments. Taken together, these data suggest that aggregate insulin resistance, inflammation, and hypertension in UCMS mice are not robust predictors of vascular dysfunction, suggesting that unidentified mechanisms may be superior predictors of poor vascular outcomes in this model.

scholarly journals Peptide Selank Enhances the Effect of Diazepam in Reducing Anxiety in Unpredictable Chronic Mild Stress Conditions in Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Anastasiya Kasian ◽  
Timur Kolomin ◽  
Lyudmila Andreeva ◽  
Elena Bondarenko ◽  
Nikolay Myasoedov ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Anxiolytic Effect ◽  
Chronic Mild Stress ◽  
Stress Conditions ◽  
Mild Stress ◽  
Unpredictable Chronic Mild Stress ◽  
Elevated Plus Maze Test ◽  
Plus Maze ◽  
The Individual ◽  
Benzodiazepine Drugs

It was shown that the anxiolytic effect of Selank is comparable to that of classical benzodiazepine drugs and that the basis of their mechanism of action may be similar. These data suggest that the presence of Selank may change the action of classical benzodiazepine drugs. To test this hypothesis, we evaluated the anxiolytic activity of Selank and diazepam in rats both under conditions of unpredictable chronic mild stress and in its absence, after the individual and combined administration of these compounds using the elevated plus maze test. We found that, even in the absence of chronic stress, the administration of a course of test substances changed anxiety indicators toward their deterioration, but the changes after the administration of a course of Selank were less pronounced. In conditions of chronic stress, anxiety indicator values after the simultaneous use of diazepam and Selank did not differ from the respective values observed before chronic stress exposure. The data obtained indicate that the individual administration of Selank was the most effective in reducing elevated levels of anxiety, induced by the administration of a course of test substances, whereas the combination of diazepam with Selank was the most effective in reducing anxiety in unpredictable chronic mild stress conditions.

scholarly journals REM sleep: unique associations with behavior, corticosterone regulation and apoptotic pathways in chronic stress in mice

2018 ◽  
Author(s):  
Mathieu Nollet ◽  
Harriet Hicks ◽  
Andrew P. McCarthy ◽  
Huihai Wu ◽  
Carla S. Möller-Levet ◽  
...  
Keyword(s):  
Machine Learning ◽  
Eye Movement ◽  
Chronic Stress ◽  
Rem Sleep ◽  
Chronic Mild Stress ◽  
Specific Aspect ◽  
Mild Stress ◽  
Rapid Eye Movement ◽  
Rapid Eye Movement Sleep ◽  
Apoptotic Pathways

AbstractOne of sleep’s putative functions is mediation of adaptation to waking experiences. Chronic stress is a common waking experience, however, which specific aspect of sleep is most responsive, and how sleep changes relate to behavioral disturbances and molecular correlates remain unknown. We quantified sleep, physical, endocrine and behavioral variables and the brain and blood transcriptome in mice exposed to nine weeks of unpredictable chronic mild stress (UCMS). Comparing 46 phenotypical variables revealed that rapid-eye-movement sleep (REMS), corticosterone regulation and coat state were most responsive to UCMS. REMS theta oscillations were enhanced whereas delta oscillations in non-REMS were unaffected. Transcripts affected by UCMS in the prefrontal cortex, hippocampus, hypothalamus and blood were associated with inflammatory and immune responses. A machine learning approach controlling for unspecific UCMS effects identified transcriptomic predictors for specific phenotypes and their overlap. Transcriptomic predictor sets for the inter-individual variation in REMS continuity and theta activity shared many pathways with corticosterone regulation and in particular pathways implicated in apoptosis, including mitochondrial pathways. Predictor sets for REMS and anhedonia, one of the behavioral changes following UCMS, shared pathways involved in oxidative stress, cell proliferation and apoptosis. RNA predictor sets for non-NREMS parameters showed no overlap with other phenotypes. These novel data identify REMS as a core and early element of the response to chronic stress, and identify apoptotic pathways as a putative mechanism by which REMS mediates adaptation to stressful waking experiences.Significance StatementSleep is responsive to experiences during wakefulness and is altered in stress-related disorders. Whether sleep changes primarily concern rapid-eye-movement sleep (REMS) or non-REM sleep, and how they correlate with stress hormones, behavioral and transcriptomic responses remained unknown. We demonstrate using unpredictable chronic (9-weeks) mild stress that REMS is the most responsive of all the measured sleep characteristics, and correlates with deficiency in corticosterone regulation. An unbiased machine learning, controlling for unspecific effects of stress, revealed that REMS correlated with RNA predictor sets enriched in apoptosis including mitochondrial pathways. Several pathways were shared with predictors of corticosterone and behavioral responses. This unbiased approach point to apoptosis as a molecular mechanism by which REMS mediates adaptation to an ecologically relevant waking experience.

scholarly journals Proteomic Insights Into Susceptibility and Resistance to Chronic-Stress-Induced Depression or Anxiety in the Rat Striatum

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiao Cai ◽  
Chen Yang ◽  
Jin Chen ◽  
Weibo Gong ◽  
Faping Yi ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Chronic Mild Stress ◽  
Rat Striatum ◽  
Mild Stress ◽  
Absolute Quantitation ◽  
Protein Targets ◽  
Parallel Reaction Monitoring ◽  
Key Factor ◽  
Depression Disorders ◽  
Isobaric Tags

Chronic stress is a key factor for the onset of anxiety and depression disorders. However, the stress-induced common and unique molecular basis of the two psychiatric disorders is not fully known and still needs to be explored. Previously, we employed a chronic mild stress (CMS) procedure to induce a rat model including depression-susceptible (Dep-Sus), anxiety-susceptible (Anx-Sus), and insusceptible (Insus) cohorts. In this work, we continuously analyze the striatal proteomes of the three stressed cohorts by the use of comparative proteomics and bioinformatics approaches. Through isobaric tags for relative and absolute quantitation (iTRAQ)-based analysis, 386 abnormally expressed proteins in total were identified. These deregulated proteins are involved in various biological functions and significant pathways that are potentially connected with resistance and susceptibility to CMS-caused anxious- or depressive-like behaviors and, hence, could act as suggestive protein targets. A further parallel reaction monitoring-based independent investigation shows that alterations in Pak5, Dgkg, Scn4b, Rb1cc1, and Acin1; Ggps1, Fntb, Nudt19, Ufd1, and Ndufab1; and Dnajb12, Hbb2, Ap2s1, Ip6k1, and Stk4 were specifically connected with Dep-Sus, Anx-Sus, or Insus groups, respectively, potentially indicating that identical CMS treatment results in the different changes in the striatal protein regulations. Overall, our current proteomics study of the striatum provides an important molecular foundation and comprehensive insights into common and specific deregulations correlated with pathophysiological mechanisms that underlie resistance and susceptibility to chronic stress–induced anxiety or depression.

scholarly journals Chronic Mild Stress Causes Bone Loss via an Osteoblast-Specific Glucocorticoid-Dependent Mechanism

Endocrinology ◽  
2017 ◽  
Vol 158 (6) ◽  
pp. 1939-1950 ◽  
Author(s):  
Holger Henneicke ◽  
Jingbao Li ◽  
Sarah Kim ◽  
Sylvia J. Gasparini ◽  
Markus J. Seibel ◽  
...  
Keyword(s):  
Bone Loss ◽  
Chronic Stress ◽  
Structural Parameters ◽  
Chronic Mild Stress ◽  
Bone Resorption Marker ◽  
Mild Stress ◽  
Male Mice ◽  
Female Mice ◽  
Glucocorticoid Signaling ◽  
The Impact

Abstract Chronic stress and depression are associated with alterations in the hypothalamic–pituitary–adrenal signaling cascade and considered a risk factor for bone loss and fractures. However, the mechanisms underlying the association between stress and poor bone health are unclear. Using a transgenic (tg) mouse model in which glucocorticoid signaling is selectively disrupted in mature osteoblasts and osteocytes [11β-hydroxysteroid-dehydrogenase type 2 (HSD2)OB-tg mice], the present study examines the impact of chronic stress on skeletal metabolism and structure. Eight-week-old male and female HSD2OB-tg mice and their wild-type (WT) littermates were exposed to chronic mild stress (CMS) for the duration of 4 weeks. At the endpoint, L3 vertebrae and tibiae were analyzed by micro–computed tomography and histomorphometry, and bone turnover was measured biochemically. Compared with nonstressed controls, exposure to CMS caused an approximately threefold increase in serum corticosterone concentrations in WT and HSD2OB-tg mice of both genders. Compared with controls, CMS resulted in loss of vertebral trabecular bone mass in male WT mice but not in male HSD2OB-tg littermates. Furthermore, both tibial cortical area and area fraction were reduced in stressed WT but not in stressed HSD2OB-tg male mice. Osteoclast activity and bone resorption marker were increased in WT males following CMS, features absent in HSD2OB-tg males. Interestingly, CMS had little effect on vertebral and long-bone structural parameters in female mice. We conclude that in male mice, bone loss during CMS is mediated via enhanced glucocorticoid signaling in osteoblasts (and osteocytes) and subsequent activation of osteoclasts. Female mice appear resistant to the skeletal effects of CMS.

scholarly journals P2X7R antagonists in chronic stress-based depression models: a review

2021 ◽  
Author(s):  
Iven-Alex von Muecke-Heim ◽  
Clemens Ries ◽  
Lidia Urbina ◽  
Jan M. Deussing
Keyword(s):  
Chronic Stress ◽  
Chronic Mild Stress ◽  
Purinergic Signalling ◽  
Mild Stress ◽  
Research Domain Criteria ◽  
Application Timing ◽  
Study Planning ◽  
Level Increase ◽  
Immune Changes ◽  
Research Domain

AbstractDepression affects around 320 million people worldwide. Growing evidence proposes the immune system to be the core interface between psychosocial stress and the neurobiological and behavioural features of depression. Many studies have identified purinergic signalling via the P2X7 receptor (P2X7R) to be of great importance in depression genesis yet only a few have evaluated P2X7R antagonists in chronic stress-based depression models. This review summarizes their findings and analyses their methodology. The four available studies used three to nine weeks of unpredictable, chronic mild stress or unpredictable, chronic stress in male mice or rats. Stress paradigm composition varied moderately, with stimuli being primarily psychophysical rather than psychosocial. Behavioural testing was performed during or after the last week of stress application and resulted in depressive-like behaviours, immune changes (NLRP3 assembly, interleukin-1β level increase, microglia activation) and neuroplasticity impairment. During the second half of each stress paradigm, a P2X7R antagonist (Brilliant Blue G, A-438079, A-804598) was applied. Studies differed with regard to antagonist dosage and application timing. Nonetheless, all treatments attenuated the stress-induced neurobiological changes and depressive-like behaviours. The evidence at hand underpins the importance of P2X7R signalling in chronic stress and depression. However, improvements in study planning and reporting are necessary to minimize experimental bias and increase data purview. To achieve this, we propose adherence to the Research Domain Criteria and the STRANGE framework.

scholarly journals PL-010 Chronic mild stress improves glucose homeostasis via myonectin-mediated suppression of sympathetic activity in high-fat diet-fed mice

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Zhengtang Qi ◽  
Jie Xia ◽  
Xiangli Xue ◽  
Xingtian Li ◽  
Zhiming Cui ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Chronic Stress ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Sympathetic Activity ◽  
Chronic Mild Stress ◽  
Mild Stress ◽  
Glycerol Release ◽  
High Fat ◽  
Adeno Associated Virus

Objective Recent studies suggest that chronic stress exposure can ameliorate the progression of diet-induced prediabetic disease, by inhibiting an increase in weight gain, caloric intake and efficiency and insulin resistance. To determine the underlying mechanism by which chronic stress improves the progression of type 2 diabetes, we developed a model of chronic mild stress in high-fat diet(HFD)-fed mice which are resistant to obesity and exhibit a healthy-like metabolic phenotype. Methods High-fat diet (HFD): 45% kcal derived from fat (Research Diets, Inc.).Mice experienced one stressor during the day and a different stressor during the night. Stressors were randomly chosen from the following list : cage tilt on a 45° angle for 1 to 16 h; food deprivation for 12 to 16 h; white noise for 1 to 16 h; strobe light illumination for 1 to 16 h; crowded housing; light cycle (continuous illumination) for 24 to 36 h; dark cycle (continuous darkness) for 24 to 36 h; water deprivation for 12 to 16 h; damp bedding (200 ml water poured into sawdust bedding) for 12 to 16 h.Recombinant adeno-associated virus (AAV): AAV9 vectors encoding myonectin under the control of the ubiquitous CMV promoter (AAV9-CMV-Vip) or an equal dose of the AAV9-CMV-null vector were delivered to C57BL/6 mice by the tail vein. Mice were deprived of food for 16 h and then subjected to test 7 days after AAV injection. Results Chronic stress improved glucose intolerance and sympathetic overactivity in HFD-fed mice. Chronic stress attenuated epinephrine(EPI)-stimulated glycerol release into blood in vivo and accelerated glycerol release from white adipose tissue followed by in vitro incubation with EPI. Chronic stress reduced plasma triglyceride but increased the levels of plasma insulin and myonectin. We further found that adeno-associated virus 9 (AAV9)-mediated myonectin overexpression improved glucose homeostasis and reduced epinephrine sensitivity. Myonectin overexpression reduced plasma norepinephrine, EPI and leptin levels, and increased insulin sensitivity in brown and white adipose tissue. Intense sympathetic activity with high-intensity running inhibited myonectin expression in skeletal muscle, whereas medium and low-intensity exercise running increased myonectin expression. Conclusions These findings suggest that chronic mild stress can improve glucose homeostasis via myonectin-mediated suppression of sympathetic activity in high-fat diet-fed mice.

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