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 Sex-Specific Microglial Activation and SARS-CoV-2 Receptor Expression Induced by Chronic Unpredictable Stress

2021 ◽  
Vol 15 ◽  
Author(s):  
Ling Yan ◽  
Mohan Jayaram ◽  
Keerthana Chithanathan ◽  
Alexander Zharkovsky ◽  
Li Tian
Keyword(s):  
Chronic Stress ◽  
Social Withdrawal ◽  
Receptor Expression ◽  
Mild Stress ◽  
Mrna Levels ◽  
Male Mice ◽  
Female Mice ◽  
Neuropilin 1 ◽  
Brain And Behavior ◽  
Viral Receptors

The coronavirus disease 2019 (COVID-19) pandemic has generated a lot of stress and anxiety among not only infected patients but also the general population across the globe, which disturbs cerebral immune homeostasis and potentially exacerbates the SARS-CoV-2 virus-induced neuroinflammation, especially among people susceptible to neuropsychiatric disorders. Here, we used a chronic unpredictable mild stress (CUMS) mouse model to study its effects on glia-mediated neuroinflammation and expression of SARS-CoV2 viral receptors. We observed that female mice showed depressive-like behavior after CUMS, whereas male mice showed enhanced anxiety and social withdrawal. Interestingly, CUMS led to increased amounts of total and MHCII+ microglia in the hippocampi of female mice but not male mice. mRNA levels of SARS-CoV-2 viral receptors angiotensin-converting enzyme 2 (Ace2) and basigin (Bsg) were also upregulated in the prefrontal cortices of stressed female mice but not male mice. Similarly, sex-specific changes in SARS-CoV-2 viral receptors FURIN and neuropilin-1 (NRP1) were also observed in monocytes of human caregivers enduring chronic stress. Our findings provided evidence on detrimental effects of chronic stress on the brain and behavior and implied potential sex-dependent susceptibility to SARS-CoV-2 infection after chronic stress.

Effects of Neonatal Caffeine Administration on Vessel Reactivity in Adult Mice

2020 ◽  
Author(s):  
Ajay Pratap Singh ◽  
Praveen Chandrasekharan ◽  
Sylvia Gugino ◽  
Sara Berkelhamer ◽  
Huamei Wang ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Systemic Blood Pressure ◽  
Systemic Hypertension ◽  
Male Mice ◽  
Treated Male ◽  
Female Mice ◽  
Adult Mice ◽  
Specific Effects ◽  
Lower Body Weight ◽  
The Impact

Abstract Objective The effects of neonatal caffeine therapy in adults born preterm are uncertain. We studied the impact of neonatal caffeine on systemic blood pressure, vessel reactivity, and response to stress in adult mice. Study Design Mice pups were randomized to caffeine (20 mg/kg/d) or saline by intraperitoneal injection for 10 days after birth. We performed tail-cuff BP (8/12 weeks), urinary 8-hydroxydeoxyguanosine and fecal corticosterone (14 weeks), and vessel reactivity in aortic rings (16 weeks) in adult mice. Results No differences were noted in systolic, diastolic, and mean blood pressures between the two groups at 8 and 12 weeks of age. However, norepinephrine-induced vasoconstriction was substantially higher in aortic rings in CAF-treated male mice. More significant vasodilator responses to nitric oxide donors in aortic rings in female mice may suggest gender-specific effects of caffeine. Female mice exposed to caffeine had significantly lower body weight over-time. Caffeine-treated male mice had substantially higher fecal corticosterone and urinary 8-hydroxydeoxyguanosine at 14 weeks, suggestive of chronic stress. Conclusion We conclude sex-specific vulnerability to the heightened vascular tone of the aorta in male mice following neonatal caffeine therapy. Altered vessel reactivity and chronic stress in the presence of other risk factors may predispose to the development of systemic hypertension in adults born preterm.

scholarly journals CRF-R1 Antagonist Treatment Exacerbates Circadian Corticosterone Secretion under Chronic Stress, but Preserves HPA Feedback Sensitivity

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2114
Author(s):  
Yadira Ibarguen-Vargas ◽  
Samuel Leman ◽  
Rupert Palme ◽  
Catherine Belzung ◽  
Alexandre Surget
Keyword(s):  
Chronic Stress ◽  
Hpa Axis ◽  
Negative Feedback ◽  
Chronic Mild Stress ◽  
Stress Conditions ◽  
Mild Stress ◽  
Circadian Activity ◽  
Corticosterone Secretion ◽  
Feedback Sensitivity ◽  
The Impact

Despite promising initial reports, corticotropin-releasing factor receptor type-1 (CRF-R1) antagonists have mostly failed to display efficacy in clinical trials for anxiety or depression. Rather than broad-spectrum antidepressant/anxiolytic-like drugs, they may represent an ‘antistress’ solution for single stressful situations or for patients with chronic stress conditions. However, the impact of prolonged CRF-R1 antagonist treatments on the hypothalamic–pituitary–adrenal (HPA) axis under chronic stress conditions remained to be characterized. Hence, our study investigated whether a chronic CRF-R1 antagonist (crinecerfont, formerly known as SSR125543, 20 mg·kg−1·day−1 ip, 5 weeks) would alter HPA axis basal circadian activity and negative feedback sensitivity in mice exposed to either control or chronic stress conditions (unpredictable chronic mild stress, UCMS, 7 weeks), through measures of fecal corticosterone metabolites, plasma corticosterone, and dexamethasone suppression test. Despite preserving HPA axis parameters in control non-stressed mice, the 5-week crinercerfont treatment improved the negative feedback sensitivity in chronically stressed mice, but paradoxically exacerbated their basal corticosterone secretion nearly all along the circadian cycle. The capacity of chronic CRF-R1 antagonists to improve the HPA negative feedback in UCMS argues in favor of a potential therapeutic benefit against stress-related conditions. However, the treatment-related overactivation of HPA circadian activity in UCMS raise questions about possible physiological outcomes with long-standing treatments under ongoing chronic stress.

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.

Abstract 390: The Absence of Abcg5 Abcg8 Reveals a Sexually Dimorphic Adaption to Impaired Biliary Cholesterol Secretion

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Jianing Li ◽  
Ailing Ji ◽  
Ryan E Temel ◽  
Deneys R van der Westhuyzen ◽  
Gregory A Graf
Keyword(s):  
Alternative Pathway ◽  
Male Mice ◽  
Biliary Cholesterol ◽  
Female Mice ◽  
Cholesterol Excretion ◽  
Biliary Cholesterol Secretion ◽  
Cholesterol Secretion ◽  
The Impact ◽  
Sterol Excretion ◽  
Secretion Rates

Objective: The ABCG5 ABCG8 (G5G8) sterol transporter is the primary mechanism for biliary cholesterol secretion, but mice maintain fecal sterol excretion in its absence. The mechanism by which mice maintain sterol excretion in the absence of this pathway is not known. Transintestinal cholesterol excretion (TICE) is an alternative pathway to hepatobiliary secretion. We investigated the impact of G5G8 deficiency on TICE in the absence of Sitosterolemia. Methods and Results: We compared both hepatobiliary and transintestinal cholesterol excretion rates in wild-type (WT) and G5G8 deficient mice of both sexes. WT and G5G8 were maintained on a plant-sterol free diet from the time of weaning to prevent the development of secondary phenotypes associated with Sitosterolemia. Biliary and intestinal cholesterol secretion rates were determined by biliary diversion with simultaneous perfusion of the proximal 10 cm of the small bowel. Among WT mice, biliary cholesterol secretion was greater in female mice compared to males. Conversely, male mice exhibited greater rates of TICE than females. As expected, WT mice had higher biliary cholesterol secretion rates than their G5G8 deficient littermates. However, the decline in biliary cholesterol secretion was far less in male mice compared to females in the absence of G5G8. In female mice, the absence of G5G8 resulted in a two-fold increase in TICE, whereas males were unaffected. Conclusion: Female mice are more dependent upon the biliary pathway for cholesterol excretion, whereas males are more dependent upon TICE. G5G8 independent pathways are present for both biliary and intestinal cholesterol secretion. Female and male mice differ in their adaptation to G5G8 deficiency in order to maintain fecal sterol excretion.

scholarly journals Social Isolation-Induced Aggression Potentiates Anxiety and Depressive-Like Behavior in Male Mice Subjected to Unpredictable Chronic Mild Stress

PLoS ONE ◽  
2011 ◽  
Vol 6 (6) ◽  
pp. e20955 ◽  
Author(s):  
Xian-cang Ma ◽  
Dong Jiang ◽  
Wen-hui Jiang ◽  
Fen Wang ◽  
Min Jia ◽  
...  
Keyword(s):  
Social Isolation ◽  
Chronic Mild Stress ◽  
Mild Stress ◽  
Male Mice ◽  
Unpredictable Chronic Mild Stress

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 Chronic Repeated Predatory Stress Induces Resistance to Quinine Adulteration of Ethanol in Male Mice

2019 ◽  
Author(s):  
Gladys A. Shaw ◽  
Maria Alexis M. Bent ◽  
Kimaya R. Council ◽  
A. Christian Pais ◽  
Ananda Amstadter ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Open Field ◽  
Traumatic Event ◽  
Drinking Behavior ◽  
Specific Pattern ◽  
Male Mice ◽  
Female Mice ◽  
Drinking Response ◽  
Field Mice ◽  
The Impact

AbstractBackgroundTrauma related psychiatric disorders, such as posttraumatic stress disorder (PTSD), and alcohol use disorder (AUD) are highly comorbid illnesses that separately present an opposing, sex-specific pattern, with increased prevalence of PTSD in females and increased prevalence of AUD diagnoses in males. Likewise, PTSD is a risk factor in the development of AUD, with conflicting data on the impact of sex in the comorbid development of both disorders. Because the likelihood of experiencing more than one traumatic event is high, we aim to utilize chronic repeated predatory stress (CRPS) to query the extent to which sex interacts with CRPS to influence alcohol consumption, or cessation of consumption.MethodsMale (n=16) and female (n=15) C57BL/6J mice underwent CRPS or daily handling for two weeks during adolescence (P35-P49) and two weeks during adulthood (P65-P79). Following the conclusion of two rounds of repeated stress, behavior was assessed in the open field. Mice subsequently underwent a two-bottle choice intermittent ethanol access (IEA) assessment (P90-131) with the options of 20% ethanol or water. After establishing drinking behavior, increasing concentrations of quinine were added to the ethanol to assess the drinking response to adulteration of the alcohol.ResultsCRPS increased fecal corticosterone concentrations and anxiety-like behaviors in the open field in both male and female mice as compared to control mice that had not been exposed to CRPS. Consistent with previous reports, we observed a sex difference in alcohol consumption such that females consumed more ethanol per gram of body mass than males. In addition, CRPS reduced alcohol aversion in male mice such that higher concentrations of quinine were necessary to reduce alcohol intake as compared to control mice. CRPS did not alter alcohol-related behaviors in female mice.ConclusionCollectively, we demonstrate that repeated CRPS can induce anxiety-like behavior in both sexes but selectively influences the response to ethanol adulteration in males.

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