Stress-Induced Morphological, Cellular and Molecular Changes in the Brain—Lessons Learned from the Chronic Mild Stress Model of Depression

Major depressive disorder (MDD) is a severe illness imposing an increasing social and economic burden worldwide. Numerous rodent models have been developed to investigate the pathophysiology of MDD. One of the best characterized and most widely used models is the chronic mild stress (CMS) model which was developed more than 30 years ago by Paul Willner. More than 2000 published studies used this model, mainly to assess novel compounds with potential antidepressant efficacy. Most of these studies examined the behavioral consequences of stress and concomitant drug intervention. Much fewer studies focused on the CMS-induced neurobiological changes. However, the stress-induced cellular and molecular changes are important as they may serve as potential translational biomarkers and increase our understanding of the pathophysiology of MDD. Here, we summarize current knowledge on the structural and molecular alterations in the brain that have been described using the CMS model. We discuss the latest neuroimaging and postmortem histopathological data as well as molecular changes including recent findings on microRNA levels. Different chronic stress paradigms occasionally deliver dissimilar findings, but the available experimental data provide convincing evidence that the CMS model has a high translational value. Future studies examining the neurobiological changes in the CMS model in combination with clinically effective antidepressant drug intervention will likely deliver further valuable information on the pathophysiology of MDD.

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Minocycline protects against oxidative damage and alters energy metabolism parameters in the brain of rats subjected to chronic mild stress

Metabolic Brain Disease ◽

10.1007/s11011-014-9602-8 ◽

2014 ◽

Vol 30 (2) ◽

pp. 545-553 ◽

Cited By ~ 24

Author(s):

Gislaine Z. Réus ◽

Helena M. Abelaira ◽

Amanda L. Maciel ◽

Maria Augusta B. dos Santos ◽

Anelise S. Carlessi ◽

...

Keyword(s):

Energy Metabolism ◽

Oxidative Damage ◽

Chronic Mild Stress ◽

Mild Stress ◽

The Brain

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β-Carboline harmine reverses the effects induced by stress on behaviour and citrate synthase activity in the rat prefrontal cortex

Acta Neuropsychiatrica ◽

10.1017/neu.2013.20 ◽

2013 ◽

Vol 25 (6) ◽

pp. 328-333 ◽

Cited By ~ 6

Author(s):

Helena Mendes Abelaira ◽

Gislaine Zilli Réus ◽

Giselli Scaini ◽

Emilio Luiz Streck ◽

José Alexandre Crippa ◽

...

Keyword(s):

Prefrontal Cortex ◽

Energy Metabolism ◽

Citrate Synthase ◽

Memory Performance ◽

Chronic Mild Stress ◽

Mild Stress ◽

Sucrose Intake ◽

The Brain

ObjectivesThe present study was aimed at evaluating the effects of the administration of β-carboline harmine on behaviour and citrate synthase activity in the brain of rats exposed to chronic mild stress (CMS) procedure.MethodsTo this aim, after 40 days of exposure to CMS procedure, rats were treated with harmine (15 mg/kg/day) for 7 days, then memory, anhedonia and citrate synthase activity were assessed.ResultOur findings demonstrated that stressed rats treated with saline increased the sucrose intake, and the stressed rats treated with harmine reversed this effect. Neither stress nor harmine treatment altered memory performance in rats. In addition, chronic stressful situations induced increase in citrate synthase activity in the prefrontal cortex, but not in the hippocampus and striatum. Treatment with harmine reversed the increase in citrate synthase activity in the prefrontal cortex.ConclusionThese findings support the hypothesis that harmine could be involved in controlling the energy metabolism.

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Chinese medicine Banxia-houpu decoction regulates c-fos expression in the brain regions in chronic mild stress model in rats

Phytotherapy Research ◽

10.1002/ptr.1391 ◽

2004 ◽

Vol 18 (3) ◽

pp. 200-203 ◽

Cited By ~ 9

Author(s):

Weiyun Zhang ◽

Jianmei Li ◽

Jixiao Zhu ◽

Zhenqiu Shi ◽

Yong Wang ◽

...

Keyword(s):

Chinese Medicine ◽

Chronic Mild Stress ◽

Brain Regions ◽

Mild Stress ◽

Stress Model ◽

Fos Expression ◽

The Brain

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Microstructural and Metabolic Recovery of Anhedonic Rat Brains: An In Vivo Diffusion MRI and 1H-MRS Approach

Data ◽

10.3390/data3030029 ◽

2018 ◽

Vol 3 (3) ◽

pp. 29 ◽

Cited By ~ 2

Author(s):

Ahmad Khan ◽

Sune Jespersen ◽

Ove Wiborg ◽

Christopher Kroenke ◽

Brian Hansen

Keyword(s):

Diffusion Mri ◽

Imaging System ◽

Chronic Mild Stress ◽

Ventral Hippocampus ◽

Control Group ◽

Mild Stress ◽

1H Mrs ◽

Unpredictable Chronic Mild Stress ◽

The Brain

This article presents longitudinal 1H-MR Spectroscopy (1H-MRS) data from ventral hippocampus and in vivo diffusion MRI (dMRI) data of the brain from control and anhedonic rats. The 1H-MRS and dMRI data were acquired using a 9.4 T preclinical imaging system. Before MRI experiments, animals were exposed to unpredictable chronic mild stress exposure for eight weeks and on the basis of a sucrose consumption test were identified as anhedonic and resilient. An age-matched group of animals, unexposed to the unpredictable chronic mild stress paradigm was considered as control. Data was acquired at the age of 18, 20 and 25 weeks in the anhedonic group and at the age of 18 and 22 weeks in the control group. This multimodal MRI data provides metabolic information of ventral hippocampus and dMRI based microstructural parameters of the brain.

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The Changes of Expression and Methylation of Genes Involved in Oxidative Stress in Course of Chronic Mild Stress and Antidepressant Therapy with Agomelatine

Genes ◽

10.3390/genes11060644 ◽

2020 ◽

Vol 11 (6) ◽

pp. 644

Author(s):

Paulina Wigner ◽

Ewelina Synowiec ◽

Paweł Jóźwiak ◽

Piotr Czarny ◽

Michał Bijak ◽

...

Keyword(s):

Oxidative Stress ◽

Nitrosative Stress ◽

Mononuclear Cells ◽

Methylation Status ◽

Chronic Mild Stress ◽

Mild Stress ◽

Oxidative And Nitrosative Stress ◽

Peripheral Blood Mononuclear ◽

Taqman Gene Expression Assay ◽

The Brain

Preclinical studies conducted so far suggest that oxidative stress processes may be associated with the mechanism of depression development. This study shows the effects of chronic administration of agomelatine on expression and the methylation status of Sod1, Sod2, Gpx1, Gpx4, Cat, Nos1, and Nos2 in the brain stricture and blood in the chronic mild stress (CMS) animal model of depression. The animals were exposed to the CMS procedure and treatment with agomelatine (10 mg/kg/day, IP) for five weeks and then were sacrificed. TaqMan Gene Expression Assay, Western blot, and methylation-sensitive high-resolution melting techniques were used to evaluate mRNA and protein expression of the genes, and the methylation status of their promoters. Gpx1, Gpx4, and Sod2 expression in the PBMCs and Sod1 and Sod2 expression in the brain were reduced in the stressed group after agomelatine administration. CMS caused an increase in the methylation of the third Gpx4 promoter in peripheral blood mononuclear cells and Gpx1 promoter in the cerebral cortex. Additionally, stressed rats treated with agomelatine displayed a significantly lower Gpx4 level in the hypothalamus. The results confirm the hypothesis that the CMS procedure and agomelatine administration change the expression level and methylation status of the promoter region of genes involved in oxidative and nitrosative stress.

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P.1.003 Inflammatory response in the brain of rats exposed to chronic mild stress

European Neuropsychopharmacology ◽

10.1016/s0924-977x(13)70005-1 ◽

2013 ◽

Vol 23 ◽

pp. S5-S6

Author(s):

C. Zecchillo ◽

F. Macchi ◽

R. Molteni ◽

G. Racagni ◽

M. Papp ◽

...

Keyword(s):

Inflammatory Response ◽

Chronic Mild Stress ◽

Mild Stress ◽

The Brain

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Cell type-specific in vivo expression of genes encoding signalling molecules in the brain in response to chronic mild stress and chronic treatment with fluoxetine

Psychopharmacology ◽

10.1007/s00213-015-3921-2 ◽

2015 ◽

Vol 232 (15) ◽

pp. 2827-2835 ◽

Cited By ~ 15

Author(s):

Lu Dong ◽

Baoman Li ◽

Alexei Verkhratsky ◽

Liang Peng

Keyword(s):

Chronic Treatment ◽

Chronic Mild Stress ◽

Mild Stress ◽

Cell Type ◽

Signalling Molecules ◽

Expression Of Genes ◽

Genes Encoding ◽

Cell Type Specific ◽

The Brain

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Learned Immobility Produces Enduring Impairment of the HPA Axis Reactivity in Mice without Replicating the Broad Spectrum of Depressive-Like Phenotype

International Journal of Molecular Sciences ◽

10.3390/ijms22020937 ◽

2021 ◽

Vol 22 (2) ◽

pp. 937

Author(s):

Sébastien Bullich ◽

Sarah Delcourte ◽

Nasser Haddjeri ◽

Bruno P. Guiard

Keyword(s):

Hpa Axis ◽

Broad Spectrum ◽

Stress Test ◽

Antidepressant Drug ◽

Chronic Mild Stress ◽

Progressive Increase ◽

Dark Phase ◽

Mild Stress ◽

The Face ◽

High Level

The forced swim stress test (FST) is widely used for screening pharmacological or non-pharmacological strategies with potential antidepressant activities. Recent data have suggested that repeated FST for five consecutive days (i.e., 5d-RFSS) could be used to generate a robust depressive-like phenotype in mice. However, the face, construct, and predictive validities of 5d-RFSS have been recently challenged. This study took advantage of recent findings showing that mice vulnerability to anxiety is enhanced when animals are stressed during the dark phase, to provide new insight into the relevance of this model. Our results showed a progressive increase in time of immobility in 5d-RFSS mice relative to control non-stressed animals (sham). Three weeks later, we noticed that 5d-RFSS mice injected with the vehicle compound (Veh) still exhibited a high level of immobility in the FST whereas this behavior was reversed by the antidepressant drug amitriptyline (AMI). However, 5d-RFSS/Veh and 5d-RFSS mice/AMI mice showed normal performances in the open field, the novelty suppressed feeding and the tail suspension tests. Despite this lack of generalized behavioral deficits, an impairment of different parameters characterizing the hypothalamic-pituitary-adrenal (HPA) axis reactivity was evidenced in 5d-RFSS mice/Veh but not in 5d-RFSS mice/AMI. Despite anomalies in the HPA axis, the activity of the central serotonergic system remained unaffected in 5d-RFSS mice relative to controls. From our results, it is suggested that learned immobility does not replicate the broad spectrum of depressive symptoms observed in other chronic models of depression such as the unpredictable chronic mild stress (UCMS) model, the chronic social defeat stress (CSDS) model or chronic corticosterone (CORT) exposure but its influence on the HPA axis is remarkable. Further experiments are warranted to makes this model suitable for modelling depression and therefore refine its translational applicability.

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Haloperidol and aripiprazole impact on the BDNF and glucocorticoid receptor levels in the rat hippocampus and prefrontal cortex: effect of the chronic mild stress

Endocrine Regulations ◽

10.2478/enr-2021-0016 ◽

2021 ◽

Vol 55 (3) ◽

pp. 153-162

Author(s):

Jana Osacka ◽

Romana Koprdova ◽

Andrej Tillinger ◽

Zdenko Pirnik ◽

Alexander Kiss

Keyword(s):

Prefrontal Cortex ◽

Weight Gain ◽

Glucocorticoid Receptor ◽

Chronic Mild Stress ◽

Mild Stress ◽

Typical Antipsychotic ◽

Mrna Levels ◽

Frozen Sections ◽

Bdnf Mrna ◽

The Brain

Abstract Objective. Changes in the brain derived neurotrophic factor (BDNF) and glucocorticoid receptor (GR) expression in the prefrontal cortex (PFC) and hippocampus (HIP) are associated with psychiatric diseases and stress response. Chronic mild stress (CMS) may alter BDNF as well as GR levels in both the PFC and the HIP. The aim of the present study was to find out whether chronic treatment with a typical antipsychotic haloperidol (HAL) and an atypical antipsychotic aripiprazole (ARI) may modify the CMS effect on the BDNF and GR expression in the above-mentioned structures. Methods. The rats were exposed to CMS for 3 weeks and from the 7th day of CMS injected with vehicle (VEH), HAL (1 mg/kg) or ARI (10 mg/kg) for 4 weeks. BDNF and GR mRNA levels were established in the PFC and the HIP by Real Time PCR, whereas, PFC and HIP samples were obtained by punching them from 500 µm thick frozen sections. C-Fos immunoreactivity was analyzed in the PFC and the HIP on 30 µm thick paraformaldehyde fixed sections. Weight gain and corticosterone (CORT) levels were also measured. Results. The CMS and HAL suppressed the BDNF and GR mRNA levels in the PFC. In the HIP, CMS elevated BDNF mRNA levels that were suppressed by HAL and ARI treatments. The CMS decreased the c-Fos immunoreactivity in the PFC in both HAL- and ARI-treated animals. In the HIP, HAL increased the c-Fos immunoreactivity that was again diminished in animals exposed to CMS. Stressed animals gained markedly less weight until the 7th day of CMS, however, later their weight gain did not differ from the unstressed ones or was even higher in CMS+HAL group. Un-stressed HAL and ARI animals gained less weight than the VEH ones. Neither CMS nor HAL/ARI affected the plasma CORT levels. Conclusion. The present data indicate that HAL and ARI in the doses 1 mg/kg or 10 mg/kg, respectively, does not modify the effect of the CMS preconditioning on the BDNF and GR mRNA levels in the PFC or the HIP. However, HAL seems to modify the CMS effect on the HIP activation.

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