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      Re-evaluation of the interrelationships among the behavioral tests in rats exposed to chronic unpredictable mild stress

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          Abstract

          The chronic unpredictable mild stress model of depression has been widely used as an experimental tool to investigate human psychopathology. Our objective was to provide an update on the validity and reliability of the chronic unpredictable mild stress model, by analyzing the interrelationships among the indexes using stepwise discriminant analysis and Pearson correlation coefficient to examine the possible combinations. We evaluated the depressive rats in both the presence and the absence of chronic unpredictable mild stress, using weight change, percentage of sucrose preference, coat state, splash test, open-field test, elevated plus-maze test, forced swimming test, and Morris water maze test. The results showed that 6-week-long chronic unpredictable mild stress produces significant depression and anxiety-like behavior. The combination of body weight change, percentage of sucrose preference, coat state score, open-field score, grooming latency of splash test, immobility time in force swimming test, and platform crossing in the Morris water maze test can effectively discriminate between normal and chronic unpredictable mild stress rats. Strong interrelationships were noted among these indexes in both open-field test and elevated plus-maze test. In conclusion, there might be certain criteria for the combination of behavioral endpoints, which is advantageous to more effectively and reliably assess the chronic unpredictable mild stress induced depression model.

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          Most cited references31

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          Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation.

          This paper evaluates the validity, reliability and utility of the chronic mild stress (CMS) model of depression. In the CMS model, rats or mice are exposed sequentially, over a period of weeks, to a variety of mild stressors, and the measure most commonly used to track the effects is a decrease in consumption of a palatable sweet solution. The model has good predictive validity (behavioural changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (almost all demonstrable symptoms of depression have been demonstrated), and construct validity (CMS causes a generalized decrease in responsiveness to rewards, comparable to anhedonia, the core symptom of the melancholic subtype of major depressive disorder). Overall, the CMS procedure appears to be at least as valid as any other animal model of depression. The procedure does, however, have two major drawbacks. One is the practical difficulty of carrying out CMS experiments, which are labour intensive, demanding of space, and of long duration. The other is that, while the procedure operates reliably in many laboratories, it can be difficult to establish, for reasons which remain unclear. However, once established, the CMS model can be used to study problems that are extremely difficult to address by other means.
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            Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal.

            Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.
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              Age differences in major depression: results from the National Comorbidity Survey Replication (NCS-R).

              Although depression appears to decrease in late life, this could be due to misattribution of depressive symptom to physical disorders that increase in late life. We studied age differences in major depressive episodes (MDE) in the National Comorbidity Survey Replication, a national survey of the US household population. DSM-IV MDE was defined without organic exclusions or diagnostic hierarchy rules to facilitate analysis of co-morbidity. Physical disorders were assessed with a standard chronic conditions checklist and mental disorders with the WHO Composite International Diagnostic Interview (CIDI) version 3.0. Lifetime and recent DSM-IV/CIDI MDE were significantly less prevalent among respondents aged 65 years than among younger adults. Recent episode severity, but not duration, was also lower among the elderly. Despite prevalence of mental disorders decreasing with age, co-morbidity of hierarchy-free MDE with these disorders was either highest among the elderly or unrelated to age. Co-morbidity of MDE with physical disorders, in comparison, generally decreased with age despite prevalence of co-morbid physical disorders usually increasing. Somewhat more than half of respondents with 12-month MDE received past-year treatment, but the percentage in treatment was lowest and most concentrated in the general medical sector among the elderly. Given that physical disorders increase with age independent of depression, their lower associations with MDE in old age argue that causal effects of physical disorders on MDE weaken in old age. This result argues against the suggestion that the low estimated prevalence of MDE among the elderly is due to increased confounding with physical disorders.
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                Author and article information

                Contributors
                Role: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: Funding acquisitionRole: Project administration
                Role: ConceptualizationRole: Methodology
                Role: Data curation
                Role: ConceptualizationRole: Supervision
                Role: Formal analysis
                Role: Supervision
                Role: ConceptualizationRole: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                20 September 2017
                2017
                : 12
                : 9
                : e0185129
                Affiliations
                [001]Department of Pharmacology, Chongqing Medical University, the Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing, China
                Chiba Daigaku, JAPAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-17-17360
                10.1371/journal.pone.0185129
                5607203
                28931086
                7e646f1d-829f-4e2b-86b7-f1b65197956c
                © 2017 Hu et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 May 2017
                : 5 September 2017
                Page count
                Figures: 8, Tables: 7, Pages: 15
                Funding
                Funded by: Chongqing Science and Technology Commission (CN)
                Award ID: No.cstc2012jjA0112
                Award Recipient :
                This work was supported by the Research Fund of Chongqing Science Technology Commission of China (NO: cstc2012jjA0112). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Carbohydrates
                Disaccharides
                Sucrose
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Carbohydrates
                Disaccharides
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                Research and Analysis Methods
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                Medicine and Health Sciences
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                Psychological Stress
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