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Dynamic changes of behaviors, dentate gyrus neurogenesis and hippocampal miR-124 expression in rats with depression induced by chronic unpredictable mild stress.

ABSTRACT: The depression-like behavior phenotype, neurogenesis in the dentate gyrus and miR-124 expression in the hippocampus are the focus of current research on the pathogenesis of depression and antidepressant therapy. The present study aimed to clarify the dynamic changes of depression-like behavior, dentate gyrus neurogenesis and hippocampal miR-124 expression during depression induced by chronic stress to reveal pathological features at different stages of depression and to further provide insight into depression treatment. Chronic unpredictable mild stress depression models were established by exposing Sprague-Dawley rats to various mild stressors, including white noise, thermal swimming, stroboscopic illumination, soiled cages, pairing with three other stressed animals, cold swimming, tail pinch, restraint and water and food deprivation. Chronic unpredictable mild stress model rats underwent dynamic observation from 1 to 8 weeks and were compared with a control group (normal feeding without any stressors). To observe changes in the depression-like behavior phenotype during chronic unpredictable mild stress-induced depression, a sucrose preference test was used to evaluate the degree of anhedonia. An open-field test was used to evaluate locomotor activity and anxiety status. Compared with the control group, chronic unpredictable mild stress rats lost weight but did not have a depression-like behavioral phenotype at 1-4 weeks. Chronic unpredictable mild stress rats presented decreased sucrose preference and locomotor activity at 5-8 weeks. In addition, chronic unpredictable mild stress rats did not have significant anxiety-like behavior during 1-8 weeks of modeling. To observe neurogenesis dysfunctions and changes in neuronal number in the dentate gyrus during chronic unpredictable mild stress-induced depression, markers (DCX and DCX/BrdU) of neural proliferation and differentiation and the neuronal marker NeuN were assessed by immunofluorescence. Compared with the control group, neurogenesis and the neuronal number in the dentate gyrus did not change from 2 to 6 weeks; however, neural proliferation and differentiation in the dentate gyrus decreased, and the number of neurons decreased until the eighth week in the chronic unpredictable mild stress group. Real-time quantitative reverse transcription polymerase chain reaction assays and fluorescence in situ hybridization were used to measure the expression of hippocampal miR-124 during chronic unpredictable mild stress-induced depression. The results showed that the expression of hippocampal miR-124 was unchanged during the first 4 weeks but increased from 5 to 6 weeks and decreased from 7 to 8 weeks compared with the control group. These findings indicate that during chronic unpredictable mild stress-induced depression, the behavioral phenotype, miR-124 expression in the hippocampus, neurogenesis in the dentate gyrus and neuronal numbers showed dynamic changes, which suggested that various pathological changes occur at different stages of depression. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Guangzhou University of Chinese Medicine of China in March 2015.

SUBMITTER: Huang YL

PROVIDER: S-EPMC7034282 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Project description:Major depression is a multidimensional disorder highly prevalent in modern society. Although several classes of antidepressants (ADs) are currently available to treat depression, the effectiveness of treatment is still limited, as many patients do not show full remission; thus, there is a need to find better patients’ directed therapeutic strategies. Neuroplastic changes in several brain regions, namely in the hippocampal dentate gyrus (DG), are amongst the best correlates of depression and of ADs actions. In this study the targets and molecular mediators of chronic stress and of four ADs from different pharmacological classes (fluoxetine, imipramine, tianeptine and agomelatine) were investigated in the DG. Using the unpredictable chronic mild stress (uCMS) animal model of depression, the molecular commonalities and specificities of the ADs were determined. All ADs, except agomelatine, could reverse the behavioral deficits produced by uCMS, and the neuroplastic changes in the DG; agomelatine reversed only the anhedonic profile in the sucrose consumption test. Chronic stress induced mild but relevant molecular changes that were mostly reversed by fluoxetine, imipramine and tianeptine. Fluoxetine reduced pro-inflammatory response and increased cell metabolism pathways. Its actions were mostly dependent on molecular changes occurring in neurons. Similarities were found between imipramine and tianeptine molecular actions and targets, as both activated pathways related to cellular protection. Moreover, no particular neural cell type enrichment was found with both treatments. Agomelatine presented a very dissimilar molecular pattern impacting greatly on Rho-GTPases-related pathways in oligodendrocytes and neurons. The recognition of these molecular alterations contributes to the understanding of the processes implicated in the onset and treatment of depression and may pave the way for more effective therapeutic interventions. We compared gene expresssion in the dentate gyros of rats which were either untreated, exposed to unpredictable chronic mild stress, or exposed to the same stress and treated with either fluoxetine, imipramine, tianeptine, or agomelatine

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Dynamic changes of behaviors, dentate gyrus neurogenesis and hippocampal miR-124 expression in rats with depression induced by chronic unpredictable mild stress.

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