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

Project description:Major depressive disorder (MDD) is the psychiatric disorder with the highest prevalence in the world. Pharmacological antidepressant treatment (AD), such as selective serotonin reuptake inhibitors [SSRI, i.e. fluoxetine (Flx)] is the first line of treatment for MDD. Despite its efficacy, lack of AD response occurs in numerous patients characterizing Difficult-to-treat Depression. ElectroConvulsive Therapy (ECT) is a highly effective treatment inducing rapid improvement in depressive symptoms and high remission rates of ~50–63% in patients with pharmaco-resistant depression. Nevertheless, the need to develop reliable treatment response predictors to guide personalized AD strategies and supplement clinical observation is becoming a pressing clinical objective. Here, we propose to establish a proteomic peripheral biomarkers signature of ECT response in an anxio/depressive animal model of non-response to AD. Using an emotionality score based on the analysis complementary behavioral tests of anxiety/depression (Elevated Plus Maze, Novelty Suppressed Feeding, Splash Test), we showed that a 4-week corticosterone treatment (35 μg/ml, Cort model) in C57BL/6JRj male mice induced an anxiety/depressive-like behavior. A 28-days chronic fluoxetine treatment (Flx, 18 mg/kg/day) reduced corticosterone-induced increase in emotional behavior. A 50% decrease in emotionality score threshold before and after Flx, was used to separate Flx-responding mice (Flx-R, n=18), or Flx non-responder mice (Flx-NR, n=7). Then, Flx-NR mice received 7 sessions of electroconvulsive seizure (ECS, equivalent to ECT in humans) and blood was collected before and after ECS treatment. Chronic ECS normalized the elevated emotionality observed in Flx-NR mice. Then, proteins were extracted from peripheral blood mononuclear cells (PBMCs) and isolated for proteomic analysis using a high-resolution MS Orbitrap. The proteomic analysis revealed a signature of 33 peripheral proteins associated with response to ECS (7 down- and 26 upregulated). These proteins were previously associated with mental disorders and involved in regulating pathways which participate to the depressive disorder etiology. remark for sample name : ECTR=Flx-NR-ES, C=cort/Veh, CFNR= Flx-NR

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