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Transcriptional analysis of the effects of early life exposure to fluoxetine on telencephalon and hypothalamus in SR4G transgenic zebrafish larvae and adults

ABSTRACT: Our previous study suggested persistent transgenerational effects of fluoxetine (FLX) exposure, in both environmental and therapeutic concentrations, on stress response and behaviour up to 3 generation withdrawn from exposure in larvae and adult zebrafish. To lay the foundations of the mechanistic of such transgenerational effects, we studied the effect of FLX on stress response in brain tissues (telencephalon and hypothalamus) of larvae and adult zebrafish using differentially expressed genes at the transcriptome level. To monitor the stress response, we used a transgenic zebrafish line (SR4G) which are expressing green fluorescence protein (GFP) in response to endogenous and exogenous glucocorticoids. The transcriptome analysis of GFP RNA as an internal control, provided us with an invaluable tool to clearly visualize and differentiate between stressed and unstressed groups as per treatments. To stimulate stress in both larvae and adult zebrafish we used a modified net stressing technique consisting of consecutive sequence of air exposure and incubation intervals. A pool of 22 larvae heads and a pool of 5 telencephalon and 5 hypothalamus dissected tissues were used as the target tissues for RNA extraction. All experiments were replicated in n=6 per 4 different groups including Control-Unstressed (Cnt-U), Control-Stressed (Cnt-S), Fluoxetine-Unstressed (FLX-U), and Fluoxetine-Stressed (FLX-S) using pools of larvae heads, telencephalon, and hypothalamus. After total RNA extraction, using Illumina technology all samples were sequence and the list of differentially expressed genes (DEGs) were produced using DSEQ pipeline in R.

ORGANISM(S): Danio rerio

PROVIDER: GSE141144 | GEO | 2022/04/26

REPOSITORIES: GEO

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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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Transcriptional analysis of the effects of early life exposure to fluoxetine on telencephalon and hypothalamus in SR4G transgenic zebrafish larvae and adults

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