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Shared and unique transcriptomic signatures of antidepressant and probiotics action in the mammalian brain

ABSTRACT: To comprehensively characterize the intrinsic molecular effects of ADs independently of the specifics of particular disease models, we generated 300 transcriptomic profiles from 10 brain regions in naive rats. Three classical tricyclic antidepressants, Bupropion, desipramine, fluoxetine, and a probiotic formulation (Lacidofil®) can massively alter gene expression in most regions [>1,500 differentially expressed genes (DEGs)], suggesting that traditional single-gene or single-pathway analyses may under-represent the complexity of molecular responses. Using spatial transcriptomics in the prefrontal cortex from an independent set of animals, we further delineated DEGs and molecular pathways that exhibited layer-specific differential regulation by probiotics and fluoxetine.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE233571 | GEO | 2024/06/06

REPOSITORIES: GEO

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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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Shared and unique transcriptomic signatures of antidepressant and probiotics action in the mammalian brain

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