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. 2020 Aug 7:14:136.
doi: 10.3389/fnbeh.2020.00136. eCollection 2020.

miR-409 and miR-411 Modulation in the Adult Brain of a Rat Model of Depression and After Fluoxetine Treatment

Patrícia Patrício  1   2 , António Mateus-Pinheiro  1   2 , Nuno Dinis Alves  1   2 , Mónica Morais  1   2 , Ana João Rodrigues  1   2 , João Miguel Bessa  1   2 , Nuno Sousa  1   2 , Luísa Pinto  1   2
Affiliations

miR-409 and miR-411 Modulation in the Adult Brain of a Rat Model of Depression and After Fluoxetine Treatment

Patrícia Patrício et al. Front Behav Neurosci. .

Abstract

Depression is a chronic debilitating disorder predicted to affect around 20% of the world population. Both brain and peripheral changes, including neuroplastic changes have been shown to occur in the brains of depressed individuals and animal models of depression. Over the past few decades, growing evidence has supported the role of miRNAs as regulators of critical aspects of brain plasticity and function, namely in the context of depression. These molecules are not only highly expressed in the brain, but are also relatively stable in bodily fluids, including blood. Previous microarray analysis from our group has disclosed molecular players in the hippocampal dentate gyrus (DG), in the context of depression and antidepressant treatment. Two miRNAs in particular-miR-409-5p and miR-411-5p-were significantly up-regulated in the DG of an unpredictable chronic mild stress (CMS) rat model of depression and reversed by antidepressant treatment. Here, we further analyzed the levels of these miRNAs along the DG longitudinal axis and in other brain regions involved in the pathophysiology of depression, as well as in peripheral blood of CMS-exposed rats and after fluoxetine treatment. The effects of CMS and fluoxetine treatment on miR-409-5p and miR-411-5p levels varied across brain regions, and miR-411-5p was significantly decreased in the blood of fluoxetine-treated rats. Additional bioinformatic analyses revealed target genes and pathways of these miRNAs related to neurotransmitter signaling and neuroplasticity functions; an implication of the two miRNAs in the regulation of the cellular and molecular changes observed in these brain regions in depression is worth further examination.

Keywords: chronic stress; depression; fluoxetine; miR-409; miR-411; neural plasticity.

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Figures

Figure 1
Figure 1
Behavioral analyses and miRNA levels after CMS exposure and fluoxetine treatment. (A) CMS protocol was applied for 6 weeks and fluoxetine treatment was performed during the last 2 weeks. Behavioral analyses and blood collection were performed at the end of the CMS protocol. (B) Novelty suppressed feeding (NSF) test was applied to evaluate anxiety-like behavior; left panel: latency to feed and right panel: appetite drive. (C) Sweet Drive Test (SDT) was used to assess anhedonia. (D) Corticosterone levels measured in the blood serum of rats between 8:00 and 9:00 (basal levels, Nadir, N) and between 20:00 and 21:00 (peak levels, Zenith, Z). (E) Relative levels of miRNA-409-5p in the dorsal (dDG) and ventral dentate gyrus (vDG), CA regions of the hippocampus (HPC), prefrontal cortex (PFC), nucleus accumbens (NAc), and in the blood. (F) Relative levels of miR-411-5p in the dDG, vDG, HPC, PFC, NAc, and in the blood. *Denotes differences between CT and CMS; #Denotes differences between CMS+VEH and CMS+FLX. Abbreviations: CT, Control; CMS, unpredictable chronic mild stress; NSF, Novelty Suppressed Feeding test; SDT, Sweet Drive test. Data presented as mean ± SEM. FLX, fluoxetine; N, Nadir; Z, Zenith. */#p < 0.05; **/##p < 0.01; ***/###p < 0.001.
Figure 2
Figure 2
Bioinformatics analyses of miR-409-5p and miR-411-5p target genes. (A) Schematic representation of the experimental approach used to identify and analyze miR-409-5p and miR-411-5p target genes. (B,C) Venn diagrams depicting the number of target genes identified by each of the miRNA target prediction tools: miRanda, miRDB, miRWalk and TargetScan (left panel), and list of the top significantly enriched pathways and protein classes identified by PANTHER database (right panel) for (B) miR-409 and (C) miR-411 target genes, respectively. The target genes predicted by three out of the four miRNA target genes predicting tools were used as input in the PANTHER database.
Figure 3
Figure 3
STRING analysis of the interactions between the target genes of (A) miR-409-5p and (B) miR-411-5p. Thicker lines indicate stronger network connections between the genes.
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