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Aberrant histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to maladaptive stress-induced gene expression programs and behavior [RNA-seq]

ABSTRACT: Major depressive disorder (MDD) is a debilitating illness that affects millions of individuals worldwide. While chronic stress increases incidence levels of MDD, stress-mediated disruptions in brain function that precipitate the disorder remain elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with MDD, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding precise roles for serotonin in the precipitation of MDD. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this phenomenon has not yet been explored following stress and/or AD exposures. Here, we employed a combination of genome-wide (ChIP-seq, RNA-seq) and western blotting analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress to examine the impact of stress exposures on H3K4me3Q5ser dynamics in DRN, as well as associations between the mark and stress-induced gene expression. Stress-induced regulation of H3K4me3Q5ser levels were also assessed in the context of AD exposures, and viralmediated gene therapy was employed to manipulate H3K4me3Q5ser levels to examine the impact of reducing the mark in DRN on stress-associated gene expression and behavior. We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity in DRN. Mice exposed to chronic stress displayed dysregulated dynamics of These findings establish a neurotransmission-independent role for serotonin in stress-associated transcriptional and behavioral plasticity in DRN.

ORGANISM(S): Mus musculus

PROVIDER: GSE216102 | GEO | 2023/08/07

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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Aberrant histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to maladaptive stress-induced gene expression programs and behavior [RNA-seq]

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