Resilient Phenotype in Chronic Mild Stress Paradigm Is Associated with Altered Expression Levels of miR-18a-5p and Serotonin 5-HT1a Receptor in Dorsal Part of the Hippocampus

Dariusz Zurawek,Lucyna Antkiewicz-Michaluk,Piotr Gruca,Marta Dziedzicka-Wasylewska

doi:10.1007/s12035-019-1622-2

Abstract

Disturbed serotonergic signaling in the hippocampus observed in many individuals vulnerable to stress has been suggested as one of the primary factors contributing to the development of depression. However, little is known about the physiology of the brain in the resilient phenotype. Resilient subjects maintain a positive mood and psychological balance despite being under the stress influence. In our study, we generated stress-vulnerable and resilient rats by using a chronic mild stress (CMS) paradigm. Using different molecular approaches, we revealed that resilient animals exhibited a significantly decreased expression level of miR-18a-5p and, in the same time, an elevated level of 5-HT1AR in dorsal, but not ventral, part of the hippocampus. Described biochemical changes were not observed in animals behaviorally vulnerable to stress. Further, in vitro analysis showed that miR-18a-5p may be a negative epigenetic regulator of 5-HT1AR since the treatment of adult hippocampal neurons with miR-18a-5p mimic significantly lowered the expression level of mRNA encoding 5-HT1AR. Moreover, bioinformatic analysis of potential target genes expressed in the hippocampus and being regulated by miR-18a-5p showed that this microRNA may regulate biological processes, such as axonogenesis, which are important in the functioning of the hippocampus in both rats and humans. All these molecular features may contribute to serotonergic homeostatic balance at the level of serotonin turnover observed in hippocampi of resilient but not stress-vulnerable rats. Delineation of further molecular and biochemical markers underlying resilience to stress may contribute to the development of new antidepressant strategies which will restore resilient phenotype in depressed patients.

Highlights

Stress, defined as the biological response of an organism to life-threatening events, is an integral component of life
Post hoc analysis revealed that anhedonic animals significantly decreased their sucrose consumption levels after the first and second weeks of the chronic mild stress (CMS) procedure compared to control and resilient littermates (Fig. 1a)
We focused on finding potential epigenetic factors and their downstream molecular targets that may be associated with the development of resilient behavior

Summary

Introduction

Stress, defined as the biological response of an organism to life-threatening events, is an integral component of life. Recent advances have enhanced our understanding of the contribution of miRNAs in pathomechanisms of depression, little is known about their role in the regulation of specific downstream molecular targets and the development of a resilient phenotype To further explore this issue, we examined the expression levels of a set of five different miRNAs (miR-18a-5p, miR-34a-5p, miR-135a-5p, miR-3203p, and miR-674-5p) in the hippocampus (HIP) and nucleus accumbens septi (NAcc) of stress-susceptible and resilient animals. Another study has shown that resilience to stress and a good prognosis of an antidepressant response are associated with lower levels of 5-HT1A autoreceptors [37] but not heteroreceptors Dysregulated function of both brain 5-HT1ARs and miRNA transcripts are important in the pathogenesis of depression. Therapeutic strategies involving pharmacological manipulations at the level of microRNA

Experimental Procedures

Results

Discussion