Abstract
Stress plays a major role in inducing depression, which may arise from interplay between complex cascades of molecular and cellular events that influence gene expression leading to altered connectivity and neural plasticity. In recent years, microRNAs (miRNAs) have carved their own niche owing to their innate ability to induce disease phenotype by regulating expression of a large number of genes in a cohesive and coordinated manner. In this study, we examined whether miRNAs and associated gene networks have a role in chronic corticosterone (CORT; 50 mg kg−1 × 21 days)-mediated depression in rats. Rats given chronic CORT showed key behavioral features that resembled depression phenotype. Expression analysis revealed differential regulation of 26 miRNAs (19 upregulated, 7 downregulated) in prefrontal cortex of CORT-treated rats. Interaction between altered miRNAs and target genes showed dense interconnected molecular network, in which multiple genes were predicated to be targeted by the same miRNA. A majority of altered miRNAs showed binding sites for glucocorticoid receptor element, suggesting that there may be a common regulatory mechanism of miRNA regulation by CORT. Functional clustering of predicated target genes yielded disorders such as developmental, inflammatory and psychological that could be relevant to depression. Prediction analysis of the two most prominently affected miRNAs miR-124 and miR-218 resulted into target genes that have been shown to be associated with depression and stress-related disorders. Altogether, our study suggests miRNA-mediated novel mechanism by which chronic CORT may be involved in depression pathophysiology.
Highlights
Depression is one of the most prevalent psychiatric disorders worldwide and is a major public health concern.[1]
How stress causes depressive symptomatology is not well-defined, there is a wellestablished connection of stress-mediated hyperactive hypothalamus–pituitary–adrenal axis (HPA) and depression, which is primarily associated with altered expression and function of glucocorticoid receptors (GRs) that may lead to feed-back inhibition, resulting in elevated levels of circulating glucocorticoids and protracted responses to stressors.[6]
We recently reported that miRNAs are highly dysregulated in the dorsolateral prefrontal cortex of depressed individuals[17] and hopeless placing two bottles of sucrose solution in each cage for 24 h; one of the bottles was replaced with water for 24 h
Summary
Depression is one of the most prevalent psychiatric disorders worldwide and is a major public health concern.[1]. MiRNAs have been under intense investigation for their role in psychiatric disorders including major depression These include studies in human postmortem brain and fibroblasts of depressed patients as well as in brains of animals that show resiliency to chronic stress.[14,15,16] In this context, we recently reported that miRNAs are highly dysregulated in the dorsolateral prefrontal cortex of depressed individuals[17] and hopeless placing two bottles of sucrose solution in each cage for 24 h; one of the bottles was replaced with water for 24 h. Immobility was defined as moving the limbs only enough to stay above water, as opposed to escaping or exploring behavior
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