Chronic corticosterone-mediated dysregulation of microRNA network in prefrontal cortex of rats: relevance to
1Department of Psychiatry and Behavioral Neurobiology, UAB Mood Disorder Program, University of Alabama at Birmingham, Birmingham, AL, USA.
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.
Insights
Chronic corticosterone (CORT) exposure in rats induced depression-like behaviors. MicroRNAs (miRNAs) and their gene networks were identified as key players in this stress-induced depression model.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Stress is a significant factor in depression, involving complex molecular and cellular changes affecting neural plasticity.
- MicroRNAs (miRNAs) are regulators of gene expression implicated in disease phenotypes.
Purpose of the Study:
- To investigate the role of miRNAs and gene networks in chronic corticosterone (CORT)-induced depression in a rat model.
- To identify specific miRNAs and their targets involved in the pathophysiology of stress-related depression.
Main Methods:
- Rats were administered chronic CORT (50 mg/kg for 21 days) to induce depression-like behaviors.
- Differential expression analysis of miRNAs in the prefrontal cortex was performed.
- Bioinformatic analyses were used to predict miRNA-target gene interactions and functional pathways.
Main Results:
- Chronic CORT exposure resulted in depression-like behaviors in rats.
- Twenty-six miRNAs were differentially regulated in the prefrontal cortex, with 19 upregulated and 7 downregulated.
- A complex molecular network involving miRNAs and their target genes was identified, with many miRNAs targeting multiple genes and showing glucocorticoid receptor element binding sites.
Conclusions:
- MicroRNA-mediated regulatory mechanisms are involved in the pathophysiology of chronic CORT-induced depression.
- Specific miRNAs, such as miR-124 and miR-218, and their associated gene networks may play critical roles in stress-related depression.
- The findings suggest a novel miRNA-dependent pathway contributing to depression.
