All ETDs from UAB

Advisory Committee Chair

Yogesh Dwivedi

Advisory Committee Members

Richard Shelton

Sylvie Mrug

Christianne Strang

Robert Sorge

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Early life stress (ELS) affects a significant portion of the US population in the form of various types of abuse and neglect, as well as household dysfunction and loss of a loved one, among others. Although these experiences happen early in life, they increase risk for mental health disorders, especially major depression (MDD), across the lifespan. MDD is a debilitating psychiatric disorder marked by periods of depressed mood and loss of pleasure in once enjoyable activities. Patients with MDD also report trouble sleeping, unintentional weight loss or gain, feelings of worthlessness, and suicidal ideation. MDD is associated with annual $100 billion financial burden because of lost productivity. Available treatment options are not particularly effective, thus a better understand of the neurobiology underlying both ELS and MDD is warranted. miRNAs have been established as master regulators of gene expression that also show promise as therapeutic targets. While there are many studies elucidating miRNA expression and signaling changes in MDD, very few have specifically explored the role of ELS in transmitting depression susceptibility.This project applied a rodent maternal separation (MS) model of ELS in two separate cohorts and next-generation sequencing to survey miRNA expression changes across the genome, as well as across key brain regions. Statistical and bioinformatic analyses were applied in order to test group and regional differences in miRNAs and to determine their target gene pathways. The first project aimed to distinguish sex and regional differences in MS-related miRNAs. In the second project, we tested the interaction between MS and restraint stress on hypothalamic miRNA expression. We also tested if environmental enrichment would convey resilience to MS via miRNA signaling. These studies revealed significant differential effects of MS on miRNA expression in males and females. We also revealed miRNA-miRNA coexpression across the prefrontal cortex, amygdala, and hippocampus. VEGFA, MAPK6, and MMP19 were highlighted as key targets of differentially expressed miRNA because of their common regulation by several miRNAs. In the hypothalamus, miRs-301 and -144, which target MAPK6 and MMP19, showed a treatment response to enrichment. Finally, we showed the first evidence of increased miRNA methylation following MS.

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