All ETDs from UAB

Advisory Committee Chair

Sarah Clinton

Advisory Committee Members

Daniel Smith

Farah Lubin

Nicole Riddle

Yogesh Dwivedi

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Understanding biological mechanisms that shape brain development and susceptibility to emotional dysfunction is crucial for generating improved treatments for depression and anxiety disorders. To study neurodevelopmental factors that influence emotionality, we use model rats that were bred for distinct behavioral responses to novelty. Rats bred for low novelty response (LRs) exhibit a high anxiety-/depressive-like phenotype compared to high novelty responder rats (HRs), which vigorously explore novelty and exhibit high impulsivity, aggression, and risk-taking. Transcriptome profiling revealed multiple gene expression differences in the early postnatal hippocampus and amygdala and in the adult amygdala of HR/LR rats. Through gene ontology analysis, we found cellular metabolism and other mitochondrial processes to be regulated during early postnatal development. We investigate oxidative metabolism through cytochrome c oxidase (COX) histochemistry in early postnatal brains. We found increased HR/LR COX activity in the hippocampus during the first week of life and in the amygdala during the first 3 weeks of life. These dramatic transcriptome differences led us to postulate that rats prone to high (versus low) anxiety/depression-like behavior are under the control of an upstream process that is regulating transcription We hypothesized that HR/LR rats exhibit distinct DNA methylation patterns in the early postnatal and/or adult limbic brain. We then found altered DNA methyltransferase (DNMT) protein levels and elevated global DNA methylation (5-methylcytosine) levels in the early postnatal amygdala of LR versus HR rats. Us-ing MethylCap-seq technology, we mapped the methylome of early postnatal and adult HR/LR amygdala to examine how alterations in DNA methylation landscapes may contribute to LR/HR gene expression and behavioral differences. Depleting the maternal dietary methyl donor in LR improved their typically high levels of depression-like behavior. Conversely, we improved the depression-like behavior in LR adults by supplementing methyl donors, which points to novel treatment strategies for individuals suffering emotional disorders. These findings highlight how inborn differences in epigenetics may shape tem-perament and risk for emotional dysfunction, and may facilitate our understanding of the developmental neurobiology of emotional disorders.

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