All ETDs from UAB

Advisory Committee Chair

Ilan A Kerman

Advisory Committee Members

Lori L McMahon

Martin E Young

Sarah M Clinton

Vladimir Parpura

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Extensive evidence implicates bi-directional relationship between mood disorders and cardiovascular disorders. Early-life experience can have strong effects both on emotional development and cardiovascular function throughout life. Studies in humans are limited to correlational analyses, which are necessarily limited in terms of revealing mechanistic underpinnings of these associations. Thus, various pre-clinical models are utilized to investigate the effects of early-life experience in various domains, such as behavior and cardiovascular function, which are likely mediated by epigenetic mechanisms. Previous studies have used maternal separation and neonatal handling in developing rodents as a way to model differences in early-life experience. The effect of early-life maternal separation has been found to be adaptive as well as maladaptive. Cumulative stress hypothesis favors the maladaptive consequence of maternal separation, which states that an individual is more likely to be vulnerable to cumulative stress throughout life. In contrast, match-mismatch hypothesis states that early-life environment shapes coping strategies in a manner that enables individuals to optimally face similar environments later in life, where early-life stress may not necessarily elicit adverse consequences but may be of adaptive value. Data presented in this thesis indicate that the effects of early-life experience may depend on inborn stress reactivity. Prolonged maternal separation (3 hrs) for first two weeks of postnatal development conferred beneficial behavioral effects in stress sensitive Wistar Kyoto (WKY) rats, but not in the stress resilient Wistar rats. Furthermore, beneficial behavioral effects were accompanied by changes in cardiovascular indices indicative of improved cardiovascular health. These behavioral and cardiovascular changes were accompanied by an increase in global DNA methylation in the hippocampus. When post-weaning WKY rats were fed with methyl-donor supplemented diet, beneficial behavioral effects were observed, reminiscent of those elicited by maternal separation. These changes were also accompanied by protective cardiovascular adaptations. Taken together, these data suggest that early-life experience has a strong effect on the behavior, brain development, and cardiovascular function throughout life. These programming effects may be mediated by epigenetic changes (i.e. differential DNA methylation) in select brain regions. On the other hand, aggression has also been implicated in cardiovascular disorders such as coronary heart disease. Previous works has shown that rats with high levels of aggression show signs of autonomic impairment and increased susceptibility to arrhythmias. However, it is not clear whether trait aggression may be influenced by early-life experience, and whether trait aggression and early-life experience may act in concert or independently in the regulation of cardiovascular function. The current study found that trait aggression (quantified by attack behavior in the resident-intruder test) was not impacted by the experience of maternal separation, suggesting that aggression is a stable and heritable trait that is not impacted by early-life environment in WKY rats. Trait aggressive rats showed increases in: resting blood pressure, wall-to-lumen ratio of the thoracic aorta, vascular sensitivity to phenylephrine application, and norepinephrine levels in left ventricle. In contrast, maternal separation did not impact resting blood pressure, but decreased resting heart rate and increased heart rate variability instead. These observations suggest that early-life experience and trait aggression affect distinct domains of cardiovascular function. Future studies will be required to tease out the biological mechanisms responsible for these programming effects of early-life experience and trait aggression.

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