Potential biological embedding of adverse and enriching environments through epigenetic mediators

In humans, adverse social exposures (ASEs) such as stress or trauma can exert both acute and long-lasting biological and psychological effects. This is especially true during critical periods of development such as childhood, adolescence, and young adulthood. Numerous biological systems are affected in response to ASEs, but variability in neuroimaging structural, functional, and connectivity measures within the fronto-limbic pathway are repeatedly observed in association with ASEs. The hippocampus, amygdala, and frontal cortex, key members of the fronto-limbic pathway, support critical cognitive functions that are notably impaired in numerous mood- and stress-related psychiatric illnesses. Replicable variability of the aforementioned neuroimaging measures are also noted in associated with psychiatric illnesses. Together, variability in these fronto-limbic structure, function, and connectivity measures are regarded as neural correlates of ASEs and neural endophenotypes of psychiatric illness. In rodents, stressor paradigms are commonly employed to investigate the molecular effects of ASEs and can be a significant source of human-relevant insight. With these rodent models, researchers have observed cognitive and neurobiological effects that mirror ASE-associated effects in humans. In contrast, environmental enrichment (EE) can exert positive physiological and cognitive effects and can rescue the negative effects of ASEs (as observed in both humans and rodents). It appears then, that the effects of ASEs and EE potentially operate on similar underlying neurobiological substrates in the fronto-limbic pathway. To this end, the molecular mechanisms supporting the biological embedding of our external environments have come under investigation. Epigenetic mechanisms, such as 5-methyl-cytosine (5mC) marks at cytosine-phosphate-guanine (CpG) base pair sequences, are now regarded as potential mediators of gene by environment interactions. However, current technological limitations make it impossible to measure epigenetics in the living human brain--the primary etiological tissue of interest regarding mental health outcomes. To overcome these barriers, researchers have forged alternative paths towards elucidating the relationships between our external environments and the epigenetic mechanisms that purportedly potentiate experience-dependent changes across the CNS. Two such methods are utilized in the current research, after an initial overview of relevant literature in Chapter 1. In Chapter 2 and 3, I use genome-scale bioinformatics approaches in tandem with structural neuroimaging measures from the fronto-limbic pathway to investigate whether variability in peripheral tissue-derived 5mC clusters may represent pathways through which ASEs experienced in childhood and adulthood may become biologically embedded. In Chapter 4, I leverage secondary data analysis methods on a mouse model of EE to investigate the effects of EE on locus-specific epigenomic and transcriptomic measures from dorsal and ventral dentate gyrus in the hippocampus. Chapter 5 discusses the implications of these findings and their contributions to the existing literature surrounding neurobiological and epigenetic variability associated with ASEs and EE. Overall, this work uses novel genome-scale bioinformatics approaches to investigate underlying epigenetic mechanisms associated with, and/or potentially responsible for the biological embedding of external environments. It provides novel insights to the fields of stress, trauma, and psychiatric illness by providing network-level and locus-specific peripheral biomarkers of ASEs, peripheral epigenetic profiles associated with neural endophenotypes of psychiatric illness, in addition to potentially mechanistic epigenetic mediators of EE-related biological embedding in the hippocampus.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Psychology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Pfeiffer, John Ryan

Contributors dc:contributor

• Uddin, Monica
• Gulley, Josh
• Juraska, Janice
• Zhao, Dave
• Derringer, Jamie

• epigenetics
• methylation
• fronto-limbic
• hippocampus
• amygdala
• cortex
• enrichment
• adverse social exposure
• peripheral

Statement dc:rights

• Copyright 2021 John Pfeiffer

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/112949

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/112949