PROGRAM | Neuroscience

By: Nicholas Collins Chair: Tania Roth Co-Chair: Jeffrey Rosen

ABSTRACT

Early life stress (ELS) in the form of trauma, abuse, or neglect has the capacity to increase the propensity for numerous psychopathologies and diseases later in life. However, not all of those who experience ELS go on to develop psychopathology or disease, making elucidating moderator variables a critical research focus. Among moderators, the caregiving relationship may promote either pathology or shift the developmental trajectory toward resilience, dependent on caregiving quality and availability. Indeed, while a deprived caregiver relationship can increase the risk for developing cardiovascular disease, anxiety, or depression, improving the caregiving relationship is known to ameliorate many of the neurobiological and behavioral consequences of ELS exposure. While underlying mechanisms surrounding these divergent pathologies remain unclear, epigenomics has emerged as a promising candidate. Translating to “above the genome”, epigenomics is broadly defined as how genes are activated and deactivated in different environmental contexts. Previous work from our lab and others have demonstrated aberrant gene expression, DNA methylation, and caregiving behavior following exposure to deficient caregiving in early life. This suggests that the interaction of caregiving and epigenomics is a sound place to explore how our early life experiences may precipitate psychopathological risk or resilience. In the present dissertation, we hypothesize that deficiencies in the caregiving relationship, including quality or availability, leads to aberrant anxiety-like and defensive behaviors later in life. Moreover, we hypothesize that the observed aberrant behavior will be paralleled with epigenomic changes in several key brain areas associated with executive function, fear responsivity, and defensive behavior. To test this, we chronically exposed developing rodents to a chronic predator odor (2,5-dihydro-2,4,5-trimethylthiazoline, TMT, a molecular derivative of fox feces). Previous work using this model determined that exposing dams with their pups to TMT during the first three weeks of life for 20-minutes per day transiently altered maternal caregiving behaviors. Moreover, the progeny displayed dampened fear responses (freezing) upon TMT re-exposure later in life. However, in this work, it is unclear if maternal caregiving (quality or availability) were driving these changes per se (Aim 1), or if it was mere chronic exposure. Additionally, it is unclear if epigenetic mechanisms such as gene expression (Aim 2) or DNA methylation (Aim 3) are associated with any observed changes in anxiety-like and defensive behaviors after ELS exposure. Results indicated both sex-specific changes in anxiety and defensive behaviors, and epigenomic changes associated with ELS exposure in candidate genes in the medial prefrontal cortex, amygdala, and olfactory bulb. Taken together, the data presented in this dissertation have helped characterize the behavioral and epigenomic consequences of an ELS model of chronic predator odor exposure in rodents. The data in this dissertation add to a growing body of literature that seeks to elucidate how ELS drives disease risk in the brain. Moreover, these data help inform mechanisms that may be measured or manipulated in the treatment of disease to shift developmental trajectories toward resilience.

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