Erin Murray - PhD Candidate, Neuroscience Graduate Program
Depression, one of the leading causes of disability worldwide, manifests in various subtypes, including postpartum depression (PPD), which presents after the critical window of pregnancy. Two common, co-occurring environmental factors, exposure to endocrine disrupting chemicals (EDCs) and psychological stress, both disrupt hypothalamic-pituitary-adrenal (HPA) function. Independently, these environmental factors are both associated with increased risk for PPD. Stress can alter neurotransmitter balance and neuroplasticity, trigger neuroinflammation, and produce depressive-like behaviors, such as reduced motivation. Of the many EDCs, perfluorooctanoic acid (PFOA) is found ubiquitously in nearly all pregnant women and infants. Although PFOA and stress both act upon the HPA axis, it remains to be determined whether co-exposure to these factors results in enhanced hormone production or enhanced disruption of the metabolic, immunological, and neurological changes that occur during pregnancy that are related to depressive-like behaviors. Preliminary data from our laboratory has shown that mouse dams exposed to stress and PFOA (100 ng/kg/day - PFOA+S) exhibit unique increases in serum corticosterone and altered metabolic profiles within the frontal cortex (FC), a region found dysregulated in patients with depression that provides critical modulatory feedback to reward-related brain regions. Additionally, our data indicates stress induced increases in activity and self-directed behaviors (grooming and increased localized spontaneous movement). However, effects on motivation, a more translationally relevant behavioral domain for depression, have yet to be evaluated. It is unclear if motivation and stress-induced activity-related behaviors are modulated by the same underlying mechanisms during pregnancy and in the postpartum period. Furthermore, HPA axis activation drives the metabolic support critical for energic homeostasis throughout pregnancy and modulates production of cytokines necessary for immune function and suppression critical to fetal growth and development. Tryptophan metabolism is known to be regulated by both immune and HPA axis, and tryptophan concentrations decrease across gestation in both serum and in brain. Therefore, it is important to understand how the bidirectional regulation between the immune and metabolic systems may be dysregulated in dams exposed to PFOA+S and how this potential dysregulation may affect behavior. To address these questions, we will use a novel resource deprivation paradigm modeling psychosocial stress to examine the combinatorial effects of both gestational stress and low dose PFOA on maternal brain and behavior in C57Bl6/J mice. We aim to 1) test the hypothesis that PFOA plus stress reduces motivation in pregnant dams by developing a behavioral assay of motivation for pup access, 2) identify molecular targets of stress-induced increases in stereotypic behavior and increased self-grooming and motivation, and 3) explore how endocrine activation by PFOA and stress modulates the relationship between tryptophan metabolism and immune markers. In addition to improving upon current rodent models of psychosocial stress in females, which is critical for strengthening the toolset used to study PPD, this project is essential for advancing a cumulative risk framework for “safe” chemical exposure levels in vulnerable populations.
Sep 27, 2024 @ 9:00 a.m.
Medical Center | K307 (3-6408)
Host: Advisor: Marissa Sobolewski, PhD