Dissertation
Impacts of chronic prenatal stress on maternal and offspring outcomes, and the mitigating effects of P7C3 compounds
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2021
DOI: 10.17077/etd.005842
Abstract
Stress during pregnancy increases offspring risk for neurodevelopmental disorders such as autism, schizophrenia, attention deficit hyperactivity disorder, and learning and mood disorders. The mother can also be adversely impacted by stress, as severe or prolonged stress may lead to stress-induced mood disorders. Due to these risks, there is a critical need to develop safe, effective treatments for protecting offspring neurodevelopment that can be administered during pregnancy. This dissertation aimed to establish the efficacy and safety of a novel nicotinamide adenine dinucleotide (NAD+)-stabilizing agent, P7C3-A20, in a preclinical model of chronic prenatal stress.To examine both maternal and offspring outcomes, I used CD1 mouse dams in a chronic restraint stress model. I measured maternal and adult offspring behavior, and I collected offspring and maternal tissue at multiple time points. Aim 1 details my maternal findings. Surprisingly, dams did not show a clear depressive-like phenotype in response to chronic stress, as is canonical in the literature. Instead, at both prenatal and postnatal time points, dams were hyperactive in response to stress, and this phenotype was not rescued by concurrent P7C3-A20 administration. However, maternal care behaviors were affected by prenatal stress, and were rescued by P7C3-A20 treatment. Aim 2 encompasses my offspring findings. Of note, this dissertation was the first to discover that the expression NAD+-producing enzymes is disrupted in the embryonic brain by prenatal stress, which is corrected by maternal P7C3-A20 administration. I also found concurrent stress-induced disruption of gamma aminobutyric acid (GABA)-related gene expression in the embryonic brain, and GABAergic systems continued to be disrupted in adult offspring. Interestingly, GABA-related perturbations were equally disrupted and rescued by P7C3-A20 in the embryonic brain across both sexes, but males and females diverged in adulthood, with males being more affected by prenatal stress and lacking complete rescue by P7C3-A20. Finally, offspring learning and affective-like behaviors were impacted by prenatal stress and rescued by P7C3-A20 in both sexes.
These studies provide support for the use of P7C3-A20 in the prevention of neurodevelopmental perturbations caused by prenatal maternal stress. While there is much work to be done in order to unravel the mechanistic underpinnings underlying prenatal stress itself as well as how P7C3-A20 modulates its effects, the results presented here demonstrate the potential for harnessing the protective effects of this compound during neurodevelopment.
Details
- Title: Subtitle
- Impacts of chronic prenatal stress on maternal and offspring outcomes, and the mitigating effects of P7C3 compounds
- Creators
- Rachel Schroeder
- Contributors
- Hanna E Stevens (Advisor)Andrew A Pieper (Advisor)Joshua Weiner (Committee Member)Aislinn Williams (Committee Member)Eric Taylor (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Neuroscience
- Date degree season
- Spring 2021
- DOI
- 10.17077/etd.005842
- Publisher
- University of Iowa
- Number of pages
- xiii, 135 pages
- Copyright
- Copyright 2021 Rachel E. Schroeder
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- includes bibliographical references (pages 110-128)
- Public Abstract (ETD)
Stress experienced during pregnancy is known to increase the risk for the baby to develop disorders later in life such as autism, attention deficit hyperactivity disorder (ADHD), learning disorders, and mood disorders. The same is true for stress-related mood disorders such as anxiety and depression in the mother. Unfortunately, the medical field is limited in how they can treat stress, anxiety, and depression during pregnancy because of concerns that medications could also impact the baby’s brain development. The goal of this dissertation was to use a mouse model to test whether a new compound, P7C3-A20, could be used to alleviate stress during pregnancy and protect the baby’s brain development.
This dissertation shows that many of the changes to the baby’s brain and behavior caused by stress during pregnancy can be fixed by giving the mother P7C3-A20. For example, this project was the first to find that in the developing brain, important enzymes for energy metabolism are disrupted by maternal stress during pregnancy, which P7C3-A20 corrects.
Overall, this dissertation shows promise for the compound P7C3-A20 to be able to protect a developing baby’s brain development if the mother is experiencing stress during her pregnancy. It also opens the door for a new area of research into how the enzymes involved in energy metabolism play a role both in normal development and in cases when development is disrupted by environmental factors experienced by the mother.
- Academic Unit
- Interdisciplinary Graduate Program in Neuroscience
- Record Identifier
- 9984097167902771
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