Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Teresa M. Reyes

Abstract

Gaining excessive weight during pregnancy occurs in over 50% of pregnancies in the United States. This excessive weight gain can lead to development of Large for Gestational Age (LGA) babies, or babies born in the top 10% for weight class at birth. LGA babies have increased risk for neurological disorders, including autism, schizophrenia and ADHD. Our lab models excessive gestational weight gain and LGA in a mouse model by feeding dams a 60% high fat (HF) diet throughout gestation and lactation. At weaning all offspring are fed control diet for the remainder of life. HF offspring have increased preference for palatable foods, increased learning and motivation deficits, disrupted gene expression in reward system neurocircuitry and both global- and promoter-specific DNA hypomethylation within the prefrontal cortex (PFC). Dietary methyl donor nutrient supplementation (MS) during pregnancy has been shown to ameliorate some of these phenotypes in HF offspring as well as alter DNA methylation patterns. Because the PFC continues developing postnatally, we were interested in understanding whether MS given during early postnatal life (3-6 weeks) would also ameliorate behavioral and molecular phenotypes. Also, because HF offspring exhibit DNA hypomethylation throughout the brain, we were interested in whether DNA methyltransferase (DNMT) function could mediate these changes. Utilizing operant behavior training, gene and protein expression analysis and mass spectrometry we were able to answer these questions. We determined that early life MS can counteract deficits in motivation and learning in female offspring. Also that MS alters the concentrations of folate and methionine intermediates and gene expression directly after supplementation in the PFC tissue of male and female offspring. Finally, we determined that perinatal HF diet alters overall DNMT activity within the PFC without altering DNMT1 or DNMT3a expression in adult male and female offspring. This work adds to our understanding that long-term behavior and disease risk can be influenced by both maternal and early life diet. Therefore, it is important to continue study the mechanistic links between excessive gestational weight gain, perinatal HF diet exposure and MS to make better dietary recommendations that may combat disease risk.

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