Epigenetic mechanisms of fetal programming of the IUGR baboon brain prefrontal cortex
SPECIFIC AIMS: The prefrontal cortex (PFC) of the brain represents the highest level of cortical hierarchy due to its important role in higher order problem solving and complex cognition. In both humans and non-human primates, the PFC does not attain full maturity until early adulthood [1]. However, the PFC is also the most sensitive region in the brain to the detrimental effects of stress exposure leading to changes in cortical gene expression through epigenetic regulation, especially during the transition from prenatal to postnatal development [2]. Thus, nutritional stress may pose significant risks for proper development of the PFC, but little is known about the impact of reduced maternal nutrient availability on fetal brain development and subsequent brain function in adulthood. In the western world in some groups of society up to 20% of babies are intrauterine growth restricted (IUGR) [3]. IUGR is responsible for much neonatal mortality and morbidity and as shown by human epidemiological studies such as the Dutch Hunger Winter [4] increased predisposition to many chronic diseases including behavioral disorders [5,6]. The extent of the problem with maternal nutrition in pregnancy is shown by the observation that in 2004, a total of 852 million people worldwide experienced food insecurity exposing millions of pregnant women and children to decreased nutrient availability [7,8].
Drs. Nathanielsz and Cox have previously developed a baboon nonhuman primate (NHP) model of decreased nutrient availability during fetal development (30% global maternal nutrient reduction, MNR) to evaluate the impact of reduced nutrient availability on primate fetal brain development with a particular emphasis on the PFC. This model leads to IUGR [9]. They reported [10] that MNR induced major cerebral developmental disturbances at mid gestation (0.5 gestation - G); however, the impact of MNR at late gestation (0.9G), as well as the mechanisms mediating these effects have not been determined. The central hypothesis of this project is that IUGR alters fetal brain developmental trajectories in late gestation via epigenetic regulation of transcriptional and translational signaling pathways. Completion of studies to address this hypothesis will allow us to address in future studies the hypothesis that fetal effects persist into adulthood and impact cognition during aging. (The 30% MNR used in this model will be referred to as IUGR throughout this proposal for consistency purposes).
There are three specific aims to address my hypothesis.
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