Epigenetic Effects on Brain and Behavior: Testing the Role of Imprinted Genes

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The mammalian brain, remarkable for its complexity and plasticity, is also profoundly sensitive. This project will use cutting-edge genomic tools to study how genes expressed in the placenta influence the brains and behavior of mothers as well as their offspring. The project focuses on imprinted genes, a group of genes that are critical to placental function and brain development. The expression of imprinted genes depends on parent-of-origin: some are expressed exclusively from the maternal copy, and some from the paternal copy. Disruption of this unusual expression pattern in mouse placenta alters the behavior and physiology of mothers. In humans, imprinted genes are linked to mood and cognition disorders. The research team will use a novel mouse model and classic behavioral tests to assess how and when imprinted genes exert their effects on mothers and offspring. They will also recruit and mentor Native American student researchers, and provide hands-on research experiences for high school science teachers. The teachers will develop lesson plans based on their research, and will enhance their scientific literacy by learning more about evolution, genetics and behavior.Placental complexity, maternal care, and a highly developed forebrain are defining features of eutherian mammals. Imprinted genes affect all three phenotypes but little is known about how these effects are integrated across tissues (placenta, brain), genotypes (mother, offspring), and development (perinatal, adult). The researchers will assess the role of imprinted genes in these interactions by measuring the effects of placental loss of imprinting (LOI) on mothers, of developmental LOI on embryonic brain and neonatal behavior, and the combined effects of LOI and maternal environment on adult brain and behavior. They do so in a tractable hybrid system, in which potentially opposing effects of LOI for paternally vs. maternally imprinted genes can be enumerated. Effects of placental LOI on mothers will be tested by profiling the behavior, neural transcriptomes (RNAseq) and hormone levels of pregnant females, and the behavior of nursing mothers. In parallel, they will measure expression (RNAseq) and DNA methylation (reduced representation bisulfite sequencing) in embryonic brain and placenta, and behavior in neonates. Cross-fostering will separate effects of altered maternal care in mothers exposed to placental LOI, from effects of developmental LOI, on behavior and neural gene expression and methylation in adult animals. These studies will test the hypothesis that imprinted genes regulate the intimate and obligate relationship between mammalian mothers and young, and will advance understanding of the combined effects of genotype, epigenotype and rearing environment on brain and behavior, and the role of imprinted genes in placental signaling and in shaping the adult brain.