Estradiol and Hippocampal Development

University Of Maryland Baltimore, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Understanding neurogenesis is an essential goal of neuroscience. Naturally occurring sex differences in neurogenesis are of inherent interest but also provide a tractable tool for exploring novel mechanisms not otherwise apparent. Using the laboratory rat we have identified and characterized a profound sex difference in hippocampal neurogenesis restricted to a perinatal sensitive period. Newborn males make up to twice as many new cells as females in the dentate gyrus, CA1 and to a lesser extent CA3 of the hippocampal formation, and 80% of those newborn cells will become neurons while only 40% will do so in females. Thus males have higher rates of both proliferation and neuronal differentiation. Sex differences in the brain are often the byproduct of increased testicular androgen production that is locally converted to estradiol in the brain. We propose the novel hypothesis that the sex difference in hippocampal neurogenesis is the product of two sources of epigenetic repression in females; 1) canonical changes to the DNA and histones via methylation and acetylation that repress pro-proliferation genes, and 2) microRNAs which regulate gene expression by degrading pro-differentiation mRNAs. We further contend that the higher level of microRNAs we detect in neonatal female hippocampus is at least in part determined by chromosome compliment, that is, XX vs XY. A candidate gene, BDNF, has emerged and detailed interrogation of BDNF gene expression and effects will be combined with broader based surveys of the hippocampal methylome and chromatin state to elucidate the source of the sex difference in neurogenesis via the following specific aims: SA1 - Identify the mechanism mediating sex differences in epigenetic control of neurogenesis in the developing hippocampus, SA2 - Determine microRNA profile and mechanism suppressing neurogenesis in developing female hippocampus and SA3 - Establish cross-talk between epigenetics and microRNAs in neonatal hippocampal neurogenesis. Completion of these aims will provide novel insight into the regulation of neurogenesis in the developing healthy brain and illuminate the source of higher male vulnerability to the consequences of neonatal brain injury or insult.