Epigenetic regulatory mechanisms during neurodevelopment

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Among other insights, this NSERC funded research has established that the natural variation associated with gene expression is much more common than DNA polymorphism. From evolutionary perspective, this variation offers among the first defence to environmental stresses particularly during neurodevelopment. Further, we have demonstrated that advances in molecular technologies to appraise this variability reliably now offers effective strategies to investigate this defence during neurodevelopment, which has remained enigmatic. Our strategy is to interrupt neurodevelopment at desired time(s) by stressors (eg. alcohol) and evaluate genome-wide changes using RNA-seq and microarrays. The results have allowed us to conclude that alcohol yields a lifelong “molecular footprint” of its encounter during neurodevelopment. Further, this “footprint” may underlie critical behavioral defects often associated with neurodevelopmental exposure to alcohol. This proposal will specifically focus on molecular studies on hippocampus that directs learning and memory often affected by prenatal alcohol. Objective 1: To assess hippocampal gene expression and DNA methylation in the adult mice that show behavioral abnormalities including learning/memory deficits caused by neurodevelopmental alcohol exposure. Objective 2: To assess if prenatal-alcohol-exposure induced behavioral and molecular landscapes could be altered (improved or worsened) by postnatal environmental enrichment (positive) and maternal separation (negative), respectively. This research will use C57BL/6J mice, as the animal model. It begins with generation of two groups of time-mated (pregnant) females. The first group is given a choice between 10% ethanol and water as the free choice of liquid (E) and the second group receives only water bottle (W). Pregnant C57BL/6J females prefer (70%) to drink 10% alcohol and the resulting progeny shows multiple behavioral effects including learning and memory deficits. Next, the resulting progeny (21 day old) from E and W mothers are subjected to three postnatal environments; raised with free access to interactive toys and running wheels (enrichment or positive environment, P); subject to maternal separation stress (negative environment, N) and normal rearing (control, C). The animals representing six groups (EP, EN, EC, WP, WN, WC) will be followed for learning and memory using Barnes Maze. The hippocampi of such mice will be assessed for molecular footprint using appropriate technologies. The results will offer a novel insight in the molecular interplays between DNA methylation and prenatal (alcohol) and postnatal environment in progression of learning and memory. The project as outlined will train HQPs with expertise in neuroscience, epigenetics and modern experimental protocols involving genomics and epigenomics. Such HQPs are needed in this, the post genome era.