br Acknowledgements Conflict of Interest br Financial Suppor

Acknowledgements Conflict of Interest
Financial Support The work was financially supported by a grant from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) at the National Institutes of Health (grant number R21AA023521-01A1 to MR). The sponsor of the study (NIAAA) had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The authors collected the data, and had full access to all of the data in the study. The authors also had final responsibility for the decision to submit the study results for publication. Author\'s Contributions
Background Cognitive performance is determined by genetic and environmental factors (Tucker-Drob and Briley, 2014). In-utero nutrition is an under-studied aspect of cognitive development (Godfrey and Barker, 2000). Whereas supplemental prenatal folic histone methyltransferase inhibitor prevents neural tube defects (Gomes et al., 2015), other nutrients required for optimal cognitive development remain largely unknown. Fruits, foliage, nuts, and seeds have been traditionally important dietary constituents for humans and early hominins (Ungar and Sponheimer, 2011). There is renewed interest in examining whole food impact on health outcomes rather than macro- and micro-nutrient separately (Simpson et al., 2015). The Canadian Healthy Infant Longitudinal Development (CHILD) study is a general population-representative birth cohort of term and near-term infants recruited while mothers were pregnant (Subbarao et al., 2015). Although epidemiological studies can infer associations, direct experimental studies, especially in model species, provide more causal and generalizable inferences. The Drosophila olfactory learning and memory model (Bolduc and Tully, 2009) has been used extensively to examine intellectual disability (van der Voet et al., 2014). Additionally, the Drosophila diet is simple and primarily composed of protein and carbohydrate (Simpson et al., 2015) allowing for easy dietary manipulation to recapitulate human findings. For example, Drosophila larvae were more viable and developed faster with increasing dietary folic acid (Blatch et al., 2010). The cyclic adenylate monophosphate (cAMP) and cAMP response element binding protein (CREB) pathway was among the first pathways linked to learning and memory in Aplysia and Drosophila (Yin et al., 1994; Brunelli et al., 1976). It was subsequently determined that Fragile X syndrome patients have altered cAMP signaling (Kelley et al., 2007) while Rubinstein-Taybi syndrome patients have a CREB pathway mutation (Petrij et al., 1995). Flies have since became a model used extensively by several groups to understand the molecular basis of intellectual disability (Androschuk et al., 2015). Drosophila mutants of rutabaga (Levin et al., 1992), a gene that encodes for a calmodulin dependent adenylate cyclase that converts ATP to cAMP (Kandel and Schwartz, 1982), were among the first learning mutants isolated in a forward genetic screen for learning. CHILD Edmonton sub-cohort data were analyzed to ascertain the effect of prenatal and postnatal fruit intake on 1-year neurodevelopment. Higher gestational fruit intake was associated with enhanced cognitive performance at 1year of age. We then took advantage of the Drosophila olfactory learning and memory model (Bolduc and Tully, 2009) to ascertain whether cognitive enhancement in healthy individuals following high prenatal fruit intake persisted across species and to decipher the molecular mechanisms with a focus on cAMP.
Methods
Discussion We have demonstrated that increasing prenatal fruit intake is associated with increased cognitive development in children using data from a population-based cohort. The influence of fruit was slightly greater among infants born earlier in gestation. Lycopene, a red carotene with antioxidant properties, was the food nutrient most strongly associated with cognitive development. Using the olfactory classical conditioning model of Drosophila, we explored the idea that a prenatal fruit-enhanced diet produces progeny with superior cognitive (learning and memory) abilities. Not only was this evident, but we also showed that this enhancement appears to require adenylate cyclase function as enhancement was not observed in D. rutabaga genetic mutants. The result of this study strongly supports the daily consumption of fruit as part of the prenatal diet for the general population of pregnant women.