The medial prefrontal cortex (mPFC), master regulator of higher-order cognitive functions, is the only
brain region that matures until late adolescence. During this period, the mPFC is sensitive to stressful
events or suboptimal nutrition. For instance, high-fat diet (HFD) feeding during adolescence markedly
impairs prefrontal-dependent cognition. It also provokes multiple changes at the cellular and synaptic
scales within the mPFC, suggesting that major transcriptional events are elicited by HFD during this
maturational period. The nature of this transcriptional reprogramming remains unknown, but may
include epigenetic processes, in particular microRNAs, known to directly regulate synaptic functions.
We used high–throughput screening in the adolescent mouse mPFC and identified 38 microRNAs
differentially regulated by HFD, in particular mir-30e-5p. We used a luciferase assay to confirm the
functional effect of mir-30e-5p on a chosen target: Ephrin-A3. Using global pathway analyses of
predicted microRNA targets, we identified biological pathways putatively affected by HFD. Axon
guidance was the top-1 pathway, validated by identifying gene expression changes of axon guidance
molecules following HFD. Our findings delineate major microRNA transcriptional reprogramming
within the mPFC induced by adolescent HFD. These results will help understanding the contribution of
microRNAs in the emergence of cognitive deficits following early-life environmental events.