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Front Mol Neurosci. 2018 Apr 13;11:126. doi: 10.3389/fnmol.2018.00126. eCollection 2018.

RNA-Sequencing Reveals Unique Transcriptional Signatures of Running and Running-Independent Environmental Enrichment in the Adult Mouse Dentate Gyrus.

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Research Center of the University of Montreal Hospital, University of Montreal, Montreal, QC, Canada.
CNS Research Group, University of Montreal, Montreal, QC, Canada.
Department of Pathology and Cell Biology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
Department of Nutrition, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
Department of Neurosciences, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.


Environmental enrichment (EE) is a powerful stimulus of brain plasticity and is among the most accessible treatment options for brain disease. In rodents, EE is modeled using multi-factorial environments that include running, social interactions, and/or complex surroundings. Here, we show that running and running-independent EE differentially affect the hippocampal dentate gyrus (DG), a brain region critical for learning and memory. Outbred male CD1 mice housed individually with a voluntary running disk showed improved spatial memory in the radial arm maze compared to individually- or socially-housed mice with a locked disk. We therefore used RNA sequencing to perform an unbiased interrogation of DG gene expression in mice exposed to either a voluntary running disk (RUN), a locked disk (LD), or a locked disk plus social enrichment and tunnels [i.e., a running-independent complex environment (CE)]. RNA sequencing revealed that RUN and CE mice showed distinct, non-overlapping patterns of transcriptomic changes versus the LD control. Bio-informatics uncovered that the RUN and CE environments modulate separate transcriptional networks, biological processes, cellular compartments and molecular pathways, with RUN preferentially regulating synaptic and growth-related pathways and CE altering extracellular matrix-related functions. Within the RUN group, high-distance runners also showed selective stress pathway alterations that correlated with a drastic decline in overall transcriptional changes, suggesting that excess running causes a stress-induced suppression of running's genetic effects. Our findings reveal stimulus-dependent transcriptional signatures of EE on the DG, and provide a resource for generating unbiased, data-driven hypotheses for novel mediators of EE-induced cognitive changes.


RNA-sequencing; dentate gyrus; environmental enrichment; exercise; hippocampal neurogenesis; social environment

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