Abstract
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.
Highlights
The hippocampus is a component of the brain’s limbic system that has been implicated in higher cognitive processes such as learning and memory, spatial navigation, and emotional regulation (Frankland et al, 1998; Bannerman et al, 2003; Kheirbek et al, 2013; Trivino-Paredes et al, 2016)
Following 41 days of continuous housing in running disk (RUN), locked disk (LD), and SOC conditions, mice were subjected to an additional 2 weeks of 8-arm radial arm maze (RAM), and novel object recognition (NOR) paradigms (Figure 1B). 6 weeks of enrichment were provided prior to behavioral testing to allow sufficient time for integration of newly generated neurons, and the respective housing conditions were maintained during the additional testing period to avoid introduction of additional variables
RUN, LD, and SOC mice did not exhibit differences in baseline locomotion that might affect performance in these behavioral tests (Figure 1C), and post-testing assessment of neurogenesis confirmed that the RUN group had increased numbers of neuroblasts after 8 weeks of EE (Figure 1D), as reported previously after 4 weeks (Bednarczyk et al, 2009, 2011; Gregoire et al, 2014)
Summary
The hippocampus is a component of the brain’s limbic system that has been implicated in higher cognitive processes such as learning and memory, spatial navigation, and emotional regulation (Frankland et al, 1998; Bannerman et al, 2003; Kheirbek et al, 2013; Trivino-Paredes et al, 2016). Synapses between axons of entorhinal cortex neurons and DG granule cells are the first synapses of the tri-synaptic circuit and represent the principal gateway to hippocampal function (Anderson et al, 2007). NSCs continuously produce new, highly plastic granule neurons through the process of adult neurogenesis, and ablation of these newly generated granule cells in rodents compromises normal learning and memory as well as regulation of stress and emotion (Kheirbek et al, 2013; Aimone, 2016)
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