Physical exercise enhances cognitive flexibility as well as astrocytic and synaptic markers in the medial prefrontal cortex

Abstract

Physical exercise enhances a wide range of cognitive functions in humans. Running-induced cognitive enhancement has also been demonstrated in rodents but with a strong emphasis on tasks that require the hippocampus. Additionally, studies designed to identify mechanisms that underlie cognitive enhancement with physical exercise have focused on running-induced changes in neurons with little attention paid to such changes in astrocytes. To further our understanding of how the brain changes with physical exercise, we investigated whether running alters performance on cognitive tasks that require the prefrontal cortex and whether any such changes are associated with astrocytic, as well as neuronal, plasticity. We found that running enhances performance on cognitive tasks known to rely on the prefrontal cortex. By contrast, we found no such improvement on a cognitive task known to rely on the perirhinal cortex. Moreover, we found that running enhances synaptic, dendritic and astrocytic measures in several brain regions involved in cognition but that changes in the latter measures were more specific to brain regions associated with cognitive improvements. These findings suggest that physical exercise induces widespread plasticity in both neuronal and nonneuronal elements and that both types of changes may be involved in running-induced cognitive enhancement.

Fig 1. Running enhances cognitive performance on tasks known to require the medial prefrontal cortex and orbitofrontal cortex.

A, Running enhances performance on the object in place (OIP) task, but not on the novel object preference (NOP) task. B, Running results in fewer trials to criterion on the SD, REV and EDS. C, Running results in fewer errors on the SD, REV and EDS. Error bars represent SEM. *p<0.05 compared with sedentary rats for A-C. Complex discrimination (CD); intradimensional shift (IDS).

Fig 2. Running alters astrocyte morphology in regions associated with increased cognitive performance.

A, S100+ astrocyte cell body area is increased in the hippocampus, medial prefrontal cortex, and orbitofrontal cortex. B, Left: S100+ astrocyte (red) colabeled with GFAP (green). Scale bar = 5 μm. Right: Representative images of astrocytes from the medial prefrontal cortex of sedentary and running animals. Scale bar = 10 μm. C, Optical density of aquaporin-4, a water channel found in the endfeet of astrocytes, was increased in the hippocampus, medial prefrontal cortex, and orbitofrontal cortex of runners. D, Left: Aquaporin-4 (green) colabels with GFAP (red). Scale bar = 5 μm. Right top: Representative images of aquaporin-4 expression in CA1 of sedentary and running animals. Scale Bar = 20 μm. Right bottom: aquaporin-4 labeling (green) is shown in close proximity to smooth muscle actin labeling (red). Scale bar = 20 μm. Error bars represent SEM. *p<0.05 compared with Sedentary for A and C.

Fig 3. Running increases the number of dendritic spines in medial prefrontal cortex and expression of synaptic markers in several regions supporting cognitive function.

A, Running increases dendritic spine density on both apical and basal dendrites in the medial prefrontal cortex. B, Representative images of DiI labeled layer 2/3 pyramidal neuron apical dendrites in the medial prefrontal cortex and in sedentary and running animals. Scale Bar = 5 μm. C, Running increases the average length of spine processes. D, Optical intensity analysis of synaptophysin (SYN) reveals increased expression in all regions studied. Inset: example of synaptophysin staining in medial prefrontal cortex. E, PSD-95 levels are also increased in all regions studied. Inset: example of PSD-95 staining in medial prefrontal cortex. Scale Bar = 10 μm. Error bars represent SEM. *p<0.05 compared with sedentary for A, C-E.