Acute and long-term treadmill running differentially induce c-Fos expression in region- and time-dependent manners in mouse brain

Acute and long-term exercise differentially affect brain functions. It has been suggested that neuronal activation is one of the mechanisms for exercise-induced enhancement of brain functions. However, the differential effects of acute and long-term exercise on the spatial and temporal profiles of neuronal activation in the brain have been scarcely explored. In this study, we profiled the expression of c-Fos, a marker of neuronal activation, in selected 26 brain regions of 2-month-old male C57/B6 mice that received either a single bout of treadmill running (acute exercise) or a 4-week treadmill training (long-term exercise) at the same duration (1 h/day) and intensity (10 m/min). The c-Fos expression was determined before, immediately after, and 2 h after the run. The results showed that acute exercise increased the densities of c-Fos⁺ cells in the ventral hippocampal CA1 region, followed by (in a high to low order) the primary somatosensory cortex, other hippocampal subregions, and striatum immediately after the run; significant changes remained evident in the hippocampal subregions after a 2-h rest. Long-term exercise increased the densities of c-Fos⁺ cells in the striatum, followed by the primary somatosensory, primary and secondary motor cortices, hippocampal subregions, hypothalamic nuclei, and lateral periaqueductal gray; significant changes remained evident in the striatum, hippocampal subregions, hypothalamic nuclei, and lateral periaqueductal gray after a 2-h rest. Interestingly, the densities of c-Fos⁺ cells in the substantia nigra and ventral tegmental area only increased after a 2-h rest after the run in the long-term exercise group. The densities of c-Fos⁺ cells were positively correlated with the expression of brain-derived neurotrophic factor in the selected brain regions. In conclusion, both acute and long-term treadmill running at mild intensity induce c-Fos expression in the limbic system and movement-associated cortical and subcortical regions, with long-term exercise involving more brain regions (i.e., hypothalamus and periaqueductal gray) and longer lasting effects.