A spatiotemporal increase of neuronal activity accompanies the motivational effect of wheel running in mice

Spatiotemporal patterns of neuronal activity underlying the motivational effect of rotating running wheels (RWs) in rodents remain largely undetermined. Here, we investigated changes of neuronal activity among brain regions associated with motivation across different intensities of motivation for RWs in mice. Daily exposure to RWs gradually increased rotation number, then became stable after approximately 3 weeks. Immunohistochemical analyses revealed that the number of c-Fos (a neuronal activity marker)-positive cells increased in the medial prefrontal cortex (mPFC), core and shell of the nucleus accumbens (NAc), dorsal striatum (Str), and lateral septum (LS) at day 1, day 9, and days 20–24, in a time-dependent manner. Additionally, despite exposure to locked RWs for over 7 days after establishing stable rotation with 3-week RW access, increased c-Fos expression was still observed in most of these brain areas. Furthermore, daily overnight RW access developed stable rotation by day 6, with high and low rotation numbers at the start and end of the overnight session, respectively. The number of c-Fos-positive cells at the start of RW rotation was significantly higher than at the end of RW rotation in most brain regions. Furthermore, after establishing stable rotation, the number of c-Fos-positive cells increased in the mPFC and shell of the NAc of mice that only observed RWs. These findings suggest that the subareas of the mPFC and NAc may be critically involved in the motivational effects of RW rotations.