Objective To investigate the effects and neural mechanisms of MSNs in the nucleus accumbens on exercise motivation in mice with different levels of physical activity.

Methods  C57BL/6J mice with high and low exercise propensity were screened through voluntary wheel running firstly. Then, sixty male mice were selected after breeding each closed line to the third generation, and the high voluntary wheel running (HVR, n=12) and low voluntary wheel running (LVR, n=12) models were established. The exercise motivation levels were assessed using an operant conditioning task, and aerobic exercise capacity and metabolic rate were evaluated using an animal gas metabolism system. Electrophysiological activity of nucleus accumbens neurons was recorded via multi-channel in vivo electrophysiological techniques. Immunofluorescence double-labeling was employed to detect co-expression of c-Fos and dopamine receptors D₁R/D₂R in the nucleus accumbens. The regulatory effects of D₁R/D₂R on exercise motivation were assessed by observing changes in voluntary exercise behavior following administration of D₁R/D₂R agonists (SKF81297 and Quinpirole) and antagonists (SCH23390 and Sulpiride).

Results The exercise motivation and maximal oxygen uptake were significantly higher in HVR mice than that of LVR mice (P＜0.01). The discharge frequency of MSNs in the nucleus accumbens of HVR mice was significantly increased following exercise cue stimulation compared to LVR mice (P＜0.01). The number of D₁R, D₂R, and c-Fos positive cells, as well as D₁R/c-Fos and D₂R/c-Fos co-expressing cells, were significantly higher in HVR mice compared to LVR mice (P＜0.01). Additionally, the number of D₂R/c-Fos co-expressing cells were more than D₁R/c-Fos co-expressing cells in HVR mice (P＜0.01). Both HVR and LVR mice showed a significant increase in voluntary running volume after the injection of SKF81297 and Quinpirole (P＜0.05, P＜0.01). Conversely, the administration of SCH23390 and Sulpiride resulted in a significant decrease in voluntary wheel running in both groups (P＜0.01). The changes in exercise behavior after drug injection was significantly higher in HVR mice compared to LVR mice (P＜0.01).

Conclusions The response of MSNs in nucleus accumbens to voluntary wheel running reward prediction signals is more effective in individuals with high exercise motivation. The expression and sensitivity differences of D₁R/D₂R in nucleus accumbens may be important factors influencing the response of MSNs to wheel running cues, and such differences may be an important neural mechanism affecting the physical activity level of individuals.