Optogenetics and fMRI were combined to examine the neural activity underlying the rewarding behavior mediated by the medial prefrontal cortex (MPFC) in rats. Animals were trained to press lever for optogenetic self-administration in MPFC. FMRI showed that MPFC photostimulation activated many regions known to receive MPFC afferents. Notably, the activation of hypothalamus, agranular insula, and ventral striatum was positively correlated with the lever press. Our finding may shed light on brain circuits involved in therapeutic effects of recent deep brain stimulation studies in major depression, in which the MPFC plays an important role.