The present study investigated the effect of SD on spatial memory and structural changes of the mPFC in a rat model. SD has been considered to be one of the saboteurs in a variety of brain disorders, including memory dysfunction, depression, and psychosis (Mishra et al., 2016[18]). The first part of this study assessed the effects of SD on memory impairment. These impairments could be correlated with neurons and cell loss in the mPFC. This finding accords with the previous studies reporting the effects of SD on the nervous system (Tung et al., 2005[26]). Other researchers have also reported that manipulations of the mPFC could impair memory in eight-arm radial maze, shuttle box and Y-maze tasks (Mehdipour et al., 2015[17]; Lapish et al., 2015[15]). Therefore, the structural changes of the mPFC (reduction in the total volume and loss of neurons and glial cells) could explain this type of memory dysfunction evaluated in the eight-arm radial maze. In line with our study, Abushov (2009[1]) reported that SD reduced the number of neurons, synapses, and behavioral reactions. In addition, Winters et al. (2011[29]) showed that SD altered synaptic and intrinsic neuronal properties in mice prefrontal cortex (Winters et al., 2011[29]). The present survey also revealed volume reduction in the three subdivisions of mPFC. These anatomic changes were correlated to the physiological activity of this region as Chauveau et al. (2014[5]) reported that SD decreased the activity of the prelimbic, infralimbic, and cingulate cortices (Chauveau et al., 2014[5]). It has also been approved that the efficient function of mPFC depended on the integrity of the cortex (Leenaars et al., 2012[16]).