Psychiatric disorders have pathophysiological changes in dysfunction and altered neuroplasticity in the hippocampus and prefrontal cortex (PFC), while atypical antipsychotics are able to modulate neuroplasticity. It has been reported that exercise may upregulate brain-derived neurotrophic factor (BDNF) expression in the hippocampus through the action of beta-hydroxybutyrate. Previously, our study showed that plasma beta-hydroxybutyrate level was reduced by exercise, but significantly increased by exercise+risperidone co-treatment in juvenile female rats. Therefore, this study aimed to assess the effects of atypical antipsychotic drug risperidone (0.9mg/kg/day, b.i.d.) and/or exercise intervention (voluntary running, 3 hours/day) for 4 weeks on neuroplasticity in the hippocampus and PFC of juvenile female rats. In the hippocampus, the mRNA expression of bdnf, ntrk2 (neurotrophic tyrosine receptor kinase 2), and grin2b (an N-methyl-D-aspartate receptor subunit) were increased by both risperidone and exercise intervention. The key ketogenesis enzyme hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthase 2) mRNA was upregulated in the hippocampus by exercise intervention. A positive correlation (r=0.59, p<0.0005) was observed between ntrk2 and oxct1 (3-oxoacid CoA-transferase 1, the key ketolysis enzyme). In the PFC, bdnf mRNA expression was upregulated by exercise intervention, while the reduction of nrtrk2 expression caused by risperidone treatment was reversed by exercise intervention (risperidone+exercise group). Hmgcs2 expression was decreased in risperidone-treated groups. Positive correlations were observed between bdnf and hmgcs2 (r=0.58, p<0.001), and ntrk2 and hmgcs2 (r=0.61, p<0.001). These results suggested that both risperidone and exercise intervention could improve neuroplasticity in the hippocampus and PFC, and that ketogenesis in these brain regions may play a role in this process.