Chemogenetic suppression of the mPFC immediately after training prevents the memory enhancement induced by DH E2 infusion. Sham, eGFP, or hM4Di control groups receiving CNO+Veh did not spend significantly more time than chance (15 s) with the novel object when tested 48 h after OR training (A, C) or with the displaced object (B, D) 24 h after training. In contrast, sham or eGFP mice receiving CNO+E2 immediately after training did spend significantly more time than chance with the moved and novel objects, displaying intact OP and OR memory. However, hM4Di mice treated with CNO+E2 immediately after training did not demonstrate intact memory, suggesting that DREADD-mediated suppression of the mPFC blocks the beneficial mnemonic effects of DH-infused E2. Bars represent the mean ± SEM; *p < 0.05 relative to chance, all Veh-infused groups, and the hM4Di-E2 group (n = 9–11/group); +p < 0.05 relative to chance and the Sham+Veh-infused and hM4Di-E2 groups (n = 9–11/group).