The paper will briefly review PFC circuits in primates and their regulation of the cingulate cortices, and then discuss the critical role of NMDAR for generating mental representations in dlPFC, the expansion in NMDAR-GluN2B transmission across the cortical hierarchy and across cortical evolution, and the role of NMDAR-GluN2B in the cingulate cortices mediating affective pain responses and depression. Here, GRIN2B is linked to major depressive disorder.