Receptor for advanced glycation end-products (RAGE) plays a critical role in retrieval behavior of mother mice at early postpartum

Abstract

Receptor for advanced glycation end-products (RAGE) is a pattern recognition molecule belonging to the immunoglobulin superfamily, and it plays a role in the remodeling of endothelial cells under pathological conditions. Recently, it was shown that RAGE is a binding protein for oxytocin (OT) and a transporter of OT to the brain on neurovascular endothelial cells via blood circulation. Deletion of the mouse RAGE gene, Ager (RAGE KO), induces hyperactivity in male mice. Impairment of pup care by mother RAGE KO mice after stress exposure results in the death of neonates 1-2 days after pup birth. Therefore, to understand the role of RAGE during the postpartum period, this study aims to examine parental behavior in female RAGE KO mice and ultrasonic vocalizations in pups. RAGE KO mothers without stress before delivery raised their pups and displayed hyperactivity at postpartum day (PPD) 3. KO dams showed impaired retrieval or interaction behavior after additional stress, such as body restraint stress or exposure to a novel environment, but such impaired behavior disappeared at PPD 7. Postnatal day 3 pups emitted ultrasonic vocalizations at >60kHz as a part of the mother-pup relationship, but the number and category of calls by RAGE KO pups were significantly lower than wild-type pups. The results indicate that RAGE is important in the manifestation of normal parental behavior in dams and for receiving maternal care by mouse pups; moreover, brain OT recruited by RAGE plays a role in damping of signals of additional external stress and endogenous stress during the early postpartum period. Thus, RAGE-dependent OT may be critical for initiating and maintaining the normal mother-child relationship.