Oxytocin neurons in the paraventricular nucleus of the hypothalamus circuit-dependently regulates social behavior, which malfunctions in BTBR mouse model of autism

Oxytocin (OXT) a neuropeptide synthesized in the hypothalamic nuclei has a variety of function including socio-emotional processes in mammals. While the neural circuits and signaling pathways in central OXT converge in the paraventricular nucleus of the hypothalamus (PVN), we illuminate specific function of discrete PVN OXT circuits, which connect to the medial amygdala (MeA) and the bed nucleus of the stria terminalis (BnST) in mouse models. The OXT(PVN)→(BnST) projections are innervated from entire portions of the PVN, while those OXT(PVN)→(MeA) projections are asymmetrically innervated from the posterior portion of the PVN. Compared with OXT neurons in B6 wild type mice, BTBR mice that are recognized as a behavior-based autism model exhibited defect in the OXT(PVN)→(BnST) projection. We demonstrate that chemogenetic activation of OXT(PVN)→(MeA) circuit enhances anxiety-like behavior and facilitates social approach behavior, while activation of OXT(PVN)→(BnST) circuit suppresses anxiety-like behavior along with inhibiting social approach. This chemogenetic manipulation on the OXT(PVN)→(BnST) circuit proves ineffective in BTBR mice. Accordingly, chemogenetic activation of OXT(PVN) neurons that stimulate both OXT circuits induces OXT receptor expressions in both MeA and BnST as with those by social encounter in B6 mice. The induction of OXT receptor genes in the BnST was not observed in BTBR mice. These data support the hypothesis that OXT circuits serve as a regulator for OXT signaling in PVN to control socio-emotional approach/avoidance behavior, and a defect of OXT(PVN)→(BnST) circuit contributes to autism-like social phenotypes in BTBR mice.