Functional disruption of oxytocin projections participates atypical social and anxiety-like behaviours in BTBR mouse model of autism

Oxytocin (OXT) neurons in the paraventricular nucleus of the hypothalamus (PVN), which send projections to the medial amygdala (MeA) and the bed nucleus of the stria terminalis (BnST), are implicated in regulation of prosocial-emotional behaviours and abnormalities resembling autism spectrum disorders (ASD). Compared with standard C57BL6J (B6) mice, BTBR mice, a behaviour-based ASD model, exhibited decreased densities of OXT PVN neurons and attenuated OXT neuronal responses to a social encounter. OXT receptor mRNA expressions in the MeA and BnST as a response to a social encounter were blunted in BTBR mice. OXT promoter retrograde viral tracing revealed that the OXT PVN→BnST projections were defective in those BTBR mice. Thus, chemogenetic excitation of OXT PVN→MeA neurons using OXT promoter adeno-associated viruses (AAV) enhanced anxiety-like behaviour and facilitated social investigation in both strains, while excitation of OXT PVN→BnST neurons attenuated anxiety-like behaviour along with social investigation in B6 mice and failed to induce a change in their socio-emotional behaviours in BTBR mice. Altogether, OXT circuits serve as a key regulator for socio-emotional behaviour; MeA-OXT projection facilitates social investigation and anxiety-like behaviour, while BnST-OXT projection conversely attenuates these behaviours; hence a defect of the OXT PVN→BnST circuits contributes to the development of ASD-like social phenotypes in BTBR mice.