Chemogenetic activation of hypothalamic oxytocin neurons reorients face exploration toward the eyes in macaques

ABSTRACT: Oxytocin (OT) shapes social behavior across species. However, in humans and non-human primates, its effects have been studied mainly through exogenous administration, despite uncertainty about the extent to which peripherally administered OT reaches the brain and limited control over the neural pathways it engages. To overcome these limitations, we developed a chemogenetic approach targeting the endogenous OT system by selectively activating OT neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of macaques using excitatory DREADDs. We combined this approach with digit-tracking, a non-invasive, calibration-free assay of face exploration in freely moving animals. In this task, subjects explored blurred face images through a finger-controlled viewing window, providing a proxy for gaze exploration and enabling behavioral assessment of OT neuron activation. DREADD-mediated activation redirected ongoing face exploration toward the eyes at the expense of non-face regions, increasing the consistency of eye-directed exploration and the time spent inspecting the eyes once reached. Immunohistochemical analysis confirmed selective DREADD expression in OT neurons of the PVN and SON. These findings provide the first causal evidence in primates that hypothalamic OT neurons regulate social visual orienting by increasing exploration of the eyes, thereby linking a hallmark effect of intranasal OT administration to defined central OT pathways and establishing chemogenetic access to this system in freely behaving macaques.