PHOTORELEASE OF OXYTOCIN IN VIVO USING LIPID NANOVESICLES MODULATES SOCIAL BEHAVIOR

Precise spatiotemporal control of neuropeptide release in vivo remains a major challenge for dissecting neuromodulatory mechanisms underlying behavior. We developed a light-triggered delivery system based on photoswitchable lipid nanovesicles (“azosomes”) incorporating azobenzene-phosphatidylcholine (Xiong et al., 2023), enabling UV-induced release of encapsulated cargo. We combined optofluidic infusion of azosomes with focal photostimulation in freely behaving mice and demonstrated stable retention in brain tissue for >30min with light-dependent (power and pulse duration), titratable release. We next loaded oxytocin (OT) into azosomes and targeted the CA3 region of the hippocampus, a site of high oxytocin receptor expression. In anesthetized mice expressing the OT sensor MTRIA-OT (Ino et al., 2022), we characterized free OT and OT-azosomes responses and confirmed specificity using the OTR antagonist OVTA, with two-color photometry and Calcein-Red co-infusion to monitor delivery. To link photorelease to behavior, we used a custom-made social interaction apparatus with an opposite-sex conspecific. Photostimulation prior to social exposure produced a robust increase in MTRIA-OT fluorescence, confirming light-dependent OT release. We then examined neuronal activity using GCaMP in Vglut1- or OTR-expressing neurons, which increased shortly before social encounter and was further enhanced following a prior 1-s photorelease delivered 5min before testing. Photorelease of OT in males reduced the latency to initiate the social contact with a female stimulus mouse. We are currently examining the effect of OT on neuronal activity. Our results establish azosomes as a versatile platform for temporally precise neuropeptide delivery and demonstrate that focal oxytocin photorelease in hippocampus selectively accelerates social approach behavior.