AimsChallenging behaviours, such as aggression and irritability, are manifested by up to two thirds of autistic individuals. However, despite the detrimental effects challenging behaviours, particularly aggression, have on life of autistic individuals and their families, currently available treatment options are typically borrowed from other areas of psychiatry, and the FDA approved drugs for treatment of ASD-associated irritability are burdened with serious side effects. Therefore, in this study we investigated the effects of oxytocin, a neuropeptide with reported prosocial and anti-aggressive effects, on aggression in a Nlgn3R451C (Nlgn3 knock-in, KI) mouse model of ASD.MethodsThe study was performed on adult, male Nlgn3 KI mice which were reported to exhibit increased levels of aggression compared to controls. The mice were treated with oxytocin prior to behavioural testing and resting state functional magnetic resonance imaging (rs-fMRI) in a 9.4T Bruker Biospec 94/20, after which c-fos immunohistochemistry was performed.ResultsOxytocin significantly reduced aggression in Nlgn3 KI mice. This behavioural change was associated with alterations in neural activity and connectivity within brain regions implicated in aggression control, e.g. ventral tegmental area, periaqueductal grey, and hypothalamus. These neurobiological shifts suggest oxytocin's capacity to modulate aggression through direct effects on specific neural circuits.ConclusionsOur findings underscore oxytocin's potential as a novel intervention for aggression in ASD, highlighting its effects on the neurobiological substrates underlying aggressive behaviours. This study not only contributes to our understanding of oxytocin's mechanism of action but also opens avenues for developing targeted treatments for challenging behaviours in ASD.