The social salience network hypothesis of autism: Disrupted network activity, oxytocin signaling, and implications for social symptoms.

Autism Spectrum Disorder (ASD) is a complex condition characterized by its heterogeneity, with significant variability in symptoms across subtypes and associated comorbidities. Despite the urgent need to develop mechanism-based therapies for the core social symptoms of ASD, progress has been hindered by the heterogeneous etiology of this neurodevelopmental disorder and our still limited understanding of the neural mechanisms underlying social behavior. The evaluation of sociosensory cues and the modulation of motivation to engage socially are fundamental components of social interaction, thought to be coordinated by a network of interconnected brain regions called the social salience network (SSN). This network is strongly modulated by the neurohormone oxytocin (OXT) to facilitate appropriate social responses. It is increasingly recognized that disruptions within the SSN contribute to the atypical social perception and engagement observed in autistic individuals. This review will summarize evidence from current clinical and preclinical literature that provides compelling evidence for SSN disruptions as a possible mechanism that underlies the social symptoms of ASD. Furthermore, we discuss OXT-mediated correction of SSN disruptions at the regional and circuit levels that rescues social phenotypes in preclinical models of ASD-risk factors. These molecular, cellular, and circuit mechanisms within the SSN could serve as promising treatment targets which may propel the development of novel and effective options for alleviating the social difficulties of autistic individuals.