DOPAMINE DYNAMICS REGULATE SOCIAL INTERACTION IN A VALPROIC ACID MODEL OF AUTISM

Autism Spectrum Disorders (ASD) are neurodevelopmental conditions characterized by impairments in social interaction and repetitive behaviors. Evidences indicates that dopaminergic dysfunction contributes to the pathophysiology of social deficits observed. The mesocorticolimbic (MCL) pathway, particularly the projection from the Ventral Tegmental Area (VTA) to the Nucleus Accumbens (NAc), plays a central role in processing social reward and motivation, and dysregulation of this circuit has been linked to ASD-related social impairments. The present study investigated dopaminergic alterations associated with social deficits in an ASD model based on in utero-exposure to valproic acid (VPA). Dopaminergic release in the NAc was assessed during a sociability test in mice exposed to VPA using fiber photometry. In addition, dopaminergic modulation was examined by selectively inhibiting or enhancing the VTA–NAc pathway using DREADDs. The results revealed an increased frequency of transient dopamine events in the NAc of VPA-exposed mice, accompanied by a reduction in social interaction time. Moreover, the duration of dopamine transients was reduced during both habituation and social interaction, indicating an alteration in basal dopaminergic signaling dynamics. Inhibition of the VTA–NAc pathway in VPA-exposed mice alleviated social deficits. Conversely, increasing dopaminergic activity within this circuit in control animals produced a marked reduction in social interaction, mimicking the behavioral phenotype observed in VPA-exposed mice, while locomotor activity remained unaffected. These findings provide evidence that hyperdopaminergic activity in the VTA-NAc pathway contributes to ASD-like social impairments and suggest that targeting this circuit could represent a potential therapeutic strategy for ameliorating social deficits in ASD.