Autism spectrum disorder (ASD) is characterized by social impairments, including impaired social cognition, social percepfion, and social attention. Recently, there has been increased interest in examining the impact of motivational systems on social functioning in ASD. The frarinework of the so-called "social motivation hypothesis" of ASD is that functional disruption in brain circuits that support social motivational may constitute a primary deficit in ASD that may have downstream effects on the development of social cognition. The mesolimbic dopamine system arising in the ventral tegmental area (VTA) and projecfing to the nucleus accumbens (NAc) is an essential substrate for the expression of many forms of motivated behaviors. Human neuroimaging studies have demonstrated reduced mesolimbic activation in ASD to social rewards, suggesting that reduced function of the mesolimbic dopaminergic system may underlie decreased sociial motivation in ASD. Whereas social deficits in ASD may be related to pathological mesolimbic dopamine system activity, it is unknown if precise neural circuit manipulations that can directly control dopamine output in the NAc to promote pro-social behaviors in animal models of ASD. In addition, the neuropeptide oxytocin (OT) is a promising therapeufic to promote social engagement in ASD and is known to regulate VTA activity in response to social rewards specifically. However the functional neural circuitry by which OT neurons regulate VTA dopaminergic activity has not been identified. These are critical gaps in our understanding of the neural cii-cuitry that controls motivated social engagement. We propose a translational project integrating optogenetic circuit manipulafions in a mouse model of ASD with a clinical functional neuroimaging evaluation of the effects of OT on reward circuits in individuals with ASD.
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