Marmoset Circuits: Developing knowledge and tools to facilitate therapeutic development for ASD

Project 1: Behavior-evoked frontal-striatal circuit hyper-activity as an underlying mechanism of ASD (PI: Guoping Feng, MIT)

Project 2: Brain-wide bases of altered social behavior in ASD model marmosets (PI: Alan Jasanoff, MIT).

This SCSB targeted project takes advantage of the unique strength and resources of the MIT research community in developing marmoset models of ASD to address a key issue: identifying neural circuit mechanisms of social deficits for developing therapeutic targets for core symptoms in idiopathic ASD.

Project 1 is led by Guoping Feng, in collaboration with Alan Jasanoff. Using recently developed hemodynamic functional ultrasound imaging (fUSI) for brain activity, the Feng lab found that in the awake state Shank3 mutant mice exhibit hyper-activation in the frontal cortex and striatum during social interaction. This is in contrast to their lower network activity observed in the resting state using fUS and fMRI. These results provide a fresh angle to investigate the neurobiological underpinning of social deficits in ASD. They hypothesize that stimulus-evoked frontal-striatal circuit hyper-activity is a key circuit mechanism of social communication deficits in a subset of ASD. They propose to test this hypothesis by studying additional mouse models as well as Shank3 mutant marmoset models of ASD. Furthermore, they will probe the causal link between stimulus-evoked frontal-striatal circuit hyper-activation and social interaction deficits in mouse and marmoset models of ASD. This study will pave the way for future studies to identify circuit-specific molecular targets for drug development.

Project 2 is led by Alan Jasanoff, in collaboration with Guoping Feng. Using 9.4T scanner and newly developed circuit-specific genetic tools for fMRI imaging in the lab, the Jasanoff lab will identify whole-brain neural circuit defects in awake Shank3 marmosets in both resting state and in visual evoked conditions. Furthermore, using a newly developed fMRI compatible activity mapping technology in the lab, the Jasanoff lab will compare whole brain activity changes after free-moving social interaction between WT and Shank3 marmosets. These studies will provide up to now the most comprehensive and specific activity mapping of the brain during social interaction in any mammals.