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

Project Summary

Collective efforts in large-scale genetic studies have identified hundreds of risk genes for ASD, enabling neurobiological dissection of pathological mechanisms and exploration of potential therapeutic strategies [1,2]. Most ASD patients have complex etiology including polygenic risks, developmental insults, and environmental factors. Although large efforts have been made on identifying converging molecular mechanisms as targets for therapeutic development, such targets have been elusive. Recently, identifying circuit mechanisms of particular behavioral abnormalities has gained tremendous traction. Thus, for idiopathic ASD, a promising therapeutic approach is to correct abnormal circuit activity. To achieve this goal, the first step is to identify the neural circuit defects underlying core symptoms of ASD.

While mice are essential models for many areas of basic and translational neuroscience research, there are also important aspects of higher brain functions that are difficult to model in rodents, partially due to the inherent differences between rodents and humans in brain development, structure, and physiology [3,4]. In particular, the prefrontal cortex is one of the largest and most developed portions of the human brain and it is a top candidate for pathological processes in psychiatric disorders. Yet, rodents have only a rudimentary prefrontal cortex and do not exhibit some of the complex cognitive functions that are mediated by this region in humans [3-5]. Furthermore, recent large-scale single cell transcriptomic analyses have revealed many differences in neuron types, connections, and gene expression patterns between rodents and primates [6-9]. Thus, new genetic models that are phylogenetically closer to humans such as non-human primates (NHP) are needed to further advance our understanding of brain function and dysfunction [10-12].

The common marmoset, a small New World primate, has emerged as a new promising NHP model [13,14]. Although evolutionarily farther from humans than Old World monkeys such as macaques, marmosets have several advantages as a genetic model: they are small, and group housed as a family (reducing housing costs); marmosets reach sexual maturity around 12-18 months and thus breeding is much faster than macaques; marmosets give birth twice a year usually with non-identical twins from each birth. This rapid reproduction cycle is a huge advantage for establishing a genetically altered marmoset line with sufficient numbers of mutant animals to power functional studies. In addition, marmosets are highly social, with strong family structures and complex vocal behaviors, rendering them a promising model for studying neurobiological mechanism of social interaction and social communication.

In this Targeted Project, we are taking advantage of the unique strength and resources of MIT research community including mouse models, marmoset models, and new neuroimaging technologies to address a key bottleneck in developing effective therapeutics for ASD: understanding the neural circuit mechanisms of social deficits in ASD. The two collaborative projects use complementary approaches to study circuit mechanisms of social and other behavioral deficits, share the same Shank3 mouse and marmoset ASD models, inform each other on different levels of analysis, and are tightly connected on the same translational goal of providing fundamental knowledge for therapeutic development.

Project I: Behavior-evoked frontal-striatal circuit hyper-activity as an underlying mechanism of ASD (PI: Guoping Feng, in collaboration with Mriganka Sur and Alan Jasanoff). Using recently developed hemodynamic functional ultrasound imaging (fUSI) for brain activity, the Feng lab found that in 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. We hypothesize that stimulus-evoked frontal-striatal circuit hyper-activity is a key circuit mechanism of social communication deficits in a subset of ASD. We propose to test this hypothesis by studying additional mouse models as well as Shank3 mutant marmoset models of ASD. Furthermore, we 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 II: Brain-wide bases of altered social behavior in ASD model marmosets (PI: 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.

References:

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