Autism spectrum disorder (ASD) is a heritable neurodevelopmental condition marked by deficits in social communication. Pinpointing the effects on sensorimotor circuits that contribute to communication deficits has been challenging, in part due to the distributed nature of circuits for social behavior. Leveraging the conservation of many ASD risk genes across species and the advanced experimental toolkit available in Drosophila melanogaster, Mala Murthy and her colleagues at Princeton University will link ASD risk genes to neural circuit function and social communication behaviors. Despite anatomical differences between insect and mammalian brains, both share common circuit motifs and organizational principles that underlie similar computations, such as processing social cues and regulating motor actions.

Aim 1 focuses on screening orthologs of 48 SFARI Gene Category 1 or S risk genes with known expression in the Drosophila nervous system for their effects on social communication behaviors. Using deep neural networks and other modeling tools, Murthy and her group will quantify and compare the behaviors of mutant and control flies to predict the involvement of specific sensorimotor circuits. This aim is grounded in the hypothesis that mutations in these genes disrupt sensorimotor processing crucial for social interactions.

Aim 2 investigates how ASD risk genes affect neural circuit function during social behaviors. The team will utilize brain-wide calcium imaging techniques to record neural activity during fictive social interactions, aligning functional data with the newly generated Drosophila connectome. This approach will help identify cell types with activity patterns correlated with social behaviors, revealing how mutations in ASD risk genes alter sensorimotor activity.

Aim 3 examines the interaction between sexual dimorphisms and ASD risk genes by comparing behavioral deficits in male and female flies. Given the higher prevalence of ASD in males, understanding how sexual dimorphisms in the nervous system intersect with ASD gene expression is crucial. Behavioral analyses will be complemented by characterizing the expression patterns of ASD risk genes in the nervous systems of both sexes.

Preliminary work from the Murthy group has established robust methods for quantifying social behaviors and mapping them to neural circuits in Drosophila, including high-throughput tools for behavioral quantification and modeling, brain-wide neural imaging, and registration to the connectome. These methods enable them to uncover even subtle changes in behavior and neural activity, essential for linking ASD risk genes to the dynamics of social communication.

This study promises to advance our understanding of ASD by providing a comprehensive analysis of how conserved risk genes affect neural circuits and behaviors. The experimental tractability of Drosophila allows for rapid screening and detailed characterization of gene function, paving the way for testable hypotheses about ASD mechanisms in mammals. The integration of behavioral quantification, neural imaging, and genetic tools in Drosophila represents a powerful approach to unraveling the neural basis of social communication deficits in ASD.