Over the years, researchers have identified many genes that are strongly associated with autism spectrum disorder (ASD), but it remains unclear whether these “risk genes” are part of common biological pathways. The lab of Ellen Hoffman, associate professor in the Child Study Center and of neuroscience, aims to identify these convergent mechanisms, which could reveal molecular targets with therapeutic potential.
With Kavli support (2017 Kavli Innovative Award, Ellen Hoffman and Michael Higley), the team developed a whole-brain mapping protocol that allows for high-throughput analysis, visualization, and quantification of larval zebrafish brain phenotypes. By combining this whole-brain mapping tool with automated behavioral assays, the Hoffman lab uncovered that mutations in 10 ASD risk genes have converging effects: they impact basic arousal and sensory processing behaviors, brain size, and activity in the developing zebrafish brain. Using RNA sequencing on the two mutant lines showing the strongest phenotypes, the team also reported dopaminergic and neuroimmune dysfunction. This convergence of behavioral features can be leveraged to identify potential pharmacological targets, which the lab is now addressing through drug screening.
Currently, Priyanka Jamadagni (2022 Kavli Postdoctoral Fellowship, Hoffman and Girgenti labs) is expanding the Hoffman lab’s research focus to include genes that are believed to be drivers of post-traumatic stress disorder (PTSD). Through the Fellowship, she aims to expand our understanding of whole-brain circuitry in the context of neurodevelopmental disorders.
This article is part of a special series highlighting the impact of the Kavli Institute for Neuroscience at Yale. The series will be published ahead of the Kavli 20th Anniversary Symposium, taking place on Friday, September 20th in TAC.