This project is developing and applying new spatial transcriptomic methods to simultaneously probe neuroanatomy and gene expression in the brains of mouse autism models providing an integrated, high-resolution picture of the impact that autism-associated genetic mutations have on gene regulation, cellular make-up of the brain and brain wiring.

Dysregulated levels of neuromodulators and other chemical signals may contribute to behavioral characteristics of ASD. Yet previous efforts have often focused on only one signal at a time, and typically provide a static description of signal levels in the brain. In the current project, Mark Andermann and colleagues plan to use novel optical methods to track and control dozens of neuromodulators and peptides in the brain of a genetic mouse model of ASD.

Infection or inflammation during critical windows of pregnancy, termed “maternal immune activation” (MIA), has been strongly associated with increased risk of neurodevelopmental and neuropsychiatric conditions in children, including autism spectrum disorder. In the current project, Brian Kalish and Yeong Shin Yim aim to discover how MIA elicits a sex-specific effect on RNA metabolism and to target these pathways to reduce MIA-associated behavioral alterations in mice.

Cognitive control deficits are one of the frequent challenges accompanying ASD. However, very little is known about the link between ASD risk genes and neural circuit mechanisms in control of cognitive control behavior. In the current project, Hirofumi Morishita plans to use mouse models to test the hypothesis that frontal-sensory projection neurons are convergingly vulnerable to multiple ASD risk gene manipulations and are also responsible for cognitive control behaviors. Findings from these studies are expected to establish pre-clinical strategies for ameliorating cognitive deficits in ASD.

Recent technological advances have identified many ASD risk genes, but how these genes affect brain development and function remains unknown, especially in primates. In the current project, Xinyu Zhao, Qiang Chang, André Sousa and Daifeng Wang plan to genetically manipulate three ASD risk genes in marmoset brain slices followed by multimodal integrative analysis of electrical activities, gene expression and chromatin accessibility of single neurons in the prefrontal cortex. The results will provide new and in-depth knowledge of the neuronal functions of these genes in primate brains.