Genetic and Neural Sources of Individual Differences in Goal-directed Learning in Health and Disease

PROJECT SUMMARY Throughout multiple species, variations in cognitive abilities can influence an individual’s ability to learn and perform goal-directed behavioral tasks which is critical for their overall success, well-being, and survival. It is unclear how individual differences in learning are influenced by genetic variation among neurotypical subjects. Further, it is unclear how polygenic risk factors ultimately result in learning deficits among individuals diagnosed with Autism Spectrum Disorder (ASD) and Intellectual Disabilities (IDs). My research project aims to understand the neurobiology of individual heritable differences. I will investigate how genetic variation alters gene expression in specific cell types and neural circuit function in individual learning. For my Dissertation Research Project, I have used large scale automated homecage training across different inbred mouse strains to establish that learning traits are heritable. Using the genetically heterogeneous Diversity Outbred (DO) mice, I have identified genes associated with learning. The expression of these genes converges onto cell types in the subicular complex, implicating its role in learning differences. Using spatial transcriptomics and anatomical tracing, I will determine how these identified genetic differences result in neuronal cell type properties and morphology in the subicular complex across inbred strains with different learning capacities. By performing calcium imaging with miniature microscopes during automated homecage task training, I will determine how neural activity in the subicular complex differs across inbred strains with different learning capacities. For my Postdoctoral Research Direction, I will leverage the skills acquired during my dissertation project to investigate how ASD and IDs arise across different genetic backgrounds. To do this, I will learn how to perform multiplexed in vivo gene editing to introduce multiple ASD/IDs risk factors into different mouse strains. I will learn multi-omic methods to assess how these perturbations alter gene expression and their subsequent impact on neural circuit function and behavior. Overall, this project will identify how genetic variation influences neural circuit properties to shape learning in healthy and disease-associated individuals.