In vivo functional genomics and foundational virtual models of brain homeostasis and resilience

The brain exhibits remarkable resilience to stress and damage, yet with advancing age, cognitive function often declines, and the risk of neurodegenerative disease rises. How do neurons and glia respond to stress and damage, and how does this ability change with age? In spite of decades of work, our mechanistic understanding of brain resilience has been fundamentally limited by the absence of the tools needed to dissect the functions of resilience processes that engage thousands of genes across many cell types, over a lifetime. To overcome this barrier, this project will build new tools for probing gene function and will use these tools to systematically unravel how the brain responds to stress at a molecular level. These data will then be used to train an AI network that will interpret how these genetic networks function to make predictions about specific pathways that control brain resilience. These predictions will then be tested in animals, setting the stage for targeted manipulations and extension to humans.