Neuronal remodeling is a conserved strategy to refine neural circuits during development. Defects in remodeling have been associated with neuropsychiatric disorders, but direct mechanistic causality is lacking. Despite its fundamental significance, how remodeling of neuronal processes affects circuit architecture and function, and how this ultimately shapes behavior, is not only unknown, but also extremely challenging to study in complex organisms. Our lab is a world-leader in the molecular mechanisms of neuronal remodeling. We use the stereotypic remodeling of the Drosophila Mushroom Body (MB), a complex circuit within the fly brain, as powerful genetic model to study this question. Recently, we uncovered that MB remodeling is coordinated at the circuit level. Furthermore, we generated a detailed expression atlas of MB neurons during development, which highlighted genes and pathways mediating cell-cell interactions as prime remodeling regulators. Thus, our discoveries suggest that the time is ripe to take on the challenge of integrating the molecular, cellular, circuit and behavioral aspects of remodeling. The MB is a perfect system for this due to its well-characterized structure and function. To accomplish this goal, we will build upon our developmental expression atlas to identify molecules that mediate cell-cell interactions during remodeling (Obj 1). We will then investigate how specific genetic/cellular perturbations of remodeling impact overall circuit architecture and connectivity (Obj 2). Finally, taking a new direction for the lab, we will use behavioral readouts of MB function to understand how specific genetic perturbations of remodeling and connectivity affect circuit function and behavior (Obj 3). While each objective is independent and expected to yield high-impact discoveries by itself, it is their combined implementation that is expected to provide the first holistic picture of neuronal remodeling from molecules to cells, circuits and function.
- HORIZON.1.1 - European Research Council (ERC) Main Programme