Molecular design for circuit engineering in the Drosophila brain

PROJECT SUMMARY Understanding how our brain produces complex feelings, decisions, and behaviors is a daunting task. Each of the ~130 trillion synapses in the human brain could potentially function as an individual processing unit, yet we lack methods to study the functional significance of individual synapses within a neural circuit even in experimentally accessible animals such as the mouse or the fly. Indeed, human genetic studies are now revealing that mutations that alter the formation or activity of synapses are commonly associated with neurological conditions ranging from autism spectrum disorder to ADHD to epilepsy. Determining the functional significance of individual synaptic connections within a circuit could provide insights into the fundamental computations that underlie brain function and help us better understand the effects of dysfunction. Here, we will use rational molecular design, in vitro screening, cell culture approaches and functional work in vivo in the Drosophila brain to develop a new, revolutionary technology that will allow scientists to re-engineer connectivity in the living brain, preventing the formation of specific synaptic contacts between neurons to test specific hypotheses on circuit dynamics and behavior. We anticipate that this work will expand our mechanistic understanding of how brain circuits function in the normal state, as well as allow the design of new experiments that accurately reproduce synaptic dysfunctions known to underlie human disease.