PROJECT SUMMARY Understanding how our brain's 100 billion neurons process information to produce complex feelings, decisions, and behaviors is a daunting task. A single neuron in the human brain may communicate with more than a hundred thousand partners. For each partner, this exchange happens at multiple specialized contact sites called synapses. Genetic studies are now revealing that mutations that alter the formation or activity of synapses are often at the root of neurological conditions ranging from autism spectrum disorder to epilepsy. Here, we will develop a new, revolutionary technology that will allow us for the first time 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. Our strategies are completely non-invasive (as they depend on genetic reagents), can be applied on large scale, and can be used to manipulate/modulate neural activity directly in behaving animals. We will initially develop our reagents for use in Drosophila, but we anticipate that our strategies will be immediately applicable to any animal model system (zebrafish, rodents, etc.). 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.

PROJECT NARRATIVE Mapping the structure and function of neural circuits is an important prerequisite to understand how groups of interconnected neurons produce perceptions and drive behavior. Here, we will develop an entirely new method to re-engineer the connectivity of brain circuits in Drosophila. Our strategies are in principle broadly applicable, and will enable to design of new experiments and interventions not possible with existing techniques.