A Genetic Strategy for Altering Neural Circuitry in Drosophila

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DESCRIPTION (provided by applicant): Neural circuits provide the physical infrastructure that supports behavior, and a major goal in neuroscience is to understand how circuits function to control behavior. At present, genetic strategies for disrupting circuit function within an intact animal focus on altering the function of single cells. However, most neurons synapse with multiple cells, and there is currently no general strategy for specifically altering just a subset of a neuron's contacts. The goal of this project is to create a genetic system for intentionally disrupting a subset of a neuron's connections, permitting the dissection of neural circuits at the level of the single contact or the single synapse. We propose to achieve our goal in Drosophila by creating artificially engineered regulators of growth cone movement that can be used to intentionally sculpt patterns of neuronal connectivity. The initial aim of the project involves characterizing a series of artificially engineered ligand/receptor pairs to determine which are able to influence growth cone navigation in the fly without unintended side effects. The second aim of the project involves characterizing the ability of these selected ligand/receptor pairs to alter the connectivity of an individually identified neuron to its identified targets, examining the consequences using histology and electrophysiology. The final aim of the project involves applying the ligand/receptor system to a well- characterized neural circuit for learning and memory, using the ligand/receptor system to dissect the functional importance of specific connections within the neural circuit. The tools developed in this work will be immediately usable by other investigators to manipulate various neural circuits in Drosophila. The tools created here could be used in other cell types for other purposes, such as the disruption of cell migration or cell contact. In addition, while this proposal will provide proof-of-principle development in the fly, variations on the strategy developed here should be feasible in mammals and could have applications as both experimental and engineering tools. The wiring pattern of the nervous system provides the physical framework for human behavior, including such fundamental processes of relevance to human health such as learning and memory. This proposal proposes to develop new ways to manipulate the wiring of the nervous system in order to study how it controls behavior. These developments will lead to new insights into learning and memory and potential applications of the basic strategy developed in this grant could be used to alter connections for therapeutic purposes.