In this application, we propose to develop genetic tools for the conditional, reversible, and tissue-specific silencing of neuronal activity in zebrafish. We then intend to use these new tools to carry out an enhancer trap screen with the aim of characterizing the zebrafish central nervous system in terms of its connectivity and functional architecture. This program will initially entail the use of the bipartite GAL4/UAS system, driving a chemically gated chloride channel in subsets of neurons. This will allow both spatial control (using tissue specific promoters) and temporal control (based on the presence or absence of the chemical gate) over protein function. A major goal of this proposal is to develop and characterize these new genetic techniques and to make the reagents available to the research community. With the ability to silence neurons conditionally and reversibly, we will then undertake an enhancer trap screen, aiming to identify a variety of expression patterns in the central nervous system. An early goal of this screen will be to characterize the expression patterns in terms of their cellular compositions, the fine structures of their individual neurons, and the pre- and postsynaptic connections that the neurons make. This preliminary work will provide important information about the connectivity within and among distinct structures in the zebrafish brain. With genetic access to these tissues, we will then silence neurons composing the trapped expression patterns, and perform behavioral analyses of the affected fish. By systematically assaying for a variety of behaviors in fish with a wide variety of expression patterns, we will eventually develop a functional atlas of the zebrafish brain, relating neural circuits to the behaviors that they mediate. Various tissues and cell types involved in the same behaviors will likely be connected functionally, and we will investigate such possible relationships anatomically. Health-relatedness: The connectivity of the human and fish nervous systems are very similar. By functionally characterizing the circuitry of the zebrafish brain, we also hope to provide insights into the pathophysiology of human behavior. The reagents and techniques developed under this proposal will advance biomedical research throughout the zebrafish community. ? ? ?
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