Alcohol abuse is one of the most devastating and costly diseases society has to face. Its mechanisms are not well understood and effective treatment is lacking. One way to study this complex disease is with the use of model organisms. Zebrafish (Danio rerio) may be a useful model system with which the mechanisms of acute and chronic effects of alcohol can be investigated. Here new behavioral test paradigms will be developed for the quantification of alcohol effects on novelty induced, agonistic, social, and predator elicited behaviors. The tests are hoped to tap into diverse functions of the brain that may be modified by alcohol. The tests may enable us to detect a range of chemical mutagen induced genetic changes, a forward genetic approach. Zebrafish is particularly appropriate as a model organism for our purpose. First, it can be kept, bred, and tested in large numbers in the laboratory (small size, large number of offspring per spawning, ease of controlling environmental factors). Second, alcohol delivery is simple (fish absorb this substance through their gills and skin). Third, a large amount of genetic information and sophisticated genetic tools are available allowing the generation of mutations and identification of novel genes. And fourth, the genes discovered show high homology to human. Despite these advantages, however, phenotypical screening methods especially for behavior of zebrafish are often lacking. Importantly, we argue that the foundation of a successful forward genetic study lies in the development of appropriate phenotypical test paradigms. Furthermore, perhaps one of the best and simplest ways to test functional changes in the brain is behavioral analysis. Thus, the primary goal of this proposal is first to develop novel behavioral paradigms that detect alcohol induced changes, and second, to technically and procedurally refine these paradigms for high throughput screening of mutants. Another goal of this proposal is to generate and identify the first mutants with the use of the newly developed behavioral screens and then to establish stable mutant zebrafish lines. Ultimately, i.e. after the tenure of the proposal, the proposed studies will lead to the identification of novel genes relevant for alcohol related behaviors in zebrafish, which is hoped will facilitate the unraveling of the mechanisms of acute and chronic alcohol effects in human. ? ? ?
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