Douglas L. Wahlsten - US grants

DESCRIPTION: (Adapted from applicant's abstract) New genetic technology has created a need for detecting changes in behavior caused by a wide variety of mutations. The goal of this project is to devise an optimal array of tests of two behavioral domains in mice, motor coordination/ataxia and learning/memory, and then demonstrate the value of these tests in a study of alcohol and fluoxetine effects on behavior tested simultaneously in two laboratories. To define the optimal array, a large number of tests will first be administered to a small number of standard mouse strains, none of which is markedly abnormal. The best of these tests will then be given simultaneously with identical apparatus and procedures in two laboratories to a large number of inbred strains, some of which have mild neurological abnormalities. This will allow us to eliminate any tests that are (a) highly correlated between strains and therefore redundant in the context of genetic screening research, (b) too sensitive or altogether insensitive to certain neurological abnormalities, or (c) too sensitive to minor environmental differences between laboratories. Finally, the refined and optimal array of behavioral tests will be used to assess effects of drugs in the two labs simultaneously. To achieve these ends, a video image analysis system will achieve high-throughput data collection and analysis by monitoring several kinds of apparatus asynchronously. The apparatus designs, testing protocols, and computer programs will be made available to other investigators, and the extensive data on inbred strains will be entered into a central database. A detailed training manual will be compiled, including norms for results when the tests are done properly with normal and abnormal mice. Designs, protocols, and data for the standardization sample will also be made available through a website. The tests will be especially useful to investigators interested in screening chemically-induced and transgenic mutations for multiple behavioral effects.

[unreadable] DESCRIPTION (provided by applicant): Individual variation in behavioral response to ethanol may be traced in part to the influence of inheritance, i.e., specific genes. For many behaviors, the genetic influences on ethanol sensitivity may account for as much as half of individual variation: therefore, non-genetic (environmental) sources of influence are also important. The overarching goal of these studies is to assess genetic and environmental influences on ethanol responses in mice, focusing on the interactions between genes and environment. We first propose to explore ethanol intoxication in two behavioral domains, motor coordination/ataxia and learning, using multiple laboratory assays. Our hypothesis is that different constellations of genes affect different tasks within a domain. We will select from the several ataxia (and learning) tasks those that are practical for use across a wide range of strains and are highly reliable within a single laboratory. We have created a unique facility for conducting identical behavioral tests at two sites (Edmonton, AB; Portland, OR), and this will allow us to identify those tasks that are also highly replicable across laboratories. Tasks that are both reliable and replicable will be used to survey the genetic contributions to each domain and to ethanol sensitivity. This will allow us to identify a smaller set of tasks that together capture a broad range of genetic influences on ethanol sensitivity. Because neuro-adaptation to ethanol is an important contributor to drug dependence, we will also study the genetic bases of acute, rapid, and chronic tolerance to ethanol in the ataxia tasks. Our second goal is to manipulate the environment systematically. We hypothesize that enriched rearing conditions, testing in the circadian light versus dark phase, and the specific experimenter conducting the behavioral tasks will affect results. Furthermore, we hypothesize that responses to environmental manipulations will differ across different strains, i.e., that genes will exert different effects on ethanol sensitivity and tolerance measures in different environments. In the final set of experiments, we will address the practical significance of these findings by exploring selected gene-environment combinations in null mutants and in lines of mice selected for extremes of behavioral sensitivity and/or tolerance to ethanol. [unreadable] [unreadable]