The long term goal of this proposal is to identify the gene(s) that influence complex behavior in the mouse. We have chosen habituation to an open field as our first behavior to be analyzed. Habituation is a form of memory whereby an animal must remember its surroundings (or a novel object) such that it can respond differently on its subsequent exposure to these surroundings. Our particular assay involves habituation to an open field. In this task, mice are placed in an open field chamber and their activity is recorded on three consecutive days. If their activity changes over the three days, the mice have """"""""habituated"""""""" to the open field. This task is therefore considered a learning paradigm since it requires the mouse to remember its previous experience in the open field. We have recently obtained preliminary data indicating that a gene (or genes) influencing this trait resides on Chromosome (Chr.) 15 of the mouse. In this grant application, we would now like to clone this gene as well as study its characteristics and effects on behavior.
Our specific aims are as follows: (1) to produce B6.D2 and D2.B6 speed congenics and subcongenics for regions of Chr. 15 in the mouse. These strains will be used to further map this habituation trait as well as provide useful strains for further behavioral studies; (2) to test Chr. 15 congenics and subcongenics for behavioral traits including habituation. A battery of tests will be used to determine if performance in the habituation task correlates with performances on other tasks. Alcohol and drug-related behaviors will also be screened; (3) to identify candidate genes for the genetic control of habituation. Candidate genes will be identified either by examining polymorphic differences between strains or by comparing differences in gene expression in target tissues; and (4) to confirm the identity of candidate genes by making transgenic mice. Three strategies will be considered--(1) BAC transgenesis with BACs containing candidate genes, (2) knockin mice containing regions of known polymorphisms in candidate genes or (3) knockout mice and complementation studies that will reveal the hemizygous influence of the candidate gene. These genetically engineered mice will be used to explore the in vivo effects of the detected polymorphisms. It is anticipated that the successful positional cloning of this gene will lead to new information on the pathways involved in the habituation process.
