This renewal application continues to address the question of """"""""what genes contribute to the variability in the ethanol-induced locomotor response (ELR)?"""""""" The main goal of the application is to map the QTLs for the ELR to a resolution of 1 cM. A secondary goal of the application is to investigate ELR correlated traits and use this information to assign additional functional attributes to the QTLs.
The specific aims may be summarized: 1. To complete the genome wide search for QTLs associated with the ELR in C57BL/6J (B6) x DBA/2J (D2) F2 intercross and to determine if there are gender specific QTLs. The focus on the B6D2 genotypes is justified a) because the parental lines are highly polymorphic (Dietrich et al. 1992, 1996) and b) because the parental lines differ markedly in the phenotype of interest. Furthermore, the preliminary data have provided proof of concept for this intercross (Section C). 2. To conduct a genome wide QTL search in a BALB/cJ (C) x LP/J (LP) F2 intercross. The CLP F2 cross was chosen a) because the parental strains are highly polymorphic between themselves and the B6 and D2 strains (Dietrich et al. 1992), b) because among inbred mouse strains, the parental strains are at the extremes of the distribution for several dopamine related phenotypes (e.g. D2 dopamine receptor density; Kanes et al. 1993; Hitzemann et al. 1995) which are likely to influence locomotor activity and c) because the strains differ significantly in the ELR (Section C). The advantage of using multiple genetic backgrounds to detect additional QTLs has been documented for other quantitative traits such as obesity (Pomp, 1997; Taylor and Phillips, 1997) and the strategy is extended here to a behavioral phenotype. 3. To construct a series of """"""""interval specific congenic strains (ISCSs)"""""""" which enables mapping the QTL into a 1 cM interval. """"""""Each ISCS is recombinant at a specific 1 cM sub-interval out of an ordered set of sub-intervals, which together comprise a wider interval to which the QTL was previously mapped"""""""" (Darvasi, 1996). 4. To continue and expand our characterization of correlated traits to the ELR phenotype. These studies will build upon the phenotypic resources generated in specific aims 1-3. The F2 individuals and congenic strains will be used to address four specific questions: One- What are the relationship between D2 receptor density and ELR? Two- To what extent can the effects of ethanol on locomotor activity be explained by ethanol's effects on GABA-Benzodiazepine (BZ) receptor systems? Three- Does the central nucleus of the amygdala (CeA) regulate the ELR phenotype? Four-Do some of the same genes which regulate ELR also regulate other acute ethanol phenotypes.
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