Individual differences in general and specific cognitive function in humans are regulated in part by genetic factors but little is known about the genes mediating this variation. Genetic regulation of complex learning can be addressed in animal models due to the highly conserved nature of brain structures. Contextual and noncontextual fear conditioning, a form of complex emotional learning, can be measured in both human and rodents. In contextual fear conditioning, learning the association of a mild shock with a sound in a particular chamber is shown as a fear response. Until recently, the genes regulating this type of complex phenotype have been difficult to map because of the polygenic nature of this regulation. The recent application of quantitative trait loci (QTL) analysis, a form of linkage analysis, allowed the identification of five QTLs on chromosomes 1, 2, 3, 10 and 16 that explain 70% of the genetic variation between C57BL/6 (B6) and DBA/2 (D2) for contextual fear conditioning. Some of these QTLs overlap with QTLs identified in other laboratories regulating emotionality or contextual fear conditioning in other genetic crosses. Thus, both QTLs that generalize across strains of mice and QTLs specific to the differences between B6 and D2 strains have been identified. The goal of the proposed studies is to narrow these QTL regions for further study.
The specific aims of the proposal are: 1.) To create congenic mouse lines for QTLs on chromosomes 1 and 3 which regulate contextual fear conditioning and noncontextual fear conditioning identified previously in a cross of B6 and D2 mice. 2.) To examine whether the QTLs for fear conditioning also regulate genetic variation in other forms of complex learning or fear-related behaviors. 3.) To characterize differences in gene expression between interval-specific congenics and the B6 background strains in naive mice and after contextual fear conditioning. Our long-term goal is to identify the genes that regulate behavioral differences in mice with the hopes that applying this information to understand regulation of human learning. Studies of this form of learning are not only applicable to normal complex learning processes but also to certain psychopathologies like post-traumatic stress syndrome.
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