Cognitive function and performance on learning and memory tasks are mediated, at least in part, by genetic factors. The long-term goal of the proposed research is to use genetic experimental strategies to identify important neural substrates for complex learning and memory processes. Data are presented indicating that C57BL/6 and DBA/2 mice differ in performance on a number of complex learning tasks that are thought to be dependent on the integrity of the hippocampal-formation including a contextual fear-conditioned freezing task and the spatial version of the Morris water task. C57BL/6 and DBA/2 mice do not differ in performance on simple discrimination tasks suggesting that the behavioral impairment in the DBA/2 strain is not due to motivational or attentional problems. Results of classical genetic analyses and recombinant inbred strain analyses indicate that complex learning and memory in these Strains is regulated by polygenic systems. The studies proposed here are designed to map the chromosomal loci that regulate complex learning and memory processes in C57BL/6 and DBA/2 mice. The quantitative trait loci (QTL) method of analysis will be used to carry out the research. QTLs are chromosomal loci that contain genes influencing traits that exhibit continuous distributions in a population. QTLs that are associated with contextual fear-conditioned freezing will be analyzed in BXD (C57BL/6 X DBA/2) recombinant inbreds strains and animals from the F2 generation of a C57BL/6 X DBA/2 cross. Breeding studies will be conducted to examine the impact of any promising QTLs on behavioral performance in this learning and memory task. The results of these studies should provide important information on genetic regulation of learning and memory in humans by virtue of the known synteny between the mouse and human genomes.
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