Molecular correlates of emotional learning using genetically selected rat lines

The genetic contributions to active avoidance learning in rodents have been well established, yet the molecular basis for genetically selected line differences remains poorly understood. To identify candidate genes influencing this active avoidance paradigm, we utilized the bidirectionally selected Syracuse high- and low-avoidance (SHA and SLA) rat lines that markedly differ in their two-way active avoidance behavior. Rats were phenotyped, rested to allow recovery from testing stress and then hippocampi were dissected for gene expression profiling (Affymetrix U34A chips; approximately 7000 known genes), comparing SLA to SHA. Next, a subset of differentially expressed genes was confirmed by real-time PCR (RT-PCR) in hippocampi. Additional studies at the protein level were performed for some genes. Using triplicate arrays on pooled hippocampal samples, differentially expressed genes were identified by microarray suite 5.0 and robust multi-array average analyses. By RT-PCR analysis in hippocampi, eight genes were nominated as potential candidate genes consistent with the differential expression from the microarray data. Four genes, Veli1 (mlin-7B), SLC3a1, Ptpro and Ykt6p, showed higher expression in SHA hippocampi than SLA. Four genes, SLC6A4, Aldh1a4, Id3a and Cd74, showed higher expression in SLA hippocampi than SHA. The active avoidance behavioral difference between lines probably emerges from 'many small things'. These potential candidate genes generate hypotheses for future testing in human association and rodent studies. Differences in levels of a pleiotropic gene like Ptpro and SLC6A4 suggest that small differences over a lifespan may contribute to large behavioral differences.