Identification of genes and pathways regulated by epigenetic mechanisms in determining general intelligence (g) of inbred mice. Mus musculus

General intelligence (g) is a common core shared by cognitive tasks. To study epigenetic regulation of “g”, 41 inbred mice raised under similar environmental conditions were subjected to five behavioral tests. We used principal component analysis to analyze 11 parameters that measure performance and reflect cognition of mice. Microarray gene expression analysis by using hippocampal RNAs of the 5, 12, and 8 mice consistently classified as having high, medium, and low cognition, respectively, by PC1 score and IQ score identified 17 genes that showed at least 1.3-fold difference in expression between mice with high and low cognition (FDR<0.30). Two of these genes were down-regulated and 15 of these genes were up-regulated in the high cognitive mice. Subsequent pathway-based analysis further identified gene-sets (GS) enriched in high cognitive mice and GS enriched in low cognitive mice. A number of genes implicated in our study have been previously associated with cognitive impairments. Our findings provide insights into genes and pathways regulated by epigenetic mechanisms in determining “g” and may shed lights on various disorders that affect cognitive function. Overall design: Male inbred mice of C57BL/6J Strain (10 week-old) were subjected to a comprehensive behavioral test battery consisting of general health and neurological screening, open field test, new social interaction test (Crawley’s version), Barnes circular maze test (BM), 8-arm radial maze test (RM), T-maze test (TM), light/dark transition test, elevated plus-maze test, hotplate, social interaction test (novel environment), tail suspension, rotarod, prepulse inhibition, Porsolt forced swimming test, cued and contextual fear conditioning (FZ), gait analysis and passive avoidance (PA) (tests were listed following the sequence the tests were being conducted). Five of the aforementioned tests, namely BM, RM, TM, FZ, and PA, measured memory and cognitive performance of mice. BM, RM, and TM tests were conducted when mice aged 10-11, 12-14, and 15-19 week-olds, respectively; whereas FZ and PA, which leave stronger impacts on mice, were conducted at later stage when mice were 33 and 37-38 week-olds, respectively. The raw data including those of other behavioral tests, which are not measuring cognitive performance of mice and therefore not described in this paper, are disclosed in mouse phenotype database (http://www.mouse-phenotype.org/) as “B6J” strain. General cognitive ability of the 39 mice with complete data on the 11 parameters of the five behavioral tests aforementioned was determined. Detailed procedures were described in our paper. Mice that were consistently ranked as having high, medium, and low cognition by both ranking systems were identified and were subjected to subsequent gene expression profiling analysis. All behavioral testing procedures have been approved by Animal Care and Use Committee of Kyoto University Graduate School of Medicine, where the tests have been performed.