Behavioral and genetic architecture of fear conditioning and related phenotypes

Contextual fear conditioning is a form of Pavlovian learning during which an organism learns to fear previously neutral stimuli following their close temporal presentation with an aversive stimulus. In mouse models, freezing behavior is typically used to quantify learned fear. This dependent variable is the sum of multiple processes, including associative/configural learning, fear and anxiety, and general activity. To explore phenotypic constructs underlying contextual fear conditioning and correlated behaviors, as well as factors that may contribute to individual differences in learning and mental health, we tested BXD recombinant inbred strains previously found to show extreme contextual fear conditioning phenotypes and BXD parental strains, C57BL/6J and DBA/ 2J, in a series of tests including locomotor, anxiety, contextual/cued fear conditioning and non-associative hippocampus-dependent learning behaviors. Hippocampal expression of two previously identified candidate genes for contextual fear conditioning was also quantified. Behavioral and gene expression data were analyzed using exploratory factor analysis (EFA), which suggested five unique constructs representing activity/anxiety/ exploration, associative fear learning, anxiety, post-shock freezing, and open field activity phenotypes. Associative fear learning and expression of one candidate gene, Hacd4, clustered as a construct within the factor analysis. Post-shock freezing during fear conditioning and expression of candidate gene Ptprd emerged as another unique construct, highlighting the independence of freezing after footshock from other fear conditioning variables in the current dataset. EFA results additionally suggest shared phenotypic variance in adaptive murine behaviors related to anxiety, general activity, and exploration. These findings inform understanding of fear learning and underlying biological mechanisms that may interact to produce individual differences in fear-and learning-related behaviors in mice.