Traits of fear resistance and susceptibility in an advanced intercross line

       

       Author: Jeffifer L. McGuire...Luke R. Johnson

       

       Background:

       Learned and fear based memories are a crucial aspect of survival, that have been found to be heritable in animals as well as humans. It is also known that patients who suffer from anxiety disorders such as post-traumatic stress disorder (PTSD) and depression have a stronger acquisition of conditioned fear. For future endophenotyping of altered fear and memory processing among high risk patients for anxiety disorders, it is key to identify a physiological profile for fear resistance and susceptibility.

       Methods:

•        Advanced intercross lines (AIL’s) are generated through selectively-random breeding over multiple generations, reducing the linkage of nearby alleles. Two AIL’s were created in this study, fear-susceptible mice and fear-resistant mice. Both of these mouse models once selected then underwent a three day analysis in order to study context fear and conditioned fear.
•        ELISA assay and qPCR to quantify specific hormone levels
•        Manganese-enhanced Magnetic Resonance Imaging

      Results:

      •      Differences between F-S and F-R were present between and within training and test days. Small difference in F-S and F-R freezing during the first tone, is significant in showing lower levels of anxiety in F-R mice, being a shock is not induced until after the first tone. After both the second tone during training day and after the cue test on day 2 the F-S mice had high percentage of freezing than F-R. However, intensely trained F-R mice showed similar freezing patterns to F-S mice, and in some cases even greater.

      •      F-S mice secreted greater amounts of morning corticosterone than F-R mice. Correspondingly, there are greater CRH mRNA expression levels in F-S mice compared to F-R Mice. However, CRHR1 expression levels were lower in F-S mice compared to the F-R mice. Mineral Corticoid Receptor (MR) was also lower in F-S mice compared to F-R mice. Finally, there was no significant expression difference of GR levels in F-S and F-R mice.

     •      Using MeMRI, it was discovered first that both groups on average had  the same hippocampal volume with no significant differences in either cohort. Importantly, after normalized to the F-R cohort, F-S mice were shown to have increased calcium dependent activity in the fear learning circuit. The F-S group predominantly showed neuronal activities in the hippocampus, which is known to play a key role in contextual fear conditioning. 

~JI