Temporal factors in the extinction of fear in inbred mouse strains differing in extinction efficacy

Kathryn Macpherson,Nicolas Singewald,Andrew Holmes,Marguerite Camp,Ozge Gunduz-Cinar,Nigel Whittle

doi:10.1186/2045-5380-3-13

Kathryn Macpherson, Nicolas Singewald + Show 4 more

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https://doi.org/10.1186/2045-5380-3-13

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Abstract

BackgroundVarious neuropsychiatric conditions, including posttraumatic stress disorder (PTSD), are characterized by deficient fear extinction, but individuals differ greatly in risk for these. While there is growing evidence that fear extinction is influenced by certain procedural variables, it is unclear how these influences might vary across individuals and subpopulations. To model individual differences in fear extinction, prior studies identified a strain of inbred mouse, 129S1/SvImJ (S1), which exhibits a profound deficit in fear extinction, as compared to other inbred strains, such as C57BL/6J (B6).MethodsHere, we assessed the effects of procedural variables on the impaired extinction phenotype of the S1 strain and, by comparison, the extinction-intact B6 strain. The variables studied were 1) the interval between conditioning and extinction, 2) the interval between cues during extinction training, 3) single-cue exposure before extinction training, and 4) extinction of a second-order conditioned cue.ResultsConducting extinction training soon after (‘immediately’) conditioning attenuated fear retrieval in S1 mice and impaired extinction in B6 mice. Spacing cue presentations with long inter-trial intervals during extinction training augmented fear in S1 and B6 mice. The effect of spacing was lost with one-trial fear conditioning in B6, but not S1 mice. A single exposure to a conditioned cue before extinction training did not alter extinction retrieval, either in B6 or S1 mice. Both the S1 and B6 strains exhibited robust second-order fear conditioning, in which a cue associated with footshock was sufficient to serve as a conditioned exciter to condition a fear association to a second cue. B6 mice extinguished the fear response to the second-order conditioned cue, but S1 mice failed to do so.ConclusionsThese data provide further evidence that fear extinction is strongly influenced by multiple procedural variables and is so in a highly strain-dependent manner. This suggests that the efficacy of extinction-based behavioral interventions, such as exposure therapy, for trauma-related anxiety disorders will be determined by the procedural parameters employed and the degree to which the patient can extinguish.

Highlights

Various neuropsychiatric conditions, including posttraumatic stress disorder (PTSD), are characterized by deficient fear extinction, but individuals differ greatly in risk for these
Freezing during the first trial-block was equivalent between groups and significantly decreased across trialblocks during extinction training in the delayed but not immediate group, there was a non-significant trend in the same direction in the immediate group
It was notable that baseline freezing on the fear probe test was higher than in other experiments (Table 1), reflecting contextual fear acquired during reinstatement

Summary

Introduction

Various neuropsychiatric conditions, including posttraumatic stress disorder (PTSD), are characterized by deficient fear extinction, but individuals differ greatly in risk for these. Individuals differ greatly in risk for anxiety disorders, including PTSD, in part likely due to the moderating influence of genetic factors [9,10] With this in mind, recent studies have sought to identify neural mechanisms underlying differences in fear and extinction behaviors between subgroups selected from larger populations [11,12,13], or identify inbred (isogenic) rodent strains that show reliable trait differences in fear extinction [14]. Recent studies have sought to identify neural mechanisms underlying differences in fear and extinction behaviors between subgroups selected from larger populations [11,12,13], or identify inbred (isogenic) rodent strains that show reliable trait differences in fear extinction [14] In this context, we recently identified an inbred strain of mouse, 129S1/SvImJ (S1), that exhibits a profound deficit in fear extinction, as compared to a reference inbred strain, C57BL/6J (B6) [15,16,17,18,19]

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