Experiment
There are marked individual differences in risk for traumarelated anxiety disorders including posttraumatic stress disorder (PTSD). Recent years have seen advances in our understanding of the neural circuits associated with trauma-related disorders, and the development of relevant assays for these behaviors in rodents. Although inherited factors are known to influence individual differences in risk for these disorders, it has been difficult to identify specific genes that moderate circuit functions to affect trauma-related behaviors. Here, the authors exploited robust inbred mouse strain differences in Pavlovian fear extinction to uncover QTL associated with this trait. They found these strain differences to be resistant to developmental crossfostering and associated with anatomical variation in basolateral amygdala (BLA) perineuronal nets, which are developmentally implicated in extinction.
With the exception of the F1 and F2 populations (which were bred in-house), subjects were adult male C57BL/6J and 129S1/SvImJ mice. The sample size used in each of the behavioral tests were determined on the basis of findings from the authors' previous fear and extinction studies (Bukalo, 2015).
C57BL/6J and 129S1/SvImJ mice were cross-fostered at three different developmental time points (prenatal, postnatal, post-weaning) and tested for fear and extinction in adulthood. C57BL/6J and 129S1/SvImJ mice were examined for BLA (prefrontal cortical and hippocampal) perineuronal nets at various ages, via immunocytochemistry of biotinconjugated lectin wisteria floribunda agglutinin (WFA). Both strains exhibited similar freezing during fear conditioning and fear retrieval, but 129S1/SvImJ froze significantly more than C57BL/6J by the final trial-block of extinction acquisition and on an extinction retrieval test.
Following testing, F2 mice (n = 371) were genotyped for QTL mapping, using R/qtl. Of 1449 SNPs on the linkage panel, 880 were genetically informative (i.e., differed between parental strains) and 778 gave the expected call with parental control DNA. All genome coordinates relative to GRCm38/mm10.
QTL analysis was performed on four traits: fear retrieval, extinction acquisition, extinction retrieval, and fear renewal.
Two significant QTL were identified:
Fearet1 (fear retrieval 1) maps to Chr 1: 73.3 - 182.4 Mb with a peak LOD score of 4.5.
Extret1 (extinction retrieval 1) maps to Chr 3: 77.1 - 93.1 Mb with a peak LOD score of 4.6.
By profiling extinction-driven BLA expression of QTL-linked genes, the authors nominated Ppid (peptidylprolyl isomerase D, a member of the tetratricopeptide repeat (TPR) protein family) as an extinction-related candidate gene. Collectively, the authors' results identify Ppid as a novel gene involved in regulating extinction via functional actions in the BLA, with possible implications for understanding genetic and pathophysiological mechanisms underlying risk for trauma-related disorders.
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