Document Type
Article
Publication Date
4-2019
Keywords
JMG
JAX Source
Mol Psychiatry 2019 Apr; 24(4):601-612
Volume
24
Issue
4
First Page
601
Last Page
612
ISSN
1476-5578
PMID
29311651
DOI
https://doi.org/10.1038/s41380-017-0003-3
Grant
AA018776,DA037927
Abstract
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, we exploited robust inbred mouse strain differences in Pavlovian fear extinction to uncover quantitative trait loci (QTL) associated with this trait. We found these strain differences to be resistant to developmental cross-fostering and associated with anatomical variation in basolateral amygdala (BLA) perineuronal nets, which are developmentally implicated in extinction. Next, by profiling extinction-driven BLA expression of QTL-linked genes, we nominated Ppid (peptidylprolyl isomerase D, a member of the tetratricopeptide repeat (TPR) protein family) as an extinction-related candidate gene. We then showed that Ppid was enriched in excitatory and inhibitory BLA neuronal populations, but at lower levels in the extinction-impaired mouse strain. Using a virus-based approach to directly regulate Ppid function, we demonstrated that downregulating BLA-Ppid impaired extinction, while upregulating BLA-Ppid facilitated extinction and altered in vivo neuronal extinction encoding. Next, we showed that Ppid colocalized with the glucocorticoid receptor (GR) in BLA neurons and found that the extinction-facilitating effects of Ppid upregulation were blocked by a GR antagonist. Collectively, our 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.
Recommended Citation
Gunduz-Cinar O,
Brockway E,
Lederle L,
Wilcox T,
Halladay L,
Ding Y,
Oh H,
Busch E,
Kaugars K,
Flynn S,
Limoges A,
Bukalo O,
MacPherson K,
Masneuf S,
Pinard C,
Sibille E,
Chesler E,
Holmes A.
Identification of a novel gene regulating amygdala-mediated fear extinction. Mol Psychiatry 2019 Apr; 24(4):601-612
Comments
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