Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
The Jackson Laboratory, Bar Harbor, ME, USA.
Mol Psychiatry. 2019 Apr;24(4):601-612. doi: 10.1038/s41380-017-0003-3. Epub 2018 Jan 8.
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.
近年来，我们对与创伤相关障碍相关的神经回路有了更多的了解，并开发了用于在啮齿动物中研究这些行为的相关检测方法。尽管已知遗传因素会影响这些疾病的个体差异易感性，但很难确定特定的基因来调节回路功能以影响与创伤相关的行为。在这里，我们利用强大的近交系小鼠在 Pavlovian 恐惧消退方面的差异，来发现与该特征相关的数量性状基因座（QTL）。我们发现这些品系差异对发育性交叉养育具有抗性，并且与外侧杏仁核（BLA）周围神经网的解剖变异相关，该变异与消退有关。接下来，通过对 QTL 相关基因的 BLA 表达进行谱分析，我们提名 Ppid（肽基脯氨酰异构酶 D，四肽重复蛋白家族的成员）作为与消退相关的候选基因。然后我们表明，Ppid 在兴奋性和抑制性 BLA 神经元群体中丰富，但在消退受损的小鼠品系中水平较低。使用基于病毒的方法直接调节 Ppid 功能，我们表明下调 BLA-Ppid 会损害消退，而上调 BLA-Ppid 则促进消退并改变体内神经元消退编码。接下来，我们表明 Ppid 与 BLA 神经元中的糖皮质激素受体（GR）共定位，并发现 Ppid 上调的消退促进作用被 GR 拮抗剂阻断。总之，我们的结果表明 Ppid 是一种通过 BLA 中的功能作用参与调节消退的新基因，这可能对理解与创伤相关障碍相关的遗传和病理生理机制具有重要意义。
