Keller Samantha M, Schreiber William B, Stanfield Briana R, Knox Dayan
Department of Psychological and Brain Sciences, University of Delaware, Newark, DE, United States.
Department of Psychological and Brain Sciences, University of Delaware, Newark, DE, United States.
Behav Brain Res. 2015;287:182-6. doi: 10.1016/j.bbr.2015.03.043. Epub 2015 Mar 31.
Using the single prolonged stress (SPS) animal model of post-traumatic stress disorder (PTSD), previous studies suggest that enhanced glucocorticoid receptor (GR) expression leads to cued fear extinction retention deficits. However, it is unknown how the endogenous ligand of GRs, corticosterone (CORT), may contribute to extinction retention deficits in the SPS model. Given that CORT synthesis during fear learning is critical for fear memory consolidation and SPS enhances GR expression, CORT synthesis during fear memory formation could strengthen fear memory in SPS rats by enhancing GR activation during fear learning. In turn, this could lead to cued fear extinction retention deficits. We tested the hypothesis that CORT synthesis during fear learning leads to cued fear extinction retention deficits in SPS rats by administering the CORT synthesis inhibitor metyrapone to SPS and control rats prior to fear conditioning, and observed the effect this had on extinction memory. Inhibiting CORT synthesis during fear memory formation in control rats tended to decrease cued freezing, though this effect never reached statistical significance. Contrary to our hypothesis, inhibiting CORT synthesis during fear memory formation disrupted extinction retention in SPS rats. This finding suggests that even though SPS exposure leads to cued fear extinction memory deficits, CORT synthesis during fear memory formation enhances extinction retention in SPS rats. This suggests that stress-induced CORT synthesis in previously stressed rats can be beneficial.
利用创伤后应激障碍（PTSD）的单次长时间应激（SPS）动物模型，先前的研究表明，糖皮质激素受体（GR）表达增强会导致线索性恐惧消退记忆保持缺陷。然而，GR的内源性配体皮质酮（CORT）如何导致SPS模型中的消退记忆保持缺陷尚不清楚。鉴于恐惧学习期间CORT的合成对恐惧记忆巩固至关重要，且SPS会增强GR表达，恐惧记忆形成期间的CORT合成可能通过增强恐惧学习期间的GR激活来强化SPS大鼠的恐惧记忆。反过来，这可能导致线索性恐惧消退记忆保持缺陷。我们通过在恐惧条件反射前给SPS大鼠和对照大鼠施用CORT合成抑制剂美替拉酮，来检验恐惧学习期间CORT合成会导致SPS大鼠线索性恐惧消退记忆保持缺陷这一假设，并观察其对消退记忆的影响。在对照大鼠的恐惧记忆形成过程中抑制CORT合成往往会减少线索性僵住反应，尽管这种效应从未达到统计学显著性。与我们的假设相反，在恐惧记忆形成过程中抑制CORT合成会破坏SPS大鼠的消退记忆保持。这一发现表明，尽管暴露于SPS会导致线索性恐惧消退记忆缺陷，但恐惧记忆形成期间的CORT合成会增强SPS大鼠的消退记忆保持。这表明在先前受过应激的大鼠中，应激诱导的CORT合成可能是有益的。
