Chronic stress enhanced fear memories are associated with increased amygdala zif268 mRNA expression and are resistant to reconsolidation.
Chronic stress enhanced fear memories are associated with increased amygdala zif268 mRNA expression and are resistant to reconsolidation.
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DOI：
10.1016/j.nlm.2015.02.004
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发表时间：
2015-04
影响因子：
2.7
通讯作者：
Conrad CD
中科院分区：
文献类型：
--
作者：
Hoffman AN;Parga A;Paode PR;Watterson LR;Nikulina EM;Hammer RP Jr;Conrad CD
长期处于压力下的大脑可能会出现一种脆弱性，在对创伤事件的反应中发展出适应不良的恐惧相关行为。在啮齿类动物中，慢性应激导致杏仁核高反应性和树突肥大，并产生创伤后应激障碍（PTSD）样表型，包括巴甫洛夫恐惧条件反射和抵抗灭绝后的夸大恐惧学习。目前尚不清楚慢性应激诱导的增强的恐惧记忆是否容易通过再巩固阻断而被破坏，这是一种用于减弱夸大的恐惧记忆的新治疗方法。我们在大鼠模型中使用慢性应激程序（钢丝网束缚6 h/d/21 d）来创建导致PTSD样表型的脆弱大脑。然后，我们检查了在获得、再活化和再活化后雷帕霉素施用（i. p.，40 mg/kg），以确定其对再巩固以及随后使用zif 268 mRNA的边缘结构的功能激活的影响。慢性应激增加杏仁核zif 268 mRNA在恐惧记忆检索在重新激活。此外，这些增强的恐惧记忆不受重新激活后雷帕霉素破坏长期恐惧记忆的影响。此外，再激活后的长期记忆处理也与杏仁核（LA和BA）的增加，海马CA 1 zif 268 mRNA的表达减少。这些结果表明，再巩固阻断作为治疗夸大的恐惧记忆的有效方法，如创伤后应激障碍，存在潜在的挑战。我们的研究结果也支持慢性应激操作结合恐惧条件反射作为一种有用的临床前方法来研究PTSD样表型。
The chronically stressed brain may present a vulnerability to develop maladaptive fear-related behaviors in response to a traumatic event. In rodents, chronic stress leads to amygdala hyperresponsivity and dendritic hypertrophy and produces a post traumatic stress disorder (PTSD)-like phenotype that includes exaggerated fear learning following Pavlovian fear conditioning and resistance to extinction. It is unknown whether chronic stress-induced enhanced fear memories are vulnerable to disruption via reconsolidation blockade, as a novel therapeutic approach for attenuating exaggerated fear memories. We used a chronic stress procedure in a rat model (wire mesh restraint for 6h/d/21d) to create a vulnerable brain that leads to a PTSD-like phenotype. We then examined freezing behavior during acquisition, reactivation and after post-reactivation rapamycin administration (i.p., 40 mg/kg) in a Pavlovian fear conditioning paradigm to determine its effects on reconsolidation as well as the subsequent functional activation of limbic structures using zif268 mRNA. Chronic stress increased amygdala zif268 mRNA during fear memory retrieval at reactivation. Moreover, these enhanced fear memories were unaffected by post reactivation rapamycin to disrupt long-term fear memory. Also, post-reactivation long term memory processing was also associated with increased amygdala (LA and BA), and decreased hippocampal CA1 zif268 mRNA expression. These results suggest potential challenges for reconsolidation blockade as an effective approach in treating exaggerated fear memories, as in PTSD. Our findings also support chronic stress manipulations combined with fear conditioning as a useful preclinical approach to study a PTSD-like phenotype.
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