Involvement of CRFR(1) in the Basolateral Amygdala in the Immediate Fear Extinction Deficit.
Involvement of CRFR(1) in the Basolateral Amygdala in the Immediate Fear Extinction Deficit.
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DOI：
10.1523/eneuro.0084-16.2016
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发表时间：
2016-09
期刊：
影响因子：
3.4
通讯作者：
Sandi C
中科院分区：
文献类型：
--
作者：
Hollis F;Sevelinges Y;Grosse J;Zanoletti O;Sandi C
一些动物和临床研究已经强调了在创伤暴露后不久进行的恐惧消退会议的无效性。这种现象被称为即时消退缺陷，是指在恐惧条件反射后不久应用的消退程序可能导致消退训练期间恐惧行为减少（在啮齿动物中，经常测量为对条件提示的冻结反应），但未能长期巩固这种减少。驱动这种立即灭绝抗性的分子机制仍不清楚。在这里，我们提出的证据参与促肾上腺皮质激素释放因子（CRF）系统在基底外侧杏仁核（BLA）在雄性Wistar大鼠。BLA内微量输注CRFR 1拮抗剂NBI 30775可增强消退回忆，而在延迟消退前给予CRF激动剂CRF 6 -33可破坏消退回忆。我们联系的直接恐惧灭绝赤字与GluA 1谷氨酸受体Ser 845和增强活性的蛋白磷酸酶钙调神经磷酸酶在BLA的去磷酸化。在用CRFR 1拮抗剂治疗后其逆转表明其依赖于CRFR 1作用。这些发现对于改善创伤治疗方法以及进一步了解恐惧相关疾病的神经生物学机制具有重要意义。
Several animal and clinical studies have highlighted the ineffectiveness of fear extinction sessions delivered shortly after trauma exposure. This phenomenon, termed the immediate extinction deficit, refers to situations in which extinction programs applied shortly after fear conditioning may result in the reduction of fear behaviors (in rodents, frequently measured as freezing responses to the conditioned cue) during extinction training, but failure to consolidate this reduction in the long term. The molecular mechanisms driving this immediate extinction resistance remain unclear. Here we present evidence for the involvement of the corticotropin releasing factor (CRF) system in the basolateral amygdala (BLA) in male Wistar rats. Intra-BLA microinfusion of the CRFR1 antagonist NBI30775 enhances extinction recall, whereas administration of the CRF agonist CRF6–33 before delayed extinction disrupts recall of extinction. We link the immediate fear extinction deficit with dephosphorylation of GluA1 glutamate receptors at Ser845 and enhanced activity of the protein phosphatase calcineurin in the BLA. Their reversal after treatment with the CRFR1 antagonist indicates their dependence on CRFR1 actions. These findings can have important implications for the improvement of therapeutic approaches to trauma, as well as furthering our understanding of the neurobiological mechanisms underlying fear-related disorders.