Ketamine Alleviates Fear Generalization Through GluN2B-BDNF Signaling in Mice
Ketamine Alleviates Fear Generalization Through GluN2B-BDNF Signaling in Mice
复制标题
氯胺酮通过 GluN2B-BDNF 信号传导缓解小鼠的恐惧泛化
DOI：
10.1007/s12264-019-00422-4
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发表时间：
2020-02-01
影响因子：
5.6
通讯作者：
Zhao, Hu
中科院分区：
文献类型：
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作者：
Asim, Muhammad;Hao, Bo;Zhao, Hu
恐惧记忆对生存至关重要。然而，这些记忆的过度概括，表现为无法区分威胁和安全刺激，这在压力相关疾病中是典型的。以前的研究支持氯胺酮对压力诱导的抑郁行为的保护作用。然而，氯胺酮对恐惧泛化的影响仍不清楚。在这项研究中，我们研究了氯胺酮对恐惧泛化小鼠模型的恐惧泛化的影响。给小鼠单次亚麻醉剂量的氯胺酮（30 mg/kg，i. p.）恐惧条件反射前1小时、恐惧条件反射前1周、恐惧条件反射后立即或恐惧条件反射后22小时。以小鼠为实验对象，观察其恐惧行为学指标（以冻结水平表示）和基底外侧杏仁核（BLA）和前额叶边缘皮质（IL-PFC）突触蛋白的表达。我们发现，只有在恐惧条件化后22小时给予氯胺酮才能显著降低恐惧泛化，并且这种效果具有剂量依赖性，并持续至少2周。在BLA和IL-PFC中，恐惧全身化小鼠显示出较低水平的脑源性神经营养因子（BDNF）和较高水平的GluN 2B蛋白，并且单次给予氯胺酮可以逆转这一点。此外，GluN 2B拮抗剂ifenprodil注入IL-PFC时可降低恐惧泛化，但注入BLA时没有影响。将ANA-12（BDNF受体TrkB的拮抗剂）输注到BLA或IL-PFC中阻断了氯胺酮对恐惧泛化的影响。这些发现支持以下结论：在恐惧条件化后22 h给予单剂量氯胺酮可增强小鼠的恐惧记忆泛化，并且GluN 2B相关的BDNF信号通路在减轻恐惧泛化中起重要作用。
Fear memories are critical for survival. Nevertheless, over-generalization of these memories, depicted by a failure to distinguish threats from safe stimuli, is typical in stress-related disorders. Previous studies have supported a protective role of ketamine against stress-induced depressive behavior. However, the effect of ketamine on fear generalization remains unclear. In this study, we investigated the effects of ketamine on fear generalization in a fear-generalized mouse model. The mice were given a single sub-anesthetic dose of ketamine (30 mg/kg, i.p.) 1 h before, 1 week before, immediately after, or 22 h after fear conditioning. The behavioral measure of fear (indicated by freezing level) and synaptic protein expression in the basolateral amygdala (BLA) and inferior-limbic pre-frontal cortex (IL-PFC) of mice were examined. We found that only ketamine administered 22 h after fear conditioning significantly decreased the fear generalization, and the effect was dose-dependent and lasted for at least 2 weeks. The fear-generalized mice showed a lower level of brain-derived neurotrophic factor (BDNF) and a higher level of GluN2B protein in the BLA and IL-PFC, and this was reversed by a single administration of ketamine. Moreover, the GluN2B antagonist ifenprodil decreased the fear generalization when infused into the IL-PFC, but had no effect when infused into the BLA. Infusion of ANA-12 (an antagonist of the BDNF receptor TrkB) into the BLA or IL-PFC blocked the effect of ketamine on fear generalization. These findings support the conclusion that a single dose of ketamine administered 22 h after fear conditioning alleviates the fear memory generalization in mice and the GluN2B-related BDNF signaling pathway plays an important role in the alleviation of fear generalization.