Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Neurosci Bull. 2020 Feb;36(2):153-164. doi: 10.1007/s12264-019-00422-4. Epub 2019 Aug 23.
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.
恐惧记忆对生存至关重要。然而，在与应激相关的障碍中，这些记忆会出现过度泛化，表现为无法区分威胁与安全刺激。先前的研究支持氯胺酮对应激诱导的抑郁行为具有保护作用。然而，氯胺酮对恐惧泛化的影响尚不清楚。在本研究中，我们在恐惧泛化的小鼠模型中研究了氯胺酮对恐惧泛化的影响。在恐惧条件反射前 1 小时、前 1 周、后立即或后 22 小时，给予小鼠单次亚麻醉剂量的氯胺酮（30mg/kg，腹腔注射）。通过检测小鼠的恐惧行为（以冻结水平表示）和杏仁核基底外侧核（BLA）和下边缘前额叶皮质（IL-PFC）中的突触蛋白表达来评估。我们发现，只有在恐惧条件反射后 22 小时给予氯胺酮才能显著降低恐惧泛化，且该作用具有剂量依赖性，至少持续 2 周。恐惧泛化的小鼠在 BLA 和 IL-PFC 中的脑源性神经营养因子（BDNF）水平较低，GluN2B 蛋白水平较高，单次给予氯胺酮即可逆转这种现象。此外，将 GluN2B 拮抗剂ifenprodil 注入 IL-PFC 可降低恐惧泛化，但注入 BLA 则无影响。将 ANA-12（BDNF 受体 TrkB 的拮抗剂）注入 BLA 或 IL-PFC 可阻断氯胺酮对恐惧泛化的作用。这些发现支持以下结论：在恐惧条件反射后 22 小时给予小鼠单次氯胺酮剂量可减轻恐惧记忆泛化，GluN2B 相关的 BDNF 信号通路在减轻恐惧泛化中起重要作用。
