Chronic fluoxetine prevents fear memory generalization and enhances subsequent extinction by remodeling hippocampal dendritic spines and slowing down systems consolidation
Chronic fluoxetine prevents fear memory generalization and enhances subsequent extinction by remodeling hippocampal dendritic spines and slowing down systems consolidation
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DOI：
10.1038/s41398-019-0371-3
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发表时间：
2019-01-31
影响因子：
6.8
通讯作者：
Alvares, Lucas de Oliveira
中科院分区：
文献类型：
--
作者：
Pedraza, Lizeth K.;Sierra, Rodrigo O.;Alvares, Lucas de Oliveira
恐惧记忆过度概括有助于焦虑症的发生和持续，是创伤后应激障碍（PTSD）病理生理学的中心标志。最近的研究结果表明，恐惧泛化与提取过程中的海马依赖性密切相关。选择性5-羟色胺再摄取抑制剂（SSRI）氟西汀已被用作PTSD的一线治疗药物;然而，它如何发挥其治疗作用仍然是一个有争议的问题。在这里，使用大鼠的背景恐惧条件反射，我们表明，慢性氟西汀治疗防止恐惧泛化，并增强随后的灭绝。此外，氟西汀治疗后，消退防止自发恢复。氟西汀影响泛化和消退的机制似乎是通过推迟系统巩固，从而维持海马参与检索。这种效应依赖于海马树突棘的重塑，以及氟西汀治疗促进的成熟蘑菇型棘的数量。为了进一步研究恐惧泛化是否是灭绝有效性的潜在预测因子，我们根据泛化率对一个大的天真群体进行了分类。我们发现，与泛化者相比，泛化者表现出更好的灭绝特征，这表明泛化率预测了灭绝的有效性。因此，我们建议选择的治疗策略应该考虑到记忆泛化的扩展，其中基于消退的治疗可以在表现出较少恐惧过度泛化的患者中诱导更好的结果。这些结果为开发通过维持海马体的记忆依赖性来防止恐惧泛化的干预措施开辟了新的途径。
Fear memory overgeneralization contributes to the genesis and persistence of anxiety disorders and is a central hallmark in the pathophysiology of post-traumatic stress disorder (PTSD). Recent findings suggest that fear generalization is closely related to hippocampal dependency during retrieval. The selective serotonin reuptake inhibitor (SSRI) fluoxetine has been used as a first-line treatment for PTSD; however, how it exerts its therapeutic effect remains a matter of debate. Here, using contextual fear conditioning in rats, we show that chronic fluoxetine treatment prevents fear generalization and enhances subsequent extinction. Moreover, fluoxetine treatment after extinction prevents spontaneous recovery. The mechanism through which fluoxetine affects generalization and extinction seems to be through the postponement of systems consolidation, thereby maintaining hippocampal involvement during retrieval. Such an effect relies on a remodeling of dendritic spines in the hippocampus, as well as the number of mature, mushroom-type spines promoted by fluoxetine treatment. In order to further investigate whether fear generalization is a potential predictor of extinction effectiveness, we categorized a large naive population according to their generalization rate. We found that discriminator rats showed a better extinction profile compared to generalizers, suggesting that the generalization rate predicts extinction effectiveness. Hence, we propose that the therapeutic strategy of choice should take into account the extension of memory generalization, in which therapies based on extinction could induce a better outcome in patients who present less fear overgeneralization. These results open new avenues for the development of interventions that prevent fear generalization by maintaining memory dependency of the hippocampus.