Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK.
Behavioural and Clinical Neuroscience Institute, Cambridge, CB2 3EB, UK.
Neuropsychopharmacology. 2019 Sep;44(10):1762-1768. doi: 10.1038/s41386-018-0299-y. Epub 2018 Dec 20.
Extinction of a cued-fear memory within the reconsolidation window has been proposed to prevent fear reacquisition by reconsolidation interference. This 'retrieval-extinction' procedure has received interest for its therapeutic potential to reduce the impact of fear memories on behavior. To fully exploit its therapeutic potential, it is critical to understand the mechanisms that underlie the 'retrieval-extinction' effect. If the effect depends upon reconsolidation of the original memory, then it would be predicted that destabilization, induced by prediction error, would be critical for observing the effect. Here, the dependency of the retrieval-extinction effect on memory destabilization or prediction error was investigated in pavlovian cued-fear conditioned adult male rats. The requirement for memory destabilization, and thus reconsolidation, for the retrieval-extinction effect was subsequently investigated using region-specific pharmacological blockade of dopamine D1-receptors. Intra-basolateral amygdala antagonism of dopamine D1-receptors did not prevent the reacquisition of fear associated with the retrieval-extinction procedure. The requirement for prediction error was assessed by using a reinforced or non-reinforced memory retrieval trial before extinction, compared to a no-retrieval, extinction-only control. Both the reinforced (no prediction error) and non-reinforced retrieval sessions led to a decrease in fear reacquisition, suggesting that engagement of prediction error does not influence the occurrence of retrieval-extinction. Together, these data suggest that retrieval-extinction does not require memory destabilization, since behavioral or pharmacological interventions that prevent destabilization did not disrupt any capacity to attenuate fear.
在再巩固窗口内消除条件恐惧记忆被提议用于通过再巩固干扰来预防恐惧重新获得。这种“检索-消除”程序因其减少恐惧记忆对行为影响的治疗潜力而受到关注。为了充分发挥其治疗潜力,理解“检索-消除”效应的机制至关重要。如果该效应取决于原始记忆的再巩固,那么可以预测,由预测误差引起的不稳定性对于观察该效应至关重要。在这里,研究了检索-消除效应是否依赖于记忆不稳定性或预测误差,这是在条件性恐惧成年雄性大鼠的听觉线索条件下进行的。随后使用多巴胺 D1 受体的区域特异性药理学阻断来研究检索-消除效应的记忆不稳定性(即再巩固)的需求。内侧基底杏仁核中多巴胺 D1 受体的拮抗作用并不能防止与检索-消除程序相关的恐惧重新获得。通过在消退之前进行强化或非强化的记忆检索试验(与无检索、仅消退的对照相比),评估了预测误差的需求。强化(无预测误差)和非强化检索试验都导致恐惧重新获得的减少,这表明预测误差的参与并不影响检索-消除的发生。这些数据表明,检索-消除不需要记忆不稳定性,因为预防不稳定性的行为或药理学干预并未破坏任何减轻恐惧的能力。