Department of Psychology and Collaborative Neuroscience Program, University of Guelph, N1G 2W1, Guelph ON, Canada
Department of Psychology and Collaborative Neuroscience Program, University of Guelph, N1G 2W1, Guelph ON, Canada.
Learn Mem. 2024 Oct 9;31(9). doi: 10.1101/lm.054039.124. Print 2024 Sep.
Memory updating is essential for integrating new information into existing representations. However, this process could become maladaptive in conditions like post-traumatic stress disorder (PTSD), when fear memories generalize to neutral contexts. Previously, we have shown that contextual fear memory malleability in rats requires activation of M1 muscarinic acetylcholine receptors in the dorsal hippocampus. Here, we investigated the involvement of this mechanism in the transfer of contextual fear memories to other contexts using a novel fear memory updating paradigm. Following brief reexposure to a previously fear conditioned context, male rats ( = 8-10/group) were placed into a neutral context to evaluate the transfer of fear memory. We also infused the selective M1 receptor antagonist pirenzepine into the dorsal hippocampus before memory reactivation to try to block this effect. Results support the hypothesis that fear memory can be updated with novel contextual information, but only if rats are reexposed to the originally trained context relatively recently before the neutral context; evidence for transfer was not seen if the fear memory reactivation was omitted or if it occurred 6 h before neutral context exposure. The transferred fear persisted for 4 weeks, and the effect was blocked by M1 antagonism. These findings strongly suggest that fear transfer requires reactivation and destabilization of the original fear memory. The novel preclinical model introduced here, and its implication of muscarinic receptors in this process, could therefore inform therapeutic strategies for PTSD and similar conditions.
记忆更新对于将新信息整合到现有表示中至关重要。然而，在创伤后应激障碍 (PTSD) 等情况下，当恐惧记忆泛化到中性环境时，这个过程可能会变得适应不良。以前，我们已经表明，大鼠背侧海马体 M1 毒蕈碱乙酰胆碱受体的激活对于情境恐惧记忆的可塑性是必需的。在这里，我们使用一种新的恐惧记忆更新范式研究了这种机制在将情境恐惧记忆转移到其他情境中的参与。在短暂重新暴露于先前恐惧条件化的环境后，雄性大鼠（每组 8-10 只）被置于中性环境中，以评估恐惧记忆的转移。我们还在记忆再激活之前将选择性 M1 受体拮抗剂哌仑西平注入背侧海马体，试图阻断这种效应。结果支持了这样的假设，即可以用新的情境信息更新恐惧记忆，但前提是大鼠在中性情境暴露前相对较近地重新暴露于最初训练的情境中；如果省略了恐惧记忆再激活，或者如果它发生在中性情境暴露前 6 小时，就不会出现转移的恐惧。转移的恐惧持续了 4 周，并且 M1 拮抗作用阻断了这种效果。这些发现强烈表明，恐惧转移需要原始恐惧记忆的再激活和不稳定性。因此，这里介绍的新的临床前模型及其对毒蕈碱受体在这个过程中的作用，可以为 PTSD 和类似情况的治疗策略提供信息。
