Laboratory of Cognition and Memory Neurobiology, Brain Institute, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690 - Bldg. 63, 3rd floor, 90610-000 Porto Alegre, RS, Brazil.
Psychobiology and Neurocomputation Laboratory (LPBNC), Department of Biophysics, Institute of Biosciences, Federal University of Rio Grande do Sul (UFRGS), Av. Bento Gonçalves, 9500, Bldg. 43422, room 208A, 91501-970 Porto Alegre, RS, Brazil.
Neuroscience. 2023 Aug 1;524:108-119. doi: 10.1016/j.neuroscience.2023.05.028. Epub 2023 Jun 5.
Memories already consolidated when reactivated return to a labile state and can be modified, this process is known as reconsolidation. It is known the Wnt signaling pathways can modulate hippocampal synaptic plasticity as well as learning and memory. Yet, Wnt signaling pathways interact with NMDA (N-methyl-D-aspartate) receptors. However, whether canonical Wnt/β-catenin and non-canonical Wnt/Ca2 + signaling pathways are required in the CA1 region of hippocampus for contextual fear memory reconsolidation remains unclear. So, here we verified that the inhibition of canonical Wnt/β-catenin pathway with DKK1 (Dickkopf-1) into CA1 impaired the reconsolidation of contextual fear conditioning (CFC) memory when administered immediately and 2 h after reactivation session but not 6 h later, while the inhibition of non-canonical Wnt/Ca signaling pathway with SFRP1 (Secreted frizzled-related protein-1) into CA1 immediately after reactivation session had no effect. Moreover, the impairment induced by DKK1 was blocked by the administration of the agonist of the NMDA receptors glycine site, D-Serine, immediately and 2 h after reactivation session. We found that hippocampal canonical Wnt/β-catenin is necessary to the reconsolidation of CFC memory at least two hours after reactivation, while non-canonical Wnt/Ca signaling pathway is not involved in this process and, that there is a link between Wnt/β-catenin signaling pathway and NMDA receptors. In view of this, this study provides new evidence regarding the neural mechanisms underlying contextual fear memory reconsolidation and contributes to provide a new possible target for the treatment of fear related disorders.
当被重新激活时，已经巩固的记忆会回到不稳定状态并可以被修改，这个过程被称为再巩固。已知 Wnt 信号通路可以调节海马突触可塑性以及学习和记忆。然而，Wnt 信号通路与 NMDA（N-甲基-D-天冬氨酸）受体相互作用。然而，经典 Wnt/β-连环蛋白和非经典 Wnt/Ca2+信号通路是否需要在海马 CA1 区参与情境性恐惧记忆再巩固仍不清楚。因此，在这里我们验证了在再激活后立即和 2 小时内将 DKK1（Dickkopf-1）抑制到 CA1 中会损害情境性恐惧条件反射（CFC）记忆的再巩固，但在 6 小时后则不会，而在再激活后立即将 SFRP1（Secreted frizzled-related protein-1）抑制到 CA1 中非经典 Wnt/Ca 信号通路则没有影响。此外，在再激活后立即和 2 小时内给予 NMDA 受体甘氨酸位点激动剂 D-丝氨酸可以阻断 DKK1 引起的损伤。我们发现，海马体中的经典 Wnt/β-连环蛋白至少在再激活后两小时内对 CFC 记忆的再巩固是必要的，而非经典 Wnt/Ca 信号通路不参与这个过程，并且 Wnt/β-连环蛋白信号通路和 NMDA 受体之间存在联系。鉴于此，这项研究为情境性恐惧记忆再巩固的神经机制提供了新的证据，并为治疗与恐惧相关的疾病提供了一个新的可能靶点。
