Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China.
Department of Cell Biology, Shandong Provincial Key Laboratory of Mental Disorders, School of Basic Medicine, Shandong University, Jinan, Shandong 250012, China.
Behav Brain Res. 2023 May 8;445:114378. doi: 10.1016/j.bbr.2023.114378. Epub 2023 Mar 2.
The Wnt signaling pathway plays a critical role in activity-dependent plasticity processes such as long-term potentiation, learning and memory. However, the role of the Wnt signaling pathway in adult extinction is still not well understood. In this study, we aimed to investigate the roles and mechanisms of the canonical Wnt/β-catenin signaling pathway in the extinction of auditory fear conditioning (AFC) in adult mice. We found that AFC extinction training induced a significant decrease in p-GSK3β and nuclear β-catenin in the medial prefrontal cortex (mPFC). Micro-infusion of the canonical Wnt inhibitor Dkk1 into the mPFC before AFC extinction training facilitated AFC extinction, suggesting that the Wnt/β-catenin pathway is involved in AFC extinction. To determine how Dkk1 affects canonical Wnt/β-catenin signaling in AFC extinction, the protein levels of p-GSK3β and β-catenin were measured. We found that DKK1 produces a decrease in p-GSK3β and β-catenin. Moreover, we found that upregulating the Wnt/β-catenin pathway using LiCl (2 µg/side) impaired AFC extinction. These findings may help us understand the role of canonical Wnt signaling pathway in memory extinction and suggest that appropriate manipulating the Wnt/β-catenin signaling pathway might be a suitable way of therapeutically treating psychiatric disorders.
Wnt 信号通路在活动依赖性可塑性过程中发挥着关键作用，如长时程增强、学习和记忆。然而，Wnt 信号通路在成年消退中的作用仍不清楚。在这项研究中，我们旨在研究经典 Wnt/β-连环蛋白信号通路在成年小鼠听觉恐惧条件反射（AFC）消退中的作用和机制。我们发现，AFC 消退训练诱导内侧前额叶皮层（mPFC）中 p-GSK3β 和核 β-连环蛋白的显著减少。在 AFC 消退训练前将经典 Wnt 抑制剂 Dkk1 微注入 mPFC 可促进 AFC 消退，表明 Wnt/β-连环蛋白途径参与 AFC 消退。为了确定 Dkk1 如何影响 AFC 消退中的经典 Wnt/β-连环蛋白信号，测量了 p-GSK3β 和 β-连环蛋白的蛋白水平。我们发现 DKK1 降低了 p-GSK3β 和 β-连环蛋白。此外，我们发现使用 LiCl（2 µg/侧）上调 Wnt/β-连环蛋白途径会损害 AFC 消退。这些发现可能有助于我们理解经典 Wnt 信号通路在记忆消退中的作用，并表明适当操纵 Wnt/β-连环蛋白信号通路可能是治疗精神障碍的一种合适方法。
