Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, 430030, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Hubei Shizhen Laboratory, Wuhan, Hubei, 430030, China.
Redox Biol. 2024 Nov;77:103391. doi: 10.1016/j.redox.2024.103391. Epub 2024 Oct 9.
Post-traumatic stress disorder (PTSD) is characterized by hypermnesia of the trauma and a persistent fear response. The molecular mechanisms underlying the retention of traumatic memories remain largely unknown, which hinders the development of more effective treatments. Utilizing auditory fear conditioning, we demonstrate that a redox-dependent dynamic pathway for dendritic spine morphogenesis in the basolateral amygdala (BLA) is crucial for traumatic memory retention. Exposure to a fear-induced event markedly increased the reduction of oxidized filamentous actin (F-actin) and decreased the expression of the molecule interacting with CasL 1 (MICAL1), a methionine-oxidizing enzyme that directly oxidizes and depolymerizes F-actin, leading to cytoskeletal dynamic abnormalities in the BLA, which impairs dendritic spine morphogenesis and contributes to the persistence of fearful memories. Following fear conditioning, overexpression of MICAL1 in the BLA inhibited freezing behavior during fear memory retrieval via reactivating cytokinesis, whereas overexpression of methionine sulfoxide reductase B 1, a key enzyme that reduces oxidized F-actin monomer, increased freezing behavior during retrieval. Notably, intra-BLA injection of semaphorin 3A, an endogenous activator of MICAL1, rapidly disrupted fear memory within a short time window after conditioning. Collectively, our results indicate that redox modulation of actin cytoskeleton in the BLA is functionally linked to fear memory retention and PTSD-like memory.
创伤后应激障碍（PTSD）的特征是对创伤的过度记忆和持续的恐惧反应。创伤性记忆保留的分子机制在很大程度上尚不清楚，这阻碍了更有效治疗方法的发展。利用听觉恐惧条件反射，我们证明了外侧杏仁核（BLA）中树突棘形态发生的氧化还原依赖性动态途径对于创伤性记忆保留至关重要。暴露于引起恐惧的事件会明显增加氧化丝状肌动蛋白（F-actin）的减少和分子相互作用与 CasL 1（MICAL1）的表达降低，MICAL1 是一种甲硫氨酸氧化酶，可直接氧化和解聚 F-actin，导致 BLA 中的细胞骨架动态异常，从而损害树突棘形态发生，并有助于恐惧记忆的持续存在。在恐惧条件反射后，BLA 中的 MICAL1 过表达通过重新激活胞质分裂抑制了恐惧记忆检索期间的冻结行为，而甲硫氨酸亚砜还原酶 B1 的过表达，一种还原氧化 F-actin 单体的关键酶，增加了检索期间的冻结行为。值得注意的是，内侧杏仁核内注射 semaphorin 3A，一种 MICAL1 的内源性激活剂，可在条件反射后的短时间窗口内迅速破坏恐惧记忆。总的来说，我们的研究结果表明，BLA 中肌动蛋白细胞骨架的氧化还原调节与恐惧记忆保留和 PTSD 样记忆有关。
