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.

中文翻译：

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肌动蛋白细胞骨架的蛋氨酸氧化通过重新激活树突状脊柱形态发生来减弱创伤性记忆保留


创伤后应激障碍 （PTSD） 的特征是对创伤的记忆过多和持续的恐惧反应。保留创伤记忆的分子机制在很大程度上仍然未知，这阻碍了更有效治疗方法的开发。利用听觉恐惧条件反射，我们证明了基底外侧杏仁核 （BLA） 树突状脊柱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。暴露于恐惧诱导的事件显着增加了氧化丝状肌动蛋白 （F-肌动蛋白） 的减少，并降低了与 CasL 1 （MICAL1） 相互作用的分子的表达，CasL 1 是一种蛋氨酸氧化酶，可直接氧化和解聚 F-肌动蛋白，导致 BLA 中的细胞骨架动力学异常，从而损害树突状脊柱形态发生并导致恐惧记忆的持续存在。在恐惧条件反射之后，BLA 中 MICAL1 的过表达通过重新激活胞质分裂抑制恐惧记忆检索过程中的冻结行为，而甲硫氨酸亚砜还原酶 B 1（一种减少氧化 F-肌动蛋白单体的关键酶）的过表达增加了检索过程中的冻结行为。值得注意的是，BLA 内注射信号素 3A（MICAL1 的内源性激活剂）在条件反射后的短时间内迅速破坏了恐惧记忆。总的来说，我们的结果表明，BLA 中肌动蛋白细胞骨架的氧化还原调节在功能上与恐惧记忆保留和 PTSD 样记忆有关。