Laboratorio de Neurobiología de la Memoria, Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Instituto de Fisiología, Biología Molecular y Neurociencias, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Universitaria, 1428 EHA Buenos Aires, Argentina.
J Neurosci. 2011 Apr 13;31(15):5562-73. doi: 10.1523/JNEUROSCI.6066-10.2011.
In fear conditioning, aversive stimuli are readily associated with contextual features. A brief reexposure to the training context causes fear memory reconsolidation, whereas a prolonged reexposure induces memory extinction. The regulation of hippocampal gene expression plays a key role in contextual memory consolidation and reconsolidation. However, the mechanisms that determine whether memory will reconsolidate or extinguish are not known. Here, we demonstrate opposing roles for two evolutionarily related transcription factors in the mouse hippocampus. We found that nuclear factor-κB (NF-κB) is required for fear memory reconsolidation. Conversely, calcineurin phosphatase inhibited NF-κB and induced nuclear factor of activated T-cells (NFAT) nuclear translocation in the transition between reconsolidation and extinction. Accordingly, the hippocampal inhibition of both calcineurin and NFAT independently impaired memory extinction, whereas inhibition of NF-κB enhanced memory extinction. These findings represent the first insight into the molecular mechanisms that determine memory reprocessing after retrieval, supporting a transcriptional switch that directs memory toward reconsolidation or extinction. The precise molecular characterization of postretrieval processes has potential importance to the development of therapeutic strategies for fear memory disorders.
在恐惧条件反射中，厌恶刺激很容易与情境特征相关联。短暂地重新暴露于训练情境会引起恐惧记忆的再巩固，而长时间的重新暴露则会诱导记忆的消退。海马体基因表达的调控在情境记忆的巩固和再巩固中起着关键作用。然而，决定记忆是会再巩固还是会消退的机制尚不清楚。在这里，我们证明了两种在小鼠海马体中进化上相关的转录因子的相反作用。我们发现，核因子-κB（NF-κB）是恐惧记忆再巩固所必需的。相反，钙调神经磷酸酶抑制 NF-κB 并在再巩固和消退之间诱导活化 T 细胞核因子（NFAT）的核易位。因此，海马体中钙调神经磷酸酶和 NFAT 的双重抑制独立地损害了记忆的消退，而 NF-κB 的抑制则增强了记忆的消退。这些发现代表了对决定检索后记忆再加工的分子机制的首次深入了解，支持了一种转录开关，该开关将记忆引导向再巩固或消退。对检索后过程的精确分子特征描述对于开发恐惧记忆障碍的治疗策略具有潜在的重要性。
