Queensland Brain Institute, The University of Queensland, Brisbane, Australia 4072.
J Neurosci. 2012 Aug 29;32(35):11930-41. doi: 10.1523/JNEUROSCI.0178-12.2012.
It is well established that the activity of chromatin-modifying enzymes is crucial for regulating gene expression associated with hippocampal-dependent memories. However, very little is known about how these epigenetic mechanisms influence the formation of cortically dependent memory, particularly when there is competition between opposing memory traces, such as that which occurs during the acquisition and extinction of conditioned fear. Here we demonstrate, in C57BL/6 mice, that the activity of p300/CBP-associated factor (PCAF) within the infralimbic prefrontal cortex is required for long-term potentiation and is necessary for the formation of memory associated with fear extinction, but not for fear acquisition. Further, systemic administration of the PCAF activator SPV106 enhances memory for fear extinction and prevents fear renewal. The selective influence of PCAF on fear extinction is mediated, in part, by a transient recruitment of the repressive transcription factor ATF4 to the promoter of the immediate early gene zif268, which competitively inhibits its expression. Thus, within the context of fear extinction, PCAF functions as a transcriptional coactivator, which may facilitate the formation of memory for fear extinction by interfering with reconsolidation of the original memory trace.
已有充分证据表明，染色质修饰酶的活性对于调节与海马依赖性记忆相关的基因表达至关重要。然而，人们对这些表观遗传机制如何影响皮质依赖记忆的形成知之甚少，特别是在对立记忆痕迹之间存在竞争时，例如在条件性恐惧的获得和消退过程中。在这里，我们在 C57BL/6 小鼠中证明，在额下前扣带皮层中 p300/CBP 相关因子 (PCAF) 的活性对于长时程增强以及与恐惧消退相关的记忆形成是必需的，但对于恐惧获得则不是必需的。此外，全身性给予 PCAF 激活剂 SPV106 可增强对恐惧消退的记忆，并防止恐惧重现。PCAF 对恐惧消退的选择性影响部分是通过瞬时募集抑制其表达的即时早期基因 zif268 启动子的抑制性转录因子 ATF4 介导的，从而竞争抑制其表达。因此，在恐惧消退的背景下，PCAF 作为转录共激活因子发挥作用，通过干扰原始记忆痕迹的再巩固，可能有助于恐惧消退记忆的形成。
