p300/CBP-associated factor selectively regulates the extinction of conditioned fear.
p300/CBP-associated factor selectively regulates the extinction of conditioned fear.
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p300/CBP 相关因子选择性调节条件性恐惧的消失。
DOI：
10.1523/jneurosci.0178-12.2012
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发表时间：
2012-08-29
期刊：
影响因子：
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通讯作者：
Bredy TW
中科院分区：
文献类型：
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作者：
Wei W;Coelho CM;Li X;Marek R;Yan S;Anderson S;Meyers D;Mukherjee C;Sbardella G;Castellano S;Milite C;Rotili D;Mai A;Cole PA;Sah P;Kobor MS;Bredy TW
众所周知，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性记忆的形成知之甚少，特别是当相反的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发生的竞争。在这里，我们在 C57/Bl6 小鼠中证明，边缘下前额皮质内的 p300/CBP 相关因子 (PCAF) 的活性是长期增强所必需的，并且是与恐惧消退相关的记忆形成所必需的，但对于恐惧获得而言却不是必需的。此外，PCAF 激活剂 SPV106 的全身给药可增强恐惧消退的记忆并防止恐惧复发。 PCAF 对恐惧消退的选择性影响部分是通过将抑制性转录因子 ATF4 瞬时募集到立即早期基因 zif268 的启动子来介导的，从而竞争性抑制其表达。因此，在恐惧消退的背景下，PCAF充当转录共激活剂，它可能通过干扰原始记忆痕迹的重新巩固来促进恐惧消退记忆的形成。
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 C57/Bl6 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 co-activator, which may facilitate the formation of memory for fear extinction by interfering with reconsolidation of the original memory trace.