School of Psychology, University of New South Wales, Sydney, 2052 New South Wales, Australia.
School of Psychology, University of New South Wales, Sydney, 2052 New South Wales, Australia
J Neurosci. 2019 Sep 11;39(37):7357-7368. doi: 10.1523/JNEUROSCI.0768-19.2019. Epub 2019 Jul 24.
Consolidation of conditioned fear to a stimulus (S1) paired with shock requires protein synthesis in the basolateral amygdala complex (BLA), whereas consolidation of conditioned fear to a stimulus (S2) paired with the fear-eliciting S1 requires DNA methylation but not protein synthesis in the BLA. The present experiments merged these protocols by exposing rats to pairings of a serial S2-S1 compound and shock to examine if/when protein synthesis in the BLA is required to consolidate fear to S2. Rats received a BLA infusion of the protein synthesis inhibitor, cycloheximide, immediately after the S2-S1-shock session and were subsequently tested with S2. The infusion disrupted consolidation of fear to S2 when there had been no prior training of S1 (Experiment 1), the prior training had consisted of unpaired presentations of S1 and shock (Experiment 4), or in pairings of S1 and sucrose (Experiment 5). Consolidation of fear to S2 was unaffected by the infusion of cycloheximide but was disrupted by the DNA methyltransferase inhibitor, 5-AZA, when S1 had been previously fear-conditioned (Experiments 2a, 2b, and 3). These findings imply that what has already been learned about S1 determines the BLA processes that consolidate fear to S2. The already-fear-conditioned S1 blocks the S2-shock association that otherwise forms (and whose consolidation requires protein synthesis in the BLA) while simultaneously acting as a learned source of danger for its S2 associate (whose consolidation requires DNA methylation but not protein synthesis in the BLA). Protein synthesis is widely thought to be crucial for consolidating new learning into stable memories, including the consolidation of conditioned fear memories in the basolateral amygdala complex (BLA). However, our data provide clear evidence that the requirement for protein synthesis to consolidate conditioned fear in the BLA depends on an animal's previous training history, and the type of learning that is consolidated. Further, within the BLA, our data show that DNA methylation, and not protein synthesis, is necessary to consolidate higher-order conditioned fear, indicating that epigenetic mechanisms may provide a more fundamental mnemonic substrate.
条件性恐惧对刺激（S1）与电击的结合的巩固需要外侧杏仁核复合体（BLA）中的蛋白质合成，而条件性恐惧对与引发恐惧的 S1 配对的刺激（S2）的巩固需要 BLA 中的 DNA 甲基化而不是蛋白质合成。本实验通过使大鼠暴露于 S2-S1 复合刺激与电击的配对中，合并了这些方案，以检查 BLA 中的蛋白质合成是否需要将恐惧巩固到 S2。在 S2-S1-电击会议后立即给予大鼠 BLA 输注蛋白合成抑制剂环己酰亚胺，并随后用 S2 对其进行测试。当没有对 S1 进行先前训练时（实验 1），当先前的训练由 S1 和电击的非配对呈现组成时（实验 4），或者在 S1 和蔗糖的配对中（实验 5），该输注会破坏对 S2 的恐惧的巩固。环己酰亚胺的输注对 S2 的恐惧巩固没有影响，但当 S1 先前已被恐惧条件化时，DNA 甲基转移酶抑制剂 5-AZA 会破坏 S2 的恐惧巩固（实验 2a、2b 和 3）。这些发现意味着已经对 S1 所学的内容决定了巩固对 S2 的恐惧的 BLA 过程。已经被恐惧条件化的 S1 阻止了否则会形成的 S2-电击关联（其巩固需要 BLA 中的蛋白质合成），同时作为其 S2 关联的习得危险源（其巩固需要 BLA 中的 DNA 甲基化但不是蛋白质合成）。蛋白质合成被广泛认为对于将新学习巩固为稳定的记忆至关重要，包括外侧杏仁核复合体（BLA）中条件性恐惧记忆的巩固。然而，我们的数据提供了明确的证据，表明 BLA 中巩固条件性恐惧所需的蛋白质合成取决于动物的先前训练历史和要巩固的学习类型。此外，在 BLA 中，我们的数据表明 DNA 甲基化而不是蛋白质合成对于巩固高级条件性恐惧是必要的，这表明表观遗传机制可能提供了更基本的记忆基质。
