Department of Psychology, Yale University, New Haven, Connecticut, USA.
PLoS One. 2013;8(1):e54463. doi: 10.1371/journal.pone.0054463. Epub 2013 Jan 21.
The study of the cellular and molecular mechanisms underlying the consolidation and reconsolidation of traumatic fear memories has progressed rapidly in recent years, yet few compounds have emerged that are readily useful in a clinical setting for the treatment of anxiety disorders such as post-traumatic stress disorder (PTSD). Here, we use a combination of biochemical, behavioral, and neurophysiological methods to systematically investigate the ability of garcinol, a naturally-occurring histone acetyltransferase (HAT) inhibitor derived from the rind of the fruit of the Kokum tree (Garcina indica), to disrupt the consolidation and reconsolidation of Pavlovian fear conditioning, a widely studied rodent model of PTSD. We show that local infusion of garcinol into the rat lateral amygdala (LA) impairs the training and retrieval-related acetylation of histone H3 in the LA. Further, we show that either intra-LA or systemic administration of garcinol within a narrow window after either fear conditioning or fear memory retrieval significantly impairs the consolidation and reconsolidation of a Pavlovian fear memory and associated neural plasticity in the LA. Our findings suggest that a naturally-occurring compound derived from the diet that regulates chromatin function may be useful in the treatment of newly acquired or recently reactivated traumatic memories.
近年来，创伤性恐惧记忆的巩固和再巩固的细胞和分子机制研究进展迅速，但很少有化合物能够在临床环境中用于治疗焦虑症，如创伤后应激障碍（PTSD）。在这里，我们使用生化、行为和神经生理学方法的组合，系统地研究了 garcinol（一种天然存在的组蛋白乙酰转移酶（HAT）抑制剂，来源于 Kokum 树（Garcinia indica）的果皮），破坏条件性恐惧记忆的巩固和再巩固的能力，条件性恐惧记忆是 PTSD 的一种广泛研究的啮齿动物模型。我们发现，将 garcinol 局部注入大鼠外侧杏仁核（LA）会损害 LA 中组蛋白 H3 的与训练和检索相关的乙酰化。此外，我们还发现，无论是在恐惧条件反射还是恐惧记忆检索后狭窄的时间窗口内，将 garcinol 注入 LA 内部或全身给药，都会显著损害 LA 中条件性恐惧记忆的巩固和再巩固，以及相关的神经可塑性。我们的研究结果表明，一种来源于饮食的、调节染色质功能的天然化合物，可能对治疗新获得或最近重新激活的创伤性记忆有用。
