Histone deactylase inhibition combined with behavioral therapy enhances learning and memory following traumatic brain injury.
Histone deactylase inhibition combined with behavioral therapy enhances learning and memory following traumatic brain injury.
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组蛋白脱纤酶抑制结合行为疗法可增强脑外伤后的学习和记忆。
DOI：
10.1016/j.neuroscience.2009.06.028
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发表时间：
2009-09-29
期刊：
影响因子：
3.3
通讯作者：
Moore, A. N.
中科院分区：
文献类型：
--
作者：
Dash, P. K.;Orsi, S. A.;Moore, A. N.
创伤性脑损伤（TBI）会诱发许多病理事件，从神经元变性和组织损失到神经元可塑性受损和神经化学物质失调。在啮齿类动物中，将脑损伤动物暴露于丰富的环境中已被证明是增强损伤后学习和记忆的有效方法。最近，人们发现环境富集可以通过涉及增强组蛋白乙酰化的表观遗传变化来增强神经元可塑性，这种特性可以通过使用组蛋白去乙酰化酶（HDAC）抑制剂来模拟。因此，我们评估了 HDAC 抑制剂丁酸钠对脑损伤小鼠学习和记忆的影响。与之前使用小鼠神经退行性变模型的报告相反，在药物治疗范例完成后进行测试时，丁酸钠（每天 1.2g/kg，持续四个星期）并没有改善学习和记忆。此外，在所报告的神经退行性疾病期间（第 0-5 天）施用丁酸钠也没有带来任何益处。然而，当与莫里斯水迷宫任务训练（受伤后第 14 天开始）同时服用时，丁酸钠可以改善脑损伤小鼠的学习和记忆能力。有趣的是，当这些小鼠随后在联想恐惧调节任务中进行测试时，观察到了持续的改善。总而言之，我们的研究结果表明，HDAC 抑制可能模仿了丰富的环境暴露后所观察到的一些认知改善，并且当治疗与行为测试同时进行时，可以观察到这种改善。
Traumatic brain injury (TBI) induces a number of pathological events ranging from neuronal degeneration and tissue loss to impaired neuronal plasticity and neurochemical dysregulation. In rodents, exposure of brain injured animals to environmental enrichment has been shown to be an effective means of enhancing learning and memory post-injury. Recently, it has been discovered that environmental enrichment may enhance neuronal plasticity through epigenetic changes that involve enhanced histone acetylation, a property that can be mimicked by the use of histone deactylase (HDAC) inhibitors. We therefore evaluated the consequences of the HDAC inhibitor sodium butyrate on the learning and memory of brain injured mice. In contrast to a previous report using a mouse neurodegeneration model, sodium butyrate (1.2g/kg daily for four weeks) did not improve learning and memory when tested after the completion of the drug treatment paradigm. In addition, sodium butyrate administration during the reported period of neurodegeneration (days 0–5) also offered no benefit. However, when administered concurrently with training in the Morris water maze task (beginning on day 14 post-injury), sodium butyrate improved learning and memory in brain injured mice. Interestingly, when these mice were subsequently tested in an associative fear conditioning task, a continued improvement was observed. Taken together, our findings indicate that HDAC inhibition may mimic some of the cognitive improvements seen following enriched environment exposure, and that the improvement is observed when the treatment is carried out current with behavioral testing.
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