Neurological mechanism and therapeutic strategy for posttraumatic stress disorders
Neurological mechanism and therapeutic strategy for posttraumatic stress disorders
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DOI：
10.1254/fpj.152.194
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发表时间：
2018-10-01
影响因子：
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通讯作者：
Matsuo, Kazuya
中科院分区：
文献类型：
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作者：
Fukunaga, Kohji;Yabuki, Yasushi;Matsuo, Kazuya
创伤后应激障碍（PTSD）最常由创伤事件和严重的公共卫生问题引起。 PTSD 的特点是对情境记忆的过度反应和恐惧消退受损，还与轻度认知障碍、注意力和学习缺陷有关。临床和动物研究表明，与情绪和恐惧相关的神经元回路（包括杏仁核、前额叶皮层和海马体）的敏感性增加，有助于 PTSD 症状的发展和持续。然而，这种对恐惧的敏感性的机制尚不清楚，有效的治疗方法也很有限。最近有报道称，补充omega 3 LCPUFA可以预防PTSD的发展，并显着改善车祸和自然灾害等意外伤害后PTSD患者的症状。重要的是，Fabp7 缺失小鼠表现出恐惧记忆巩固和焦虑相关行为的增强，类似于人类的 PTSD 样行为。在这篇综述中，我们重点关注 Fabp3(-/-) 缺失小鼠的 PTSD 行为表型。 Fabp3(-/-) 缺失小鼠表现出认知缺陷、运动过度和恐惧消退受损，从而表现出类似 PTSD 的行为。长期服用雷美替胺（一种褪黑激素受体激动剂）可改善 Fabp3(-/-) 小鼠测试的所有 PTSD 样行为。与恐惧消退受损的机制相关，我们观察到 Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII) 在基底外侧杏仁核 (BLA) 中自磷酸化增加，但在 Fabp3(-/-) 小鼠的海马中保持不变。同样，暴露于情境恐惧条件后，BLA 中 c-Fos 阳性神经元的数量显着增加。最后，长期给予雷美替胺可恢复 Fabp3(-/-) 小鼠 BLA 中异常的 c-Fos 表达和 CaMKII 自磷酸化。总而言之，Fabp3(-/-) 小鼠表现出类似 PTSD 的行为，而雷美替胺是人类 PTSD 治疗的一个有吸引力的候选者。
Posttraumatic stress disorder (PTSD) is most often induced by traumatic events and serious public health problems. PTSD is characterized by excessive response to contextual memory and impaired fear extinction and also associated with mild cognitive impairment, attention and learning deficits. Clinical and animal studies suggest that increased susceptibility of emotion- and fear-related neuronal circuits, including those in the amygdala, prefrontal cortex and hippocampus, contributes to development and retention of PTSD symptoms. However, mechanisms underlying this susceptibility to fear are not known and the useful therapeutic approaches are limited. Recently, there have been reports that omega 3 LCPUFA supplementation can prevent development of PTSD and significantly ameliorate symptoms in patients with PTSD after accidental injury such as motor vehicle accidents and natural calamities. Importantly, Fabp7 null mice exhibit enhancement of fear memory consolidation and anxiety-related behaviors that resemble PTSD-like behaviors in humans. In this review, we focused behavioral phenotype of PTSD in Fabp3(-/-) null mice. The Fabp3(-/-) null mice exhibit cognitive deficits, hyperlocomotion and impaired fear extinction, and thus show PTSD-like behaviors. Chronic administration of ramelteon, a melatonin receptor agonist, improved all PTSD-like behaviors tested in Fabp3(-/-) mice. Relevant to mechanisms underlying impaired fear extinction, we observed that Ca2+/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation increases in the basolateral amygdala (BLA) but remained unchanges in the hippocampus of Fabp3(-/-) mice. Likewise, the number of c-Fos positive neurons in BLA significantly increased after exposure to contextual fear conditions. Finally, chronic ramelteon administration restored abnormal c-Fos expression and CaMKII autophosphorylation in the BLA of Fabp3(-/-) mice. Taken together, Fabp3(-/-) mice show PTSD-like behaviors, and ramelteon is an attractive candidate for PTSD therapeutics in human.