创伤后应激障碍的组蛋白修饰机制

doi:10.3724/SP.J.1042.2022.00098

摘要/Abstract

摘要：

创伤后应激障碍是一种具有复杂病因学的精神疾病, 多发生于个体受到重大创伤事件后。创伤后应激障碍的发生发展过程受到环境和遗传易感性的共同作用, 存在着较大的个体差异; 而表观遗传学作为一门研究多变环境因素调控基因表达的可遗传变化的学科, 近年来在创伤后应激障碍的研究中受到越来越多的重视。表观遗传机制之一——组蛋白修饰机制在创伤后应激障碍的发生中起着重要作用, 并且由于组蛋白修饰可以受到多种酶的调控, 其灵活的可逆化和精细调控为相应的药物研发提供了可能性和便利。因此, 深入探讨创伤后应激障碍的组蛋白修饰机制, 对于相关疾病的临床治疗及药物研发具有十分重要的意义。当前创伤后应激障碍的组蛋白修饰研究主要使用动物模型, 临床研究较少; 组蛋白的类型则主要关注组蛋白H3和H4乙酰化; 此外, 同以往的研究结果一致, 组蛋白修饰水平的变化主要发生在前额叶、海马体和杏仁核区域, 参与免疫系统、血清素系统和神经肽Y能系统等相关通路的调节。当前PTSD组蛋白修饰的研究结果间还存在较大的异质性, 未来的研究应采用更加一致和实用的分析和报道方法, 以最大限度地发挥研究的影响。

关键词: 创伤后应激障碍, 组蛋白修饰, PTSD啮齿动物模型, 药物研发

Abstract:

Post-traumatic stress disorder (PTSD) is a mental disorder with complex etiologies that usually occurs after people are exposed to traumatic events. In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the criteria for PTSD included symptoms of intrusion, avoidance, negative alterations in cognitions and mood, and alterations in arousal and reactivity. The World Mental Health Surveys on Trauma and PTSD showed that more than 70% of individuals would experience traumatic events at least once in lifetime, while only a few would develop PTSD, suggesting individual differences in the genesis and development of PTSD.
Previous studies have proved that both genetic and environmental factors could influence the risk of PTSD, thus epigenetics, as a discipline investigating the interaction between environment and genes, has attracted the attention of researchers. Among the epigenetic mechanisms, histone modification has received widespread attention and has been researched in depth. Modification of histones by adding one or more chemical groups (such as acetyl group, methyl group, etc.) can lead to changes in chromatin structure and gene transcriptional activity, consequently regulating the level of gene expression. In recent years, histone modification has been implicated as an essential part in the pathogenesis of PTSD for the following reason: the development of PTSD is usually related to the maladaptation of fear memory induced by traumatic events, and histone modification plays an important role in the consolidation and extinction of fear memory correspondingly.
At present, techniques commonly used for the measurement of histone modification are Western Blotting and chromatin immunoprecipitation (ChIP), both based on the antibody technology. By combining ChIP with quantitative PCR (qPCR) technology, DNA microarray (also known as gene chip) technology or deep sequencing (Seq) technology, researchers can study the relationship between various types of histone modification and gene expression. What’s more, animal models are the main methods to explore the association between histone modification and PTSD, using electric shocks (e.g., inescapable foot shock, tail shock, and tone shock), social stress (e.g., predator exposure), and single prolonged stress (SPS) to simulate symptoms of PTSD in the laboratory.
We systematically searched and screened the literatures of histone modification in PTSD through PubMed (http://www.ncbi.nlm.nih.gov/pubmed/), PsychINFO (http://psycnet.apa.org/), and PsychArticles (http://psycnet.apa.org/), with finally 16 literatures selected for detailed integration and discussion. In spite of the nonnegligible heterogeneity among these studies, they proved the overall effect of histone modification was closely associated with the development of PTSD. Histone modification that enriched in the promoter regions of candidate genes like the Bdnf and Cdk5, could significantly increase the risk of PTSD. Alterations in levels of histone acetylation and methylation in hippocampus, amygdala, and prefrontal cortex are associated with PTSD, playing key roles in the consolidation, reconsolidation, and extinction of fear memory in PTSD-like animals. It is worth noting that histone modification is mainly involved in the regulation of the immune system, the serotonergic system, the neuropeptide Y-ergic system, and the NMDA receptor-related pathways. In addition, histone modification can be regulated by a variety of enzymes, leading to flexible regulation of PTSD, making drugs that target histone modification good choices for clinical treatment of PTSD.
Studying the neurobiological mechanisms of PTSD in human patients has been blocked by many factors; moreover, applying the results of animal models of PTSD to clinical research is a long way off. Therefore, using animal models to investigate the role of histone modification in the etiology of PTSD will remain a mainstream approach for some time to come.

Key words: post-traumatic stress disorder, histone modification, rodent model of PTSD, drug development

中图分类号:

B845

张萦倩, 赵光义, 韩雨薇, 张静怡, 曹成琦, 王力, 张昆林. (2022). 创伤后应激障碍的组蛋白修饰机制. 心理科学进展 , 30(1), 98-114.

ZHANG Yingqian, ZHAO Guangyi, HAN Yuwei, ZHANG Jingyi, CAO Chengqi, WANG Li, ZHANG Kunlin. (2022). The mechanisms of histone modification in post-traumatic stress disorder. Advances in Psychological Science, 30(1), 98-114.

图/表 3

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被试		提取组织	创伤类型 (PTSD模型)	组蛋白修饰类型	测量技术	参考文献
大鼠	SD大鼠	海马体	SPS模型; 情景恐惧条件反射	组蛋白H3和H4乙酰化	ChIP-qPCR; 免疫印迹技术	(Takei et al., 2011)
	SD大鼠	外侧杏仁核	经典恐惧条件反射的巩固和再巩固	组蛋白H3乙酰化	免疫印迹技术	(Maddox, Watts, Doyere, & Schafe, 2013)
	SD大鼠	海马体	SPS模型; 情景恐惧条件反射的形成与消退	组蛋白H3和H4乙酰化	免疫印迹技术	(Matsumoto et al., 2013)
	SD大鼠	海马体, 杏仁核, 前额皮质	SPS模型	组蛋白H3和H4乙酰化	免疫印迹技术	(Solanki et al., 2015)
	SD大鼠	前额皮层质边缘下区, 前额皮质边缘前区; 基底杏仁核, 外侧杏仁核, 中央外侧杏仁核, 中央内侧杏仁核	经典恐惧条件反射的形成与消退	组蛋白H3和H4乙酰化	免疫组化	(Siddiqui et al., 2017)
	Wister 大鼠	海马体	SPS模型	组蛋白H3和H4乙酰化	ELISA	(Alzoubi et al., 2018)
	SD大鼠	前额皮质边缘前区, 前额皮层质边缘下区	恐惧条件反射的形成与消退(立刻消退/延迟消退)	组蛋白H3和H4乙酰化	免疫组化	(Singh et al., 2018)
	Wistar 大鼠	海马体	SPS模型	组蛋白H3和H4乙酰化	ELISA	(Alzoubi et al., 2019)
	SD大鼠	外侧杏仁核, 基底杏仁核, 中央外侧杏仁核, 中央内侧杏仁核; 前额皮质边缘前区和下区	经典恐惧条件反射的形成与消退	组蛋白H3和H4乙酰化	免疫组化	(Siddiqui et al., 2019)
	Wistar大鼠	海马体	SPS模型	组蛋白H3和H4乙酰化	ELISA	(Ahmed et al., 2020)
	Wistar 大鼠	海马体, 前额皮质	足底电击(IFS)	组蛋白H3二甲基化	免疫印迹技术; ChIP-qPCR	(Zhao et al., 2020)
小鼠	C57Bl6/J 小鼠	杏仁核	经典恐惧条件反射	组蛋白H3磷酸化; 组蛋白H3和H4乙酰化; 组蛋白H3二甲基化和三甲基化	免疫印迹技术	(Koshibu et al., 2011)
	印度小家鼠	杏仁核	天敌模型	组蛋白H3和H4乙酰化	免疫印迹技术	(Ragu Varman & Rajan, 2015)
	C57BL/6J 小鼠	海马体CA1区	情景恐惧条件反射	组蛋白H3乙酰化和甲基化	定量染色质免疫沉淀	(Sase et al., 2019)
	H2A.Z 敲除小鼠	海马体CA1区	单次电击情景恐惧条件反射; SEFL模型	组蛋白变体H2A.Z结合力增强; 条件性诱导敲除H2A.Z	ChIP; qPCR; 免疫印迹	(Ramzan et al., 2020)
人类	退伍军人	外周血单核细胞(PBMCs)	战争	组蛋白H3三甲基化	ChIP-seq	(Bam et al., 2016a)

被试		提取组织	创伤类型 (PTSD模型)	组蛋白修饰类型	测量技术	参考文献
大鼠	SD大鼠	海马体	SPS模型; 情景恐惧条件反射	组蛋白H3和H4乙酰化	ChIP-qPCR; 免疫印迹技术	(Takei et al., 2011)
	SD大鼠	外侧杏仁核	经典恐惧条件反射的巩固和再巩固	组蛋白H3乙酰化	免疫印迹技术	(Maddox, Watts, Doyere, & Schafe, 2013)
	SD大鼠	海马体	SPS模型; 情景恐惧条件反射的形成与消退	组蛋白H3和H4乙酰化	免疫印迹技术	(Matsumoto et al., 2013)
	SD大鼠	海马体, 杏仁核, 前额皮质	SPS模型	组蛋白H3和H4乙酰化	免疫印迹技术	(Solanki et al., 2015)
	SD大鼠	前额皮层质边缘下区, 前额皮质边缘前区; 基底杏仁核, 外侧杏仁核, 中央外侧杏仁核, 中央内侧杏仁核	经典恐惧条件反射的形成与消退	组蛋白H3和H4乙酰化	免疫组化	(Siddiqui et al., 2017)
	Wister 大鼠	海马体	SPS模型	组蛋白H3和H4乙酰化	ELISA	(Alzoubi et al., 2018)
	SD大鼠	前额皮质边缘前区, 前额皮层质边缘下区	恐惧条件反射的形成与消退(立刻消退/延迟消退)	组蛋白H3和H4乙酰化	免疫组化	(Singh et al., 2018)
	Wistar 大鼠	海马体	SPS模型	组蛋白H3和H4乙酰化	ELISA	(Alzoubi et al., 2019)
	SD大鼠	外侧杏仁核, 基底杏仁核, 中央外侧杏仁核, 中央内侧杏仁核; 前额皮质边缘前区和下区	经典恐惧条件反射的形成与消退	组蛋白H3和H4乙酰化	免疫组化	(Siddiqui et al., 2019)
	Wistar大鼠	海马体	SPS模型	组蛋白H3和H4乙酰化	ELISA	(Ahmed et al., 2020)
	Wistar 大鼠	海马体, 前额皮质	足底电击(IFS)	组蛋白H3二甲基化	免疫印迹技术; ChIP-qPCR	(Zhao et al., 2020)
小鼠	C57Bl6/J 小鼠	杏仁核	经典恐惧条件反射	组蛋白H3磷酸化; 组蛋白H3和H4乙酰化; 组蛋白H3二甲基化和三甲基化	免疫印迹技术	(Koshibu et al., 2011)
	印度小家鼠	杏仁核	天敌模型	组蛋白H3和H4乙酰化	免疫印迹技术	(Ragu Varman & Rajan, 2015)
	C57BL/6J 小鼠	海马体CA1区	情景恐惧条件反射	组蛋白H3乙酰化和甲基化	定量染色质免疫沉淀	(Sase et al., 2019)
	H2A.Z 敲除小鼠	海马体CA1区	单次电击情景恐惧条件反射; SEFL模型	组蛋白变体H2A.Z结合力增强; 条件性诱导敲除H2A.Z	ChIP; qPCR; 免疫印迹	(Ramzan et al., 2020)
人类	退伍军人	外周血单核细胞(PBMCs)	战争	组蛋白H3三甲基化	ChIP-seq	(Bam et al., 2016a)

被试	样本量	提取组织	创伤类型	表型	性别	结果	参考文献
SD大鼠	n = 7~15	海马体	SPS模型+情景恐惧条件反射	恐惧记忆巩固	雄	僵直反应显著增强; Bdnf启动子区(外显子I和IV)组蛋白H3和H4乙酰化水平↑; Bdnf (包括外显子I和IV)的总mRNA和蛋白质水平↑; TrkB蛋白水平↑	(Takei et al., 2011)
C57BL/6J小鼠	n = 8~10	海马体CA1区	情景恐惧条件反射	长时记忆提取能力	雄	雄鼠长时记忆提取能力强于雌鼠; 雄性特异性Cdk5的表观遗传激活; Cdk5启动子区 H3K9/14乙酰化水平↑; Bdnf 的IV外显启动子 H3K9/14乙酰化水平↑	(Sase et al., 2019)
					雌	Cdk5的靶向乙酰化仅降低雌鼠的长时记忆提取能力; Bdnf 的IV外显启动子 H3K9/14乙酰化水平↑; 磷酸化tau蛋白水平↑
人类	PTSD+: 17/PTSD-: 16	外周血单核细胞(PBMCs)	战争	PTSD	男/女	PTSD患者全表观基因组上组蛋白H3的K4, K9, K27和K36三甲基化水平变化显著; TBX-21和IFNG表达水平↑; TBX-21和IFNG基因区域H3K4三甲基化水平↑; IFNG转录起始点附近DNA甲基化水平↓; IL-12B转录本丰度↑; IL-12B启动子区H3K4三甲基化水平↑; IL-12B启动子区DNA甲基化水平↓; PTSD患者许多水平下降的miRNA靶向IFNG和IL-12	(Bam et al., 2016a)
Wistar 大鼠	N = 72/ n = 12	海马体, 前额皮质	足底电击(IFS)	焦虑样行为, 社交行为, 空间学习与记忆	雄	IFS诱发大鼠的PTSD样行为; IFS诱发大鼠神经元树突分支减少和长度缩短; H3K9二甲基化水平↑; Bdnf启动子区结合的H3K9二甲基化水平↑; BDNF mRNA和蛋白质表达量↓; 所有变化均可持续到成年期, Unc0642能缓解大部分症状	(Zhao et al., 2020)
H2A.Z 敲除小鼠	n = 6~16	海马体CA1区	单次电击情景恐惧条件反射; SEFL模型	恐惧记忆, 非压力性记忆, 痛觉敏感性	雄	H2A.Z敲除诱发雄鼠恐惧记忆习得↑; H2A.Z抑制非压力性记忆(与性别无关);	(Ramzan et al., 2020)
					雌	雌鼠B2m、Fkbp5和Th结合H2A.Z能力强于雄鼠; H2A.Z敲除雌鼠 Fos、Arc、Gadd45b、Fkbp5和Th (趋势)结合 H2A.Z能力弱于控制组雌鼠; H2A.Z抑制非压力性记忆(与性别无关); H2A.Z敲除降低雌鼠的恐惧记忆习得和疼痛反应

被试	样本量	提取组织	创伤类型	表型	性别	结果	参考文献
SD大鼠	n = 7~15	海马体	SPS模型+情景恐惧条件反射	恐惧记忆巩固	雄	僵直反应显著增强; Bdnf启动子区(外显子I和IV)组蛋白H3和H4乙酰化水平↑; Bdnf (包括外显子I和IV)的总mRNA和蛋白质水平↑; TrkB蛋白水平↑	(Takei et al., 2011)
C57BL/6J小鼠	n = 8~10	海马体CA1区	情景恐惧条件反射	长时记忆提取能力	雄	雄鼠长时记忆提取能力强于雌鼠; 雄性特异性Cdk5的表观遗传激活; Cdk5启动子区 H3K9/14乙酰化水平↑; Bdnf 的IV外显启动子 H3K9/14乙酰化水平↑	(Sase et al., 2019)
					雌	Cdk5的靶向乙酰化仅降低雌鼠的长时记忆提取能力; Bdnf 的IV外显启动子 H3K9/14乙酰化水平↑; 磷酸化tau蛋白水平↑
人类	PTSD+: 17/PTSD-: 16	外周血单核细胞(PBMCs)	战争	PTSD	男/女	PTSD患者全表观基因组上组蛋白H3的K4, K9, K27和K36三甲基化水平变化显著; TBX-21和IFNG表达水平↑; TBX-21和IFNG基因区域H3K4三甲基化水平↑; IFNG转录起始点附近DNA甲基化水平↓; IL-12B转录本丰度↑; IL-12B启动子区H3K4三甲基化水平↑; IL-12B启动子区DNA甲基化水平↓; PTSD患者许多水平下降的miRNA靶向IFNG和IL-12	(Bam et al., 2016a)
Wistar 大鼠	N = 72/ n = 12	海马体, 前额皮质	足底电击(IFS)	焦虑样行为, 社交行为, 空间学习与记忆	雄	IFS诱发大鼠的PTSD样行为; IFS诱发大鼠神经元树突分支减少和长度缩短; H3K9二甲基化水平↑; Bdnf启动子区结合的H3K9二甲基化水平↑; BDNF mRNA和蛋白质表达量↓; 所有变化均可持续到成年期, Unc0642能缓解大部分症状	(Zhao et al., 2020)
H2A.Z 敲除小鼠	n = 6~16	海马体CA1区	单次电击情景恐惧条件反射; SEFL模型	恐惧记忆, 非压力性记忆, 痛觉敏感性	雄	H2A.Z敲除诱发雄鼠恐惧记忆习得↑; H2A.Z抑制非压力性记忆(与性别无关);	(Ramzan et al., 2020)
					雌	雌鼠B2m、Fkbp5和Th结合H2A.Z能力强于雄鼠; H2A.Z敲除雌鼠 Fos、Arc、Gadd45b、Fkbp5和Th (趋势)结合 H2A.Z能力弱于控制组雌鼠; H2A.Z抑制非压力性记忆(与性别无关); H2A.Z敲除降低雌鼠的恐惧记忆习得和疼痛反应

被试	样本量	提取组织	创伤类型	表型	性别	结果	参考文献
SD大鼠	n = 5~9	杏仁核外侧核	经典恐惧条件反射的巩固和再巩固	恐惧记忆巩固和再巩固	雄	在恐惧记忆形成或提取阶段后不久注射garcinol, 会损害恐惧记忆巩固和再巩固及其相关的神经可塑性; 局部注射garcinol到杏仁核会损害恐惧记忆形成和提取相关的组蛋白H3乙酰化	(Maddox, Watts, Doyere, & Schafe, 2013)
SD大鼠	n = 6~10	海马体	SPS模型+情景恐惧条件反射的形成与消退	恐惧消退	雄	伏立诺他增强SPS大鼠恐惧记忆消退能力; 伏立诺他使海马体中NR2B、CaMKII α和β蛋白水平↑; 伏立诺他使组蛋白H3和H4乙酰化水平↑	(Matsumoto et al., 2013)
SD大鼠	n = 4~10	海马体, 杏仁核, 前额皮质	SPS模型	焦虑和抑郁样行为, 短时和长时记忆	雄	葡萄粉(GP)预防SPS模型诱导的行为和记忆损伤现象; 葡萄粉抑制SPS模型诱导的血浆皮质酮水平的上升; SPS大鼠而非GP-SPS大鼠杏仁核中BDNF水平↓; 葡萄粉促使SPS大鼠海马体和杏仁核中组蛋白H3乙酰化和HDAC5表达水平↑	(Solanki et al., 2015)
SD大鼠	n = 8~12	前额皮质边缘下区, 前额皮质边缘前区; 基底杏仁核, 外侧杏仁核, 中央外侧杏仁核, 中央内侧杏仁核	恐惧条件反射的形成与消退	恐惧记忆习得, 恐惧记忆消退	雄	恐惧记忆形成和消退阶段前额皮质和杏仁核亚核中c-fos和CBP蛋白水平及组蛋白H3和H4乙酰化水平改变	(Siddiqui et al., 2017)
Wister 大鼠	n = 12~15	海马体	SPS模型	短时和长时记忆	雄	己酮可可碱预防SPS模型中PTSD样行为诱发的短时和长时记忆损伤; 己酮可可碱使SPS诱发下降的GSH/GSSG比率、过氧化氢酶、谷胱甘肽过氧化物酶(GPx)、BDNF和组蛋白H3乙酰化水平恢复正常	(Alzoubi et al., 2018)
SD大鼠	N = 80~100/n = 20~24	前额皮质边缘下区, 前额皮质边缘前区	恐惧条件反射的形成与消退(立刻消退/延迟消退)	立刻消退或延迟消退	NA	立刻消退组较延迟消退组表现出更低的从边缘下区到边缘前区的神经回路电信号水平; 立刻消退组较延迟消退组表现出边缘下区更低的c-fos和CBP蛋白、组蛋白H3/H4乙酰化水平	(Singh et al., 2018)
Wistar 大鼠	N = 84/ n = 18~24	海马体	SPS模型	记忆损伤, 焦虑和抑郁	雄	依他唑酯治疗阻止PTSD相关氧化应激生物标志物(GSH、GSSG、GPx、TBARS)、BDNF和组蛋白H3乙酰化水平的上升	(Alzoubi et al., 2019)
SD大鼠	N=80~96/n =10~12	基底杏仁核, 外侧杏仁核, 中央外侧杏仁核, 中央内侧杏仁核; 前额皮质边缘下区, 前额皮质边缘前区	恐惧条件反射的形成与消退	恐惧记忆习得, 恐惧记忆消退	雄	恐惧记忆形成和消退阶段前额皮质和杏仁核亚核中c-fos蛋白、HDAC1/HDAC2及组蛋白H3和H4乙酰化水平改变	(Siddiqui et al., 2019)
被试	样本量	提取组织	创伤类型	表型	性别	结果	参考文献
Wistar 大鼠	n = 12	海马体	SPS模型	短时和长时记忆损伤	雄	维生素E预防SPS模型诱导的记忆损伤; 维生素E阻止SPS诱导的氧化应激生物标志物、组蛋白H3乙酰化和BDNF水平的下降	(Ahmed et al., 2020)
C57Bl6/J小鼠	n = 3~14	杏仁核	恐惧条件反射的形成	情景记忆和高音调恐惧的长时记忆	雄	核抑制蛋白磷酸酶1(PP1)促进情景记忆可高音调恐惧相关的长时记忆形成, 促进转录相关的长时程增强; 蛋白磷酸酶1抑制使组蛋白H3上丝氨酸S10磷酸化、H3K14和H4K5乙酰化、H3K36三甲基化、CREB水平↑, 使NFκB水平↓	(Koshibu et al., 2011)
印度小家鼠	N = 102/ n = 6~22	杏仁核	天敌模型	本能恐惧反应, 焦虑样行为	雄	丰富条件下小鼠表现出更少的恐惧反应和焦虑样行为丰富条件下小鼠暴露在天敌面前后, 5-HT、SERT、5-HT_1A、CaMKII/CREB、组蛋白H3和H4乙酰化水平↑, 5-HT_2C、HDAC1、HDAC2水平↓; 丰富条件下小鼠暴露在天敌面前后, BDNF转录水平、NPY及其受体Y1表达水平↑, NPY的Y2受体表达水平↓	(Ragu Varman & Rajan, 2015)