ISSN 1671-3710
CN 11-4766/R
主办:中国科学院心理研究所
出版:科学出版社

心理科学进展 ›› 2022, Vol. 30 ›› Issue (1): 98-114.doi: 10.3724/SP.J.1042.2022.00098

• 研究前沿 • 上一篇    下一篇

创伤后应激障碍的组蛋白修饰机制

张萦倩, 赵光义, 韩雨薇, 张静怡, 曹成琦, 王力, 张昆林()   

  1. 中国科学院心理研究所心理健康重点实验室, 北京 100101
    中国科学院大学心理学系, 北京 100049
  • 收稿日期:2020-11-17 出版日期:2022-01-15 发布日期:2021-11-25

The mechanisms of histone modification in post-traumatic stress disorder

ZHANG Yingqian, ZHAO Guangyi, HAN Yuwei, ZHANG Jingyi, CAO Chengqi, WANG Li, ZHANG Kunlin()   

  1. CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China
    Department of Psychology, University of Chinese Academy of Sciences, Beijing 100049, China
  • Received:2020-11-17 Online:2022-01-15 Published:2021-11-25

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

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