Inserm UMR S894, Centre de Psychiatrie et Neuroscience, Université Paris Descartes, Paris, France.
EA 4475, Pharmacologie de la Circulation Cérébrale, Faculté de Pharmacie, Université Paris Descartes, Paris, France.
Prog Mol Biol Transl Sci. 2018;158:159-193. doi: 10.1016/bs.pmbts.2018.03.002. Epub 2018 Jun 12.
This review examines the epigenetic of neurotrophin signaling in anxiety, affective disorders and related symptoms associated with drug addiction, in particular alcoholism. It is first important to understand the epigenetics of aversion memories, as they are so central to anxiety and affective disorders symptomology. The crucial role of neurotrophins in memory formation, in particular the brain-derived nerve growth factor (BDNF), is explored at the physiological and behavioral levels. Numerous studies describe how various epigenetic phenomena, mainly histone acetylation, histone methylation, DNA methylation, but also other less known epigenetic phenomena such as histone poly[ADP]-ribosylation and 5-HT2C receptor pre-mRNA editing, exert significant regulatory roles in aversion memory and fear extinction memory formation. Other models of anxiety and affective disorders, that use stress or transgenic constructs directed at elements of the stress axis or the serotonergic system, are then explored in relation with the epigenetic of neurotrophin signaling. Epigenetic marks differentially change according to brain areas. In the hippocampus for example, anxious or chronically stressed animals tend to show epigenetic changes that are at the opposite of those observed after memory consolidation following a brief aversive stimulus. Behaviorally relevant epigenetic changes have been found to be reversible by drug treatments. Surprisingly, moderate alcohol consumption may trigger, on the long term, changes of BDNF expression and of its epigenetic elements that are somehow similar to those produced by antidepressant drugs. However, alcohol withdrawal associated with anxiety symptoms has not yet been very well explored. Overall, it appears that a multidisciplinary view on the epigenetics of neurotrophin secretion might bring innovative treatments to psychiatric diseases involving stress and fear memories.
这篇综述探讨了神经营养因子信号转导的表观遗传学在焦虑、情感障碍和与药物成瘾相关的症状中的作用，特别是酒精成瘾。首先，了解厌恶记忆的表观遗传学非常重要，因为它们是焦虑和情感障碍症状学的核心。神经生长因子（BDNF）等神经营养因子在记忆形成中的关键作用在生理和行为水平上得到了探讨。许多研究描述了各种表观遗传现象，主要是组蛋白乙酰化、组蛋白甲基化、DNA 甲基化，但也包括其他不太知名的表观遗传现象，如组蛋白多聚[ADP]-核糖基化和 5-HT2C 受体前体 mRNA 编辑，如何在厌恶记忆和恐惧遗忘记忆形成中发挥重要的调节作用。然后，探讨了其他焦虑和情感障碍模型，这些模型使用应激或针对应激轴或 5-羟色胺能系统的转基因构建体，与神经营养因子信号转导的表观遗传学有关。表观遗传标记根据大脑区域的不同而发生变化。例如，在海马体中，焦虑或慢性应激的动物往往表现出与短暂厌恶刺激后记忆巩固时观察到的相反的表观遗传变化。行为相关的表观遗传变化可以通过药物治疗逆转。令人惊讶的是，长期适度饮酒可能会引发 BDNF 表达及其表观遗传元件的变化，这些变化在某种程度上类似于抗抑郁药物产生的变化。然而，与焦虑症状相关的酒精戒断尚未得到很好的研究。总的来说，对神经营养因子分泌的表观遗传学进行多学科研究可能会为涉及应激和恐惧记忆的精神疾病带来创新的治疗方法。
