Epigenetic regulation of stress-induced glucocorticoid action in the dentate gyrus and its behavioural implications

齿状回应激诱导糖皮质激素作用的表观遗传调控及其行为意义

• 批准号: BB/T015551/1
• 负责人: Johannes Reul
• 金额: $ 74.2万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT015551%2F1
• 关键词: Epigenetic; regulation; stress; induced; glucocorticoid

Stress affects the lives of both humans and animals in our society. Psychological stress, like marital problems and bullying, is very debilitating for mental health and wellbeing in humans. Our farmed and companion animals can also suffer from psychological stress such as overcrowding, long-distance transportation and abuse. Successful coping with such stressful events involves adaptive and cognitive processes in the brain that make the individual more resilient to similar stressors in the future. Some events, certainly when uncontrollable and repeated, can be highly traumatic leading to psychosomatic and behavioural disturbances and psychiatric diseases (anxiety and depression). To help people to cope with stress in their lives, to develop directives to reduce stress and to improve wellbeing of our companion and farmed animals, we need to obtain better insight into how the brain responds to psychologically stressful events. Currently, however, we do not fully understand how the healthy brain generates physiological and behavioural responses to stressful events and adapts in the long-term to such events. Stressful events result in the secretion of 'stress hormones' or glucocorticoid (GC) hormones from the adrenal glands into the blood stream. Work of the PI over the past 35+ years has contributed greatly to the concept that these hormones act in the brain to coordinate physiological and behavioural responses to stress through binding to two different GC hormone-binding 'receptors'. These receptors, called MRs and GRs, are protein molecules located in nerve cells. As a result of a stressful challenge, GC hormone is secreted and binds to these receptors resulting in translocation to the cell nucleus. The hormone-receptor complex can then bind to certain genes within the DNA and regulate the expression of those genes. These genes are important to change the function of nerve cells in order to respond and adapt properly to the challenge i.e. elicit an appropriate behavioural response. Presently, however, it is unclear which receptor-bound genes are important in the adaptive responses to stress. Furthermore, accessibility of the DNA for MRs and GRs may be regulated by so-called epigenetic mechanisms as these involve changes in the structure and function of proteins to which the DNA is attached. Such epigenetic mechanisms are however still unresolved. We recently discovered a specific epigenetic 'mark' ('H3K9ac-S10p') that may play a role in controlling the binding of MR and GR to genes leading to changes in the expression of these genes. Interestingly, in previous research we found that this epigenetic mark is strongly linked with the learning of an adaptive behavioural response after a stressful challenge (forced swimming). Combined assessment of these observations has led us to the idea that the presence of the H3K9ac-S10p mark can distinguish MR- and GR-bound genes that are specifically involved in learning the adaptive behavioural response after stress. After identifying these genes in hippocampal neurons, we wish to select a few of the genes and test if suppression of their activity would impair the expression of behavioural adaptation to forced swim stress. This work is of fundamental importance to increase our understanding into how the brain adapts to stressful events and will help to develop novel approaches to alleviate the burden of stress-related disorders in humans and animals.

压力影响着我们社会中人类和动物的生活。心理压力，如婚姻问题和欺凌，对人类的心理健康和福祉非常不利。我们的养殖和伴侣动物也可能遭受心理压力，如过度拥挤，长途运输和虐待。成功应对这种压力事件涉及大脑中的适应和认知过程，使个体在未来对类似的压力源更具弹性。有些事件，当然是无法控制和反复发生的事件，可能造成严重创伤，导致身心和行为障碍以及精神疾病（焦虑和抑郁）。为了帮助人们科普生活中的压力，制定减轻压力的指令，改善我们的伴侣和养殖动物的健康状况，我们需要更好地了解大脑如何应对心理压力事件。然而，目前我们还不完全了解健康的大脑如何对压力事件产生生理和行为反应，并长期适应这些事件。应激事件导致肾上腺分泌“应激激素”或糖皮质激素（GC）进入血液。PI在过去35年多的工作极大地促进了这一概念，即这些激素在大脑中起作用，通过与两种不同的GC酶结合“受体”结合来协调对压力的生理和行为反应。这些受体，称为MR和GR，是位于神经细胞中的蛋白质分子。作为压力挑战的结果，GC激素被分泌并结合到这些受体，导致易位到细胞核。然后，受体复合物可以与DNA中的某些基因结合，并调节这些基因的表达。这些基因对于改变神经细胞的功能非常重要，以便适当地响应和适应挑战，即引起适当的行为反应。然而，目前还不清楚哪些受体结合基因在对压力的适应性反应中是重要的。此外，DNA对MR和GR的可接近性可能受到所谓的表观遗传机制的调节，因为这些机制涉及DNA所连接的蛋白质的结构和功能的变化。然而，这种表观遗传机制仍然没有得到解决。我们最近发现了一种特定的表观遗传“标记”（“H3 K9 ac-S10 p”），它可能在控制MR和GR与基因的结合中发挥作用，从而导致这些基因表达的变化。有趣的是，在之前的研究中，我们发现这种表观遗传标记与压力挑战（强迫游泳）后的适应性行为反应的学习密切相关。对这些观察结果的综合评估使我们产生了这样的想法，即H3 K9 ac-S10 p标记的存在可以区分MR和GR结合的基因，这些基因专门参与学习压力后的适应性行为反应。在海马神经元中识别出这些基因后，我们希望选择一些基因并测试抑制它们的活性是否会损害对强迫游泳应激的行为适应的表达。这项工作对于增加我们对大脑如何适应压力事件的理解具有根本重要性，并将有助于开发新的方法来减轻人类和动物的压力相关疾病的负担。