Role of corticosteroid receptor DNA binding in stress-induced hippocampal gene transcription in relation to glucocorticoid and behavioural responses

皮质类固醇受体 DNA 结合在应激诱导的海马基因转录中与糖皮质激素和行为反应相关的作用

• 批准号: BB/N015045/1
• 负责人: Johannes Reul
• 金额: $ 57.23万
• 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: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN015045%2F1
• 关键词: Role; corticosteroid; receptor; DNA; binding

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. For many years it is known that 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 has been instrumental to the development of 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 thought to be important to change the function of nerve cells in order to respond and adapt properly to the challenge. Presently, however, it is unclear how these receptors bind to the genes. It has been assumed for decades that MR and GR binding to genes is proportional to the receptor's occupancy level by hormone; our pre-work indicate this is indeed the case for GRs but surprisingly not for MRs. Under baseline (Bs; non-stress) conditions GR occupancy by GCs is low as well as GR binding to genes whereas after stress GR occupancy is high and its gene binding is too. In contrast, despite a high level of MR occupancy by GCs under Bs conditions its DNA binding is low and only increases after exposure to a stressful challenge. This is an entirely new finding which could mean that the existing assumptions about the role of MRs and GRs in the brain need to be revised. We aim to investigate under which conditions (different types of stress, specific hormone stimulation) MRs and GRs bind to genes in the hippocampus (a part of the brain that is particularly involved in the regulation of GC secretion and behavioural responses after stress) and the consequences of this binding for the expression of these genes and for glucocorticoid and behavioural responses to stress. We have also planned to study whether for the fine-tuning of MR and GR binding additional proteins ('steroid receptor co-regulators') is required. In addition to acute stress models (e.g. forced swim stress, restraint stress), we will use a model of repeated variable stress as well. In this model it has been shown that hippocampal MRs and GRs have declined and GC secretion and anxiety and learning behaviour are disturbed. This model will increase our insight into how changes in MR and GR binding to genes contribute to the changes in expression of these genes as well as hormonal and behavioural changes. This work is of fundamental importance to increase our understanding into how stress affects brain function and will help to develop new ways to reduce the burden of stress-related disorders in humans and animals.

在我们的社会中，压力影响着人类和动物的生活。心理压力，如婚姻问题和欺凌，对人类的心理健康和幸福非常不利。我们饲养的动物和同伴动物也会遭受心理压力，如过度拥挤、长途运输和虐待。成功地应对这种压力事件需要大脑中的适应和认知过程，使个人在未来对类似的压力源更具弹性。有些事件，当然是在无法控制和反复发生的时候，可能会造成极大的创伤，导致心身和行为障碍以及精神疾病(焦虑和抑郁)。为了帮助人们应对生活中的压力，制定减少压力的指令，并改善我们的同伴和饲养动物的健康状况，我们需要更好地了解大脑对心理压力事件的反应。然而，目前我们还不完全了解健康的大脑如何对应激事件产生生理和行为反应，以及如何长期适应这些事件。多年来，众所周知，应激事件会导致‘应激激素’或糖皮质激素(GC)从肾上腺分泌到血液中。PI的工作有助于这一概念的发展，即这些激素通过与两种不同的GC激素结合的‘受体’在大脑中作用，协调对压力的生理和行为反应。这些受体被称为MRS和GRs，是位于神经细胞中的蛋白质分子。作为应激挑战的结果，GC激素被分泌并与这些受体结合，导致移位到细胞核。然后，激素受体复合体可以与DNA中的某些基因结合，并调节这些基因的表达。这些基因被认为对改变神经细胞的功能，以便适当地应对挑战和适应具有重要意义。然而，目前还不清楚这些受体是如何与基因结合的。几十年来，人们一直认为MR和GR与基因的结合与激素对受体的占有率成正比；我们的前期工作表明，GR确实如此，但令人惊讶的是，MRS并非如此。在基线(BS；非胁迫)条件下，GCs的GR占有率较低，GR与基因的结合较低，而胁迫后GR占有率较高，其基因结合力也较高。相比之下，尽管在BS条件下GC的MR占有率很高，但其DNA结合很低，只有在暴露于应激挑战后才会增加。这是一项全新的发现，这可能意味着关于MRS和GRS在大脑中作用的现有假设需要修改。我们的目标是研究在哪些条件下(不同类型的压力，特定的激素刺激)MRS和GRS与海马体(大脑的一部分，特别参与调节应激后GC分泌和行为反应)中的基因结合，以及这种结合对这些基因的表达以及糖皮质激素和行为应激反应的影响。我们还计划研究对于MR和GR结合的微调是否需要额外的蛋白质(‘类固醇受体共同调节因子’)。除了急性应激模型(如强迫游泳应激、束缚应激)外，我们还将使用重复可变应激模型。在该模型中，已发现海马区MRS和GRs减少，GC分泌、焦虑和学习行为受到干扰。这个模型将增加我们对MR和GR与基因结合的变化如何有助于这些基因表达的变化以及荷尔蒙和行为变化的洞察。这项工作对于增加我们对压力如何影响大脑功能的理解具有至关重要的意义，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。

项目成果

Stress: Genetics, Epigenetics and Genomics

压力：遗传学、表观遗传学和基因组学

• DOI: 10.1016/b978-0-12-813156-5.00020-0
• 发表时间: 2021
• 作者: Haque S

Distinct regulation of hippocampal neuroplasticity and ciliary genes by corticosteroid receptors.

• DOI: 10.1038/s41467-021-24967-z
• 发表时间: 2021-08-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Mifsud KR;Kennedy CLM;Salatino S;Sharma E;Price EM;Haque SN;Gialeli A;Goss HM;Panchenko PE;Broxholme J;Engledow S;Lockstone H;Cordero Llana O;Reul JMHM
• 通讯作者: Reul JMHM

The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice.

伴侣FKBP5塑造了雄性小鼠下丘脑室室核中急性应激反应。

• DOI: 10.1038/s41380-021-01044-x
• 发表时间: 2021-07
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Häusl AS;Brix LM;Hartmann J;Pöhlmann ML;Lopez JP;Menegaz D;Brivio E;Engelhardt C;Roeh S;Bajaj T;Rudolph L;Stoffel R;Hafner K;Goss HM;Reul JMHM;Deussing JM;Eder M;Ressler KJ;Gassen NC;Chen A;Schmidt MV
• 通讯作者: Schmidt MV

Genomic regulation of Krüppel-like-factor family members by corticosteroid receptors in the rat brain.

• DOI: 10.1016/j.ynstr.2023.100532
• 发表时间: 2023-03
• 期刊: NEUROBIOLOGY OF STRESS
• 影响因子: 5
• 作者: Kennedy, Clare L. M.;Price, Emily M.;Mifsud, Karen R.;Salatino, Silvia;Sharma, Eshita;Engledow, Simon;Broxholme, John;Goss, Hannah M.;Reul, Johannes M. H. M.
• 通讯作者: Reul, Johannes M. H. M.

Metyrapone unexpectedly activates Fkbp5 gene transcription in the hippocampus

美替拉酮意外激活海马中的 Fkbp5 基因转录

• 发表时间: 2018
• 作者: Kennedy CLM