Sex differences in stress-induced corticosteroid receptor interaction with the rat brain genome: Gene transcriptional and behavioural implications

压力强烈地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性过程来增加个人的弹性。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，我们需要增加对大脑如何对心理压力事件做出反应的理解。然而，目前我们还不完全了解健康的大脑如何对应激事件做出生理和行为反应，以及如何长期适应这些事件。应激事件导致糖皮质激素(GC)激素从肾上腺分泌到血液中。GC通过与两种不同的GC激素结合的“受体”在大脑中起作用，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。应激诱导的GC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。近年来，我们在阐明应激后MR和GR影响的基因及其功能方面取得了重大进展。然而，应该强调的是，与应激/GC领域的大多数工作一样，这项工作是在雄性实验动物(如大鼠)上进行的。目前，MR和GR是如何在基因水平上影响女性大脑功能的尚不清楚。然而，这一知识非常重要，因为女性处理和应对压力事件的方式和反应与男性不同。显然，这一科学领域的现状是非常令人惊讶的，因为一半的人类和相当大比例的同伴/饲养动物是雌性的。因此，我们的目标是研究GCs通过MR和GR在应激后如何影响雌性大鼠大脑中基因的活动，以深入了解为什么雌性大鼠对压力的反应不同于雄性。我们的第一步将是研究女性和男性大脑的整个基因组，以确定在压力挑战后与MR和GR相互作用的基因的身份，以及这种相互作用如何改变这些基因的活性。我们将在雌性发情周期的不同阶段进行这项调查。此外，使用生物信息学过程称为路径分析，这项研究将使我们能够识别MRS和GRS在应激后调节的分子、细胞和行为功能，比较两性之间的差异。这些分析将为我们提供一个进一步研究的感兴趣的基因清单。随后，我们将比较男性和女性对不同形式的压力的反应，因为他们处理具有挑战性的情况的方式不同。女性荷尔蒙和雌激素一样，被认为与男性和女性对压力的不同反应密切相关。因此，在另一项单独的研究中，我们将通过抑制这些激素的合成来研究它们的作用，并确定应激后对大脑中MR和GR分子作用的影响。最后，由于男性和女性表现出情绪上的差异，这可能是GC作用的不同所支持的，我们将研究MR和GR与两性感兴趣的基因的相互作用，以及他们在服用诱导焦虑的药物后的焦虑相关行为。这项工作将在很大程度上有助于缩小关于压力如何影响女性大脑功能的知识差距。

Stress strongly influences the lives of both humans and animals. Psychological stress, like marital problems and bullying, is very debilitating for mental health 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 processes in the brain to increase the individual's resilience. 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 increase our understanding of how the brain responds to psychologically stressful events. Presently, 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 glucocorticoid (GC) hormones ('stress hormones') from the adrenal glands into the blood. GCs 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. Stress-induced GCs bind 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. Recently, we made significant progress in elucidating the genes and their functions affected by MR and GR after stress. It should be underscored, however, that this work, like most work in the stress/GC field, was conducted on male experimental animals (e.g. rats). Currently, it is completely unknown how MR and GR affect brain function at the gene level in females. This knowledge is however of great importance because females process and respond to stressful events differently than males. Clearly, the present situation in this scientific field is highly surprisingly given that half of humanity and a significant proportion of our companion/farmed animals is female.Therefore, it is our aim to investigate how GCs via MR and GR affect the activity of genes in the female rat brain after stress to gain insight into why females respond differently to stress than males. Our first step will be to investigate the entire genome of both the female and male brain for the identity of the genes interacting with MR and GR after a stressful challenge and how this interaction alters the activity of these genes. We will conduct this investigation at different stages of the females' oestrus cycle. Furthermore, using a bioinformatics process called pathway analysis, this study will allow us to identify the molecular, cellular and behavioural functions regulated by MRs and GRs after stress comparatively between the two sexes. These analyses will provide us with a list of genes of interest for further study.Subsequently, we will compare males and females in their response to different forms of stress because they process challenging situations differently. Female sex hormones like oestrogens are thought to be strongly involved in the different responses to stress in males and females. Therefore, in a separate study we will investigate the role of these hormones by inhibiting their synthesis and determine the impact on the molecular action of MR and GR in the brain after stress. Finally, as males and females show differences in emotionality which may be underpinned by differences in GC action, we will study the interaction of MR and GR with genes of interest in both sexes and their anxiety-related behaviour after administration of an anxiety-inducing drug. This work will substantially contribute to closing the gap in knowledge about how stress affects brain function in females.