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过程，以增加个人的弹性。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，我们需要增加对大脑如何应对心理压力事件的理解。然而，目前我们并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。压力事件导致肾上腺分泌糖皮质激素（GC）激素（“压力释放物”）进入血液。GC在大脑中通过与两种不同的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。应激诱导的GC与这些受体结合，导致易位至细胞核。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。这些基因被认为是重要的改变神经细胞的功能，以响应和适应适当的挑战。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要进展。然而，应该强调的是，这项工作与应激/GC领域的大多数工作一样，是在雄性实验动物（例如大鼠）上进行的。目前，完全不知道MR和GR如何在基因水平上影响女性的大脑功能。然而，这种知识非常重要，因为女性处理和应对压力事件的方式与男性不同。显然，在这一科学领域的现状是非常令人惊讶的，考虑到一半的人类和我们的伴侣/养殖动物的显着比例是女性，因此，它是我们的目的是调查如何通过MR和GR GC影响基因的活性在雌性大鼠大脑中的压力后，以了解为什么女性的反应不同于男性的压力。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，使用称为通路分析的生物信息学过程，这项研究将使我们能够确定在应激后比较两性之间由MR和GR调节的分子、细胞和行为功能。这些分析将为我们提供一个感兴趣的基因清单，供进一步研究。随后，我们将比较男性和女性对不同形式压力的反应，因为他们处理挑战性情况的方式不同。女性性激素如雌激素被认为与男性和女性对压力的不同反应密切相关。因此，在一项单独的研究中，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不同的情绪，这可能是由GC行动的差异，我们将研究MR和GR与感兴趣的基因在两种性别和他们的焦虑相关的行为后，管理的焦虑诱导药物的相互作用。这项工作将大大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.