Paradoxical effects of estrogen in stress susceptibility

项目总结/摘要 与男性相比，焦虑症在女性中的患病率更高。这一点尤其适用于 创伤后应激障碍（PTSD）;一种焦虑症，源于恐惧记忆的持续性， 创伤压力暴露女性患PTSD的可能性是男性的两倍， 从慢性创伤后应激障碍（症状经历超过一年）比男性。卵巢激素，特别是 雌激素水平与女性对创伤压力的敏感性增强有关。但这 与人类实验相比，高雌激素水平可以抑制焦虑和啮齿动物的压力， 模型显示，压力暴露导致男性持续的恐惧记忆表达， 在女性身上也有同样的效果。雌激素水平如何同时成为发展焦虑的危险因素 创伤后的障碍和防止高水平的焦虑和持续的恐惧记忆表达诱导 因为压力？雌激素与雌激素受体（ER）结合，导致ER移位至细胞核 在细胞中发挥基因组效应，这种效应可以持续数小时到数天。这些雌激素受体诱导的基因组效应可能 对雌激素的保护作用至关重要。女性的月经周期持续21 - 45天， 5 - 7天，雌激素水平长期偏低。雌性啮齿动物有一个持续4 - 5天的发情周期 雌激素水平低的时间短得多因此，ER激活（通过基因组机制） 雌性大鼠的雌激素水平可能永远不会下降，因为雌激素水平在短时间内很低。在女性中， 雌激素水平在较长一段时间内处于低水平，这意味着雌激素受体诱导的激活可能会成为 长期减少，这一时期的减少ER效应可能代表了一个应激敏感期。因此，在本发明中， 高水平的循环雌激素可能赋予压力弹性，但压力敏感性可能会随之而来， 在自然循环的女性中，雌激素水平从高到长期低。为了验证这个假设，我们将 首次表明，长期拮抗雌鼠的ER与发情周期，将使他们更多的 易受压力对持续恐惧记忆的影响（具体目标#1）。接下来，我们将展示慢性 在恐惧回路的关键节点内拮抗ER将使具有发情周期的雌性大鼠更 易受压力对持续恐惧记忆的影响（具体目标#2）。最后，我们将使用fMRI在 唤醒大鼠，以表明在发情周期的雌性大鼠中的慢性ER拮抗作用会使它们变得更 容易受到压力引起的大脑体积和恐惧内功能连接变化的影响。 电路.这项研究建议将有助于解释如何循环雌激素水平可以同时导致压力 易感性，并且与解释为什么女性人类具有如此高的发展压力的风险有关- 诱发焦虑症

Project Summary/Abstract Anxiety disorders have a higher prevalence rate in women when compared to men. This is particularly so for post traumatic stress disorder (PTSD); an anxiety disorder that stems from fear memory persistence induced by traumatic stress exposure. Women are twice as likely to suffer from PTSD as men and more likely to suffer from chronic PTSD (symptoms experienced greater than a year) than men. Ovarian hormones, and specifically estrogen levels, have been implicated in enhanced susceptibility to traumatic stress in women. However, this contrasts with human experiments that have demonstrated high estrogen levels inhibit anxiety and rodent stress models that have shown stress exposure that leads to persistent fear memory expression in males does not have this same effect in females. How can estrogen levels simultaneously be a risk factor for developing anxiety disorders after trauma and protect against high levels of anxiety and persistent fear memory expression induced by stress? Estrogen binds to estrogen receptors (ERs), which results in the translocation of ERs to the nucleus of cells where they exert genomic effects that can last for hours - days. These ER-induced genomic effects could be critical for the protective effects of estrogen. The menstrual cycle in women lasts 21 - 45 days with a period of 5-7 days where estrogen levels are chronically low. Female rodents have an estrous cycle that last 4-5 days with a considerably shorter period of low estrogen levels. As a result, ER activation (via genomic mechanism) may never decrease in female rats, because estrogen levels are low for a short period of time. In women, estrogen levels are low for a longer period of time, which means that ER-induced activation may become chronically decreased, and this period of decreased ER effect may represent a stress-susceptibility period. Thus, high levels of circulating estrogens may endow stress resilience, but stress susceptibility may follow when estrogen levels go from high to chronically low in naturally cycling females. To test this hypothesis, we will first show that chronically antagonizing ERs in female rats with an estrous cycle will make them more susceptible to the effects of stress on persistent fear memory (specific aim #1). Next, we will show that chronic antagonism of ERs within critical nodes of the fear circuit will make female rats with an estrous cycle more susceptible to the effects of stress on persistent fear memory (specific aim #2). Lastly, we will use fMRI in awake rats to show that chronic ER antagonism in female rats with an estrous cycle will make them more susceptible to the effects of stress-induced changes in brain volume and functional connectivity within the fear circuit. This research proposal will help explain how cycling estrogen levels can simultaneously lead to stress susceptibility, and is relevant to explaining why female humans have such a higher risk for developing stress- induced anxiety disorders.