Paradoxical effects of estrogen in stress susceptibility

项目摘要/摘要 与男性相比，女性焦虑症的患病率更高。尤其是对于 创伤后应激障碍(PTSD)；一种焦虑障碍，源于由以下因素引起的恐惧记忆持久性 创伤应激暴露。女性患创伤后应激障碍的可能性是男性的两倍，而且更有可能遭受创伤后应激障碍 慢性创伤后应激障碍(症状超过一年)比男性更多。卵巢激素，特别是 雌激素水平，被认为与女性对创伤应激的敏感性增加有关。不过，这个 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 表现出压力暴露导致男性持续恐惧记忆表达的模型没有 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为焦虑症的危险因素 创伤后的障碍和对高水平焦虑和持续恐惧记忆表达的保护 因为压力？雌激素与雌激素受体(ER)结合，导致ER移位到核内。 它们发挥基因组效应的细胞可持续数小时至数天。这些内质网诱导的基因组效应可能 对于雌激素的保护作用至关重要。女性的月经周期为21-45天，每周一次。 雌激素水平长期处于低水平的5-7天。雌性啮齿动物有一个持续4-5天的发情周期 低雌激素水平的时间要短得多。结果，内质网激活(通过基因组机制) 雌性大鼠可能永远不会减少，因为雌激素水平在短时间内是低的。在女性身上， 雌激素水平在较长一段时间内处于低水平，这意味着雌激素诱导的激活可能会成为 慢性降低，这段ER效应降低的时期可能代表了一个应激敏感期。因此， 高水平的循环雌激素可以赋予压力韧性，但紧随其后的是压力易感性。 在自然骑行的女性中，雌激素水平从高到长期低。为了检验这一假设，我们将 首次表明，长期拮抗动情周期雌性大鼠的雌激素受体将使它们更 容易受到压力对持久恐惧记忆的影响(具体目标1)。接下来，我们将展示慢性 在恐惧环路的关键节点内拮抗ER将使处于发情周期的雌性大鼠更 容易受到压力对持久恐惧记忆的影响(具体目标2)。最后，我们将在以下方面使用fMRI 唤醒大鼠表明，在发情周期的雌性大鼠中，慢性ER拮抗将使它们 易受应激诱导的大脑体积和恐惧中的功能连接改变的影响 巡回赛。这项研究建议将有助于解释循环雌激素水平如何同时导致压力。 易感性，并与解释为什么女性患压力的风险如此之高有关- 诱发性焦虑症。

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.