Psychosocial disruption of estradiol action on behavior

描述(由申请人提供)：心理社会压力是焦虑症和临床抑郁症发展的诱因，也是抑制积极社会行为的诱因。虽然心理社会压力是由许多情况造成的，但社会经济水平与抑郁症和其他精神疾病的发生有很强的相关性。此外，女性比男性更容易患上精神病。由于雌二醇(E_2)已被证明可以改善情绪和增加动机行为，因此E_2作用的中断对这些应激诱导的精神病理可能是重要的。然而，E2对情绪的重要性尚不清楚，因为雌激素过低并不会一致地在女性中产生情绪障碍，升高的E2也不会明确地改善情绪。我们假设，在经历慢性不可预测的心理社会压力的个体中，E2‘S积极影响情绪和社会行为的能力受到损害，这一因素解释了E2对情绪影响的大部分变异性。对于女性来说，很难理解持续的心理社会压力是如何扰乱E2的。然而，生活在分层社会中的动物物种为研究这一问题提供了一个有效的行为学模型。在分层社会中，从属雌性动物既表现出应激诱导的边缘-下丘脑-垂体-肾上腺(LHPA)轴的调节失调，又降低了对E2的行为敏感性。在这些研究中，我们将检验一种假设，即社会从属关系会产生一种生理状态，削弱E2‘S对动机和焦虑的有利影响，因此需要更高水平的E2来引导性行为和从属行为。此外，我们将使用高度选择性的雌激素受体(ER)-a和ER-a激动剂来确定心理社会压力如何破坏ER功能的特定方面。最后，由于E2与5-羟色胺(5-HT)系统广泛相互作用来调节情绪，我们将检验这一假设，即编码5-羟色胺再摄取转运体(SERT)基因启动子区具有特定多态性的从属个体，即使与E2共同治疗，也更容易受到心理社会压力的这种破坏性影响；在与情绪性相关的特定大脑区域显示较少的5-羟色胺结合活性；并且对5-羟色胺再摄取抑制剂的治疗行为反应较差。这些研究将量化社会和情感行为；将使用一系列激素替代策略和对5HT和LHPA轴的神经内分泌评估；将使用神经成像来量化大脑中的5HT活动。这一系列研究的结果将与生活在紧张的社会环境中的女性的精神病理学的发展特别相关。公共卫生相关性：了解慢性心理社会压力如何扰乱性腺激素雌二醇积极影响情绪和社会动机行为的能力，将有助于更彻底地理解女性是如何出现精神病态的。此外，这些研究将表明，特定的基因多态可能会进一步削弱雌二醇的积极行为功效。这些研究将描述可能导致制定治疗干预措施的机制，以防止或最大限度地减少心理社会压力对女性情绪健康的不利影响。

DESCRIPTION (provided by applicant): Psychosocial stress is a precipitating factor in the development of anxiety illnesses and clinical depression, and in the inhibition of positive social behaviors. While psychosocial stress results from a number of situations, there is a strong correlation between socio-economic level and the occurrence of depression and other mental illnesses. Moreover, women are more likely than men to suffer from psychopathology. Because estradiol (E2) has been shown to improve affect and increase motivational behavior, a disruption in E2 action may be important for these stress-induced psychopathologies. However, the importance of E2 on emotion is unclear because hypoestrogenism does not uniformly produce mood disorders in women nor does elevated E2 unequivocally improve affect. We hypothesize that E2's ability to positively affect emotional and social behavior is compromised in individuals experiencing chronic unpredictable psychosocial stress, and that this factor accounts for much of the variability in the effects of E2 on emotion. Understanding how persistent psychosocial stress disrupts E2 is difficult in women. However, animal species which live in a stratified society wherein subordinate females exhibit both stress-induced dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis and reduced behavioral sensitivity to E2, provide an ethologically valid model with which to study this question. In these studies we will test the hypothesis that social subordination produces a physiological state that blunts E2's beneficial effect on motivation and anxiety and hence necessitates higher levels of E2 to induce sexual and affiliative behaviors. In addition, we will employ highly selective estrogen receptor (ER)-a and ER-a agonists to determine how psychosocial stress disrupts specific aspects of ER function. Lastly, because E2 interacts extensively with the serotonergic (5HT) system to regulate emotion, we will test the hypothesis that subordinate individuals with a specific polymorphism in the promoter region of the gene encoding the 5HT reuptake transporter (SERT), are more vulnerable to this disruptive effect of psychosocial stress even when co-treated with E2; show less 5HT binding activity in specific brain areas associated with emotionality; and are less behaviorally responsive to treatment with 5HT reuptake inhibitors. These studies will quantify social and emotional behaviors; will use a range of hormone replacement strategies and neuroendocrine assessments of the 5HT and LHPA axis; and will employ neuroimaging to quantify 5HT activity in the brain. Results from this series of studies will be particularly pertinent to development of psychopathology in women living in stressful social environments. PUBLIC HEALTH RELEVANCE: Understanding how chronic psychosocial stress disrupts the ability of the gonadal hormone estradiol to positively influence emotion and socially motivated behaviors will provide a more thorough understanding of how psychopathologies emerge in women. Furthermore, these studies will show how a specific genetic polymorphism may further diminish the positive behavioral efficacy of estradiol. These studies will characterize mechanisms that may lead to the development of therapeutic interventions to prevent or minimize the adverse consequences of psychosocial stress on female emotional health.