Psychosocial disruption of estradiol action on behavior

描述（由申请人提供）：心理社会压力是焦虑疾病和临床抑郁症发展的促成因素，并抑制积极的社会行为。虽然社会心理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之间存在很强的相关性。此外，女性比男性更容易患精神疾病。因为雌二醇（E2）已被证明可以改善情感和增加动机行为，E2作用的中断可能对这些压力引起的精神病理很重要。然而，E2对情绪的重要性尚不清楚，因为雌激素水平低下并不一定会导致女性情绪障碍，E2水平升高也并不一定会改善情绪。我们假设E2积极影响情绪和社会行为的能力在经历慢性不可预测的社会心理压力的个体中受到损害，并且这一因素解释了E2对情绪影响的变异性。在女性中，理解持续的社会心理压力如何扰乱E2是很困难的。然而，生活在分层社会中的动物物种，其中从属的雌性表现出应激诱导的边缘-下丘脑-垂体-肾上腺（LHPA）轴的失调和对E2的行为敏感性降低，为研究这个问题提供了一个行为学上有效的模型。在这些研究中，我们将检验这样一个假设，即社会从属会产生一种生理状态，这种状态会减弱E2对动机和焦虑的有益作用，因此需要更高水平的E2来诱导性和附属行为。此外，我们将使用高选择性雌激素受体(ER)-a和ER-a激动剂来确定社会心理压力如何破坏ER功能的特定方面。最后，由于E2与5 -羟色胺能（5HT）系统广泛相互作用以调节情绪，我们将验证以下假设：在编码5HT再摄取转运体（SERT）的基因启动子区域具有特定多态性的次要个体，即使与E2共同治疗，也更容易受到社会心理压力的破坏性影响；在与情绪相关的特定大脑区域显示较少的5HT结合活性；并且对5HT再摄取抑制剂治疗的行为反应较差。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5HT和LHPA轴的神经内分泌评估；并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特别与生活在压力社会环境中的妇女的精神病理学发展有关。公共卫生相关性：了解慢性社会心理压力如何破坏性腺激素雌二醇对情绪和社会动机行为产生积极影响的能力，将有助于更彻底地了解女性精神病理是如何出现的。此外，这些研究将显示一种特定的基因多态性如何进一步削弱雌二醇的积极行为功效。这些研究将确定可能导致发展治疗干预措施的机制，以预防或尽量减少心理社会压力对女性情绪健康的不利后果。

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.