Psychosocial disruption of estradiol action on behavior

雌二醇对行为的社会心理干扰

• 批准号: 8424377
• 负责人: DONNA J TOUFEXIS
• 金额: $ 28.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424377
• 关键词: Accounting; Acute; Adrenal Glands; Affect; Agonist; Alleles; Animal Model; Animals; Anti-Anxiety Agents; Anxiety; Area; Attenuated; Behavior; Behavioral; Binding; Brain; Characteristics; Chronic; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Coupled; Development; Dose; Emotional; Emotions; Endogenous depression; Estradiol; Estrogen Receptors; Etiology; Exhibits; Exposure to; Female; Fright; Gender; Genes; Genetic; Genetic Polymorphism; Genotype; Gonadal Hormones; Gonadal Steroid Hormones; Health; Hormones; Housing; Hypothalamic structure; Individual; Lead; Length; Life; Macaca mulatta; Mediating; Mental Depression; Mental disorders; Modeling; Monkeys; Mood Disorders; Motivation; Neurosecretory Systems; Physiological; Pituitary Gland; Precipitating Factors; Problem behavior; Promoter Regions; Psychopathology; Psychosocial Stress; Receptor Activation; Reproduction; Rodent; Series; Serotonin; Sex Behavior; Social Behavior; Social Environment; Social status; Societies; Stress; System; Testing; Therapeutic Effect; Therapeutic Intervention; Variant; Woman; acute stress; adverse outcome; affiliative behavior; attenuation; base; density; emotion regulation; experience; hypothalamic-pituitary-adrenal axis; improved; inhibitor/antagonist; men; motivated behavior; neuroimaging; neuroprotection; prevent; promoter; psychosocial; receptor; receptor binding; receptor function; response; reuptake; serotonergic regulation; social; social stress; socioeconomics; stressor

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.

描述（由申请人提供）：社会心理压力是焦虑症和临床抑郁症发展以及积极社会行为抑制的促发因素。虽然社会心理压力是由多种情况引起的，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，女性比男性更有可能患有精神病理学。由于雌二醇 (E2) 已被证明可以改善情感并增加动机行为，因此 E2 作用的破坏可能对这些压力诱发的精神病理学很重要。然而，E2 对情绪的重要性尚不清楚，因为雌激素不足并不一定会导致女性情绪障碍，E2 升高也不会明确改善情绪。我们假设，在经历长期不可预测的社会心理压力的个体中，E2 积极影响情绪和社会行为的能力受到损害，并且这个因素解释了 E2 对情绪影响的大部分变异性。对于女性来说，理解持续的社会心理压力如何破坏 E2 是很困难的。然而，生活在分层社会中的动物物种，其中从属雌性表现出压力引起的边缘-下丘脑-垂体-肾上腺（LHPA）轴失调和对 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，我们将检验这样的假设：社会从属会产生一种生理状态，削弱 E2 对动机和焦虑的有益作用，因此需要更高水平的 E2 来诱导性行为和亲和行为。此外，我们将采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扰乱 ER 功能的特定方面。最后，由于 E2 与血清素能 (5HT) 系统广泛相互作用来调节情绪，我们将检验以下假设：在编码 5HT 再摄取转运蛋白 (SERT) 的基因启动子区域具有特定多态性的从属个体更容易受到这种影响。即使与 E2 共同治疗，也会产生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出较少的 5HT 结合活性；并且对 5HT 再摄取抑制剂治疗的行为反应较差。这些研究将量化社交和情感行为；将使用一系列激素替代策略以及 5HT 和 LHPA 轴的神经内分泌评估；并将利用神经影像学来量化大脑中的 5HT 活性。这一系列研究的结果将与生活在压力社会环境中的女性的精神病理学发展特别相关。公共卫生相关性：了解慢性心理社会压力如何破坏性腺激素雌二醇积极影响情绪和社会动机行为的能力，将有助于更全面地了解女性如何出现精神病理学。此外，这些研究将表明特定的基因多态性如何可能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治疗干预措施发展的机制，以预防或尽量减少社会心理压力对女性情绪健康的不利影响。

项目成果

Oestradiol alters central 5-HT1A receptor binding potential differences related to psychosocial stress but not differences related to 5-HTTLPR genotype in female rhesus monkeys.

雌二醇改变雌性恒河猴中与心理社会压力相关的中枢 5-HT1A 受体结合电位差异，但不改变与 5-HTTLPR 基因型相关的差异。

• 发表时间: 2014-02
• 影响因子: 3.2
• 作者: Michopoulos, V;Perez Diaz, M;Embree, M;Reding, K;Votaw, J R;Mun, J;Voll, R J;Goodman, M M;Wilson, M;Sanchez, M;Toufexis, D
• 通讯作者: Toufexis, D