The Neuroregulatory Effects of Gonadal Steroids in Humans

性腺类固醇对人类的神经调节作用

• 批准号: 8939989
• 负责人: Peter Schmidt
• 金额: $ 68.89万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8939989
• 关键词: Adrenal Glands; Affective; Affective Symptoms; Affinity; Age; Agonist; Alleles; Amygdaloid structure; Androgens; BDNF gene; Back; Behavioral; Brain; Brain region; Brain-Derived Neurotrophic Factor; COMT gene; Catechol Estrogens; Cerebrovascular Circulation; Characteristics; Clinical; Cognitive; Collaborations; Complex; Data; Dopamine; Enantone; Endocrine; Estradiol; Estrogens; Estrone; Exposure to; Female; Functional Magnetic Resonance Imaging; Functional disorder; Genetic; Genetic Polymorphism; Genotype; Goals; Gold; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Heterozygote; Hippocampus (Brain); Homozygote; Hormonal; Hormones; Hot flushes; Human; Hypogonadism; Imaging Techniques; Individual Differences; Investigation; Knock-in Mouse; Knowledge; Left; Magnetic Resonance Imaging; Maps; Measurement; Measures; Menstrual cycle; Mental Depression; Metabolism; Methodology; Methods; Molecular; Mood Disorders; Mus; Nervous System Physiology; Neuraxis; Ovarian; Ovarian Ablation; Ovarian hormone; Pattern; Performance; Perimenopause; Perinatal; Physiological; Play; Positron-Emission Tomography; Predisposition; Prefrontal Cortex; Premenopause; Prevalence; Procedures; Process; Progesterone; Protocols documentation; Psyche structure; Recruitment Activity; Regulation; Relative (related person); Reporting; Response Elements; Rewards; Role; Rotation; Sex Characteristics; Short-Term Memory; Sleep; Staging; Steroids; Stress; System; Technology; Testing; Testosterone; Time; Universities; Variant; Visuospatial; Wild Type Mouse; Woman; Work; behavior observation; cingulate cortex; clinically significant; comparison group; depressive symptoms; gonad function; human tissue; hypothalamic-pituitary-adrenal axis; in vivo; male; meetings; men; neuroimaging; neurophysiology; neurosteroids; performance tests; pre-clinical; psychobiology; relating to nervous system; reproductive; response; serotonin transporter; sex; treatment response; trend; young woman

The protocols involved in this project are as follows: 05-M-0059, 81-M-0126, and 92-M-0174.This report includes work arising from the following protocols: NCT00026832, NCT00100360, NCT00001177, and NCT00001322. Behavioral observations show that clinically significant depressive symptoms are rare accompaniments of induced hypogonadism in these healthy premenopausal women. Additionally, neither night-time hot flushes nor disturbed sleep are sufficient to cause depressive symptoms in hypogonadal young women (reported in MH002537-23 DIRP: Psychobiology and Treatment of Perimenopausal Mood Disorders). Thus this paradigm serves as an excellent comparison group for the women with reproductive endocrine-related mood disorders who undergo identical hormone manipulations. We are pursuing our original findings that ovarian steroids modulate prefrontal cortical activity in women by augmenting older gold-standard imaging techniques (i.e., O15 PET), in which the technology is relatively stable over time and the activation task paradigms are kept relatively constant over the long-term course of these studies, with newer hypothesis-driven, cutting edge task paradigms and analytic approaches (i.e., fMRI). During N-back activation, ovarian steroids (or their absence) modulate functional connectivity between the DLPFC and hippocampus. Specifically, hormone condition had significant effects on the direction of hippocampal functional connectivity with both left and right DLPFC: the expected working memory-related negative correlation was observed during estradiol; however, during progesterone there was a positive hippocampal-right DLPFC correlation but there was no significant correlation during ovarian suppression with Lupron alone (i.e., hypogonadism). These data demonstrate that ovarian steroids modulate hippocampal-PFC functional connectivity, consistent with a role for these hormones in modulating the hippocampus at the cellular level. Interestingly, our findings indicate that progesterone and estradiol have opposite effects on this in vivo measure of hippocampal-DLPFC cooperativity, substantiating the complex influence of gonadal steroids in brain circuitry and calling for further clinical and preclinical investigation. In collaboration with Karen Berman, we examine the effects of the presence of common allelic variations in the BDNF gene and in the COMT gene in women undergoing multimodal neuroimaging procedures during each of the hormonal conditions established within the GnRH agonist-induced hypogonadism and ovarian steroid add-back protocol. We examined the impact of the interaction of BDNF Val66Met polymorphism and ovarian hormones on PET measurements of rCBF while women performed the 2-back working memory task and a 0-back sensorimotor control. We observed that BDNF genotype interacts with estradiol to impact hippocampal function during working memory. We found a significant interaction between BDNF genotype and hormone condition in right hippocampal activation (2-back vs. 0-back), and a similar trend in the left hippocampus. Post-hoc analyses revealed Met carriers showed robust estradiol-specific changes, whereas Val homozygous women showed no change in activation across hormone conditions. In Met carriers the hippocampus was abnormally activated (not deactivated) during estradiol but not during the hypogonadal state or progesterone replacement. Analyses of the 0-back and 2-back conditions done separately (an approach made possible by using PET), clearly indicate that these changes were due to neural activity during the working memory (2-back) condition and not the sensorimotor (0-back) control task. This study is the first in humans to demonstrate a BDNF genotype by hormone interaction on a cognitively-related neurophysiological response. These data suggest that the Met allele of the BDNF gene conveys an abnormal sensitivity to the presence of estradiol on hippocampal function, similar to that reported in the Met knock-in mice compared with wild type mice. Results of similar studies in women with PMDD are close to completion pending the recruitment of a sufficient number of Met carriers to repeat this analysis in these women whose affective symptoms are menstrual cycle dependent. Finally, a recent collaboration with Dr. McEwen at the Rockefeller University will explore hippocampal function on both behavioral and molecular levels in humanized met knock-in female mice. In a second analysis, we employed similar methods (i.e., the N-back task) to examine the impact of the COMT Val158Met genotype on PET measured rCBF in the PFC. COMT plays an important role in the regulation of intrasynaptic dopamine levels in the PFC and also has a high affinity for the hydroxylated metabolites of estradiol/estrone (i.e., catecholestrogens). Moreover, the activity of COMT is reported to be both sexually dimorphic and modulated by estradiol (by an estrogen response element ERE in some human tissues). In contrast to the predominance of hippocampal findings with BDNF genotype, results of the COMT by hormone interaction analysis were focused on the DLPFC, a finding that reflected estradiol-related changes in both Val and Met homozygotes. Specifically, the Met homozygotes showed a significant increase in DLPFC activation during estradiol compared with hypogonadism, whereas Val homozygotes showed the opposite pattern with significantly lower activation during estradiol but not hypogonadism or progesterone-replaced conditions). DLPFC activation in heterozygotes was intermediate between the two homozygous groups. These data are consistent with observations that both COMT genotype and stage of the menstrual cycle influence working memory-related activations in the PFC and clearly define a COMT genotype by hormone interaction. Thus, the effects of genotype on PFC function in women cannot be inferred in the absence of knowledge about reproductive state. The mechanisms underlying this observation remain to be defined but are consistent with estradiol impacting PFC dopamine tuning through effects on DA synthesis or metabolism with attendant alterations in DLPFC efficiency. Investigations of the relevance of this genotype by hormone interaction on PFC function to women with PMDD are currently underway. Finally, despite well-established sex differences in several cognitive domains (e.g., visuospatial ability), few studies in humans have distinguished between those sex differences evident in the presence of circulating sex hormones and those sex differences present in the relative absence of circulating levels of estradiol and testosterone, respectively (i.e., true sex differences reflecting organizational differences in brain function occurring independent of differences in current exposure to estradiol or testosterone). We evaluated cognitive performance in healthy men and women before (eugonadal) and during GnRH agonist-induced hypogonadism. The well-documented male advantage in visuospatial performance, which we observed during eugonadal conditions, was maintained despite the short-term suppression of gonadal function in both men and women. Significant main effects of sex (but not of either hormone condition or sex by hormone condition) were observed: men performed better than women on visuospatial tasks (mental rotation, line orientation, Money Road Map, complex figure drawing, embedded figures, and maze completion) during both eugonadism and hypogonadism. No significant main or interactive effects of sex or hormone condition were observed in any other cognitive test domain. These findings suggest that, in humans, sex differences in visuospatial performance do not require the presence of circulating sex steroids and, therefore, are not simply reflections of sex differences in the relative exposures to estradiol and testosterone.

该项目涉及的协议如下：05-M-0059、81-M-0126 和 92-M-0174。本报告包括以下协议产生的工作：NCT00026832、NCT00100360、NCT00001177 和 NCT00001322。 行为观察表明，在这些健康的绝经前女性中，临床上显着的抑郁症状很少伴随诱发性性腺功能减退症。 此外，夜间潮热或睡眠障碍都不足以导致性腺功能减退的年轻女性出现抑郁症状（MH002537-23 DIRP：心理生物学和围绝经期情绪障碍的治疗）。 因此，对于患有生殖内分泌相关情绪障碍且接受相同激素操作的女性来说，这一范例是一个极好的对照组。 我们正在追求我们的原始发现，即卵巢类固醇通过增强旧的金标准成像技术（即 O15 PET）来调节女性前额皮质活动，其中该技术随着时间的推移相对稳定，并且激活任务范式在这些研究的长期过程中保持相对恒定，并采用更新的假设驱动、前沿任务范式和分析方法（即， 功能磁共振成像）。 在 N-back 激活期间，卵巢类固醇（或它们的缺失）调节 DLPFC 和海马体之间的功能连接。 具体来说，激素状况对海马与左右 DLPFC 功能连接的方向有显着影响：在雌二醇期间观察到预期的工作记忆相关负相关；然而，在孕激素期间，海马-右侧 DLPFC 存在正相关性，但在单独使用亮普瑞（即性腺功能减退症）的卵巢抑制期间没有显着相关性。 这些数据表明，卵巢类固醇调节海马-PFC 功能连接，与这些激素在细胞水平调节海马的作用一致。 有趣的是，我们的研究结果表明，黄体酮和雌二醇对海马-DLPFC 协同性的体内测量具有相反的影响，证实了性腺类固醇对大脑回路的复杂影响，并需要进一步的临床和临床前研究。 我们与 Karen Berman 合作，研究了 BDNF 基因和 COMT 基因中常见等位基因变异对接受多模式神经影像检查的女性的影响，这些变异是在 GnRH 激动剂诱导的性腺功能减退症和卵巢类固醇添加方案中建立的每种激素条件下进行的。 我们研究了女性执行 2-back 工作记忆任务和 0-back 感觉运动控制时 BDNF Val66Met 多态性和卵巢激素相互作用对 rCBF PET 测量的影响。 我们观察到 BDNF 基因型与雌二醇相互作用，影响工作记忆期间的海马功能。 我们发现右侧海马激活中 BDNF 基因型和激素状况之间存在显着的相互作用（2-back 与 0-back），并且左侧海马也有类似的趋势。 事后分析显示，Met 携带者表现出强烈的雌二醇特异性变化，而 Val 纯合子女性在激素条件下的激活没有变化。在 Met 携带者中，海马在雌二醇期间异常激活（而不是失活），但在性腺功能减退状态或黄体酮替代期间则不会。 对 0-back 和 2-back 条件分别进行的分析（通过使用 PET 实现的方法）清楚地表明，这些变化是由于工作记忆（2-back）条件下的神经活动而不是感觉运动（0-back）控制任务期间的神经活动造成的。 这项研究首次在人类中通过激素相互作用证明 BDNF 基因型对认知相关的神经生理反应的影响。 这些数据表明，BDNF 基因的 Met 等位基因对雌二醇的存在对海马功能具有异常敏感性，与 Met 敲入小鼠中报道的与野生型小鼠相比相似。 在患有经前抑郁症 (PMDD) 的女性中进行的类似研究的结果已接近完成，有待招募足够数量的 Met 携带者，以便在这些情感症状依赖于月经周期的女性中重复这一分析。最后，最近与洛克菲勒大学 McEwen 博士的合作将探索人源化 Met 敲入雌性小鼠的行为和分子水平上的海马功能。 在第二次分析中，我们采用类似的方法（即 N-back 任务）来检查 COMT Val158Met 基因型对 PET 测量的 PFC 中 rCBF 的影响。 COMT 在 PFC 突触内多巴胺水平的调节中发挥着重要作用，并且对雌二醇/雌酮的羟基化代谢物（即儿茶酚雌激素）也具有高亲和力。 此外，据报道，COMT 的活性具有性别二态性，并受雌二醇（通过某些人体组织中的雌激素反应元件 ERE）调节。 与 BDNF 基因型在海马中的发现占主导地位相反，激素相互作用分析的 COMT 结果集中在 DLPFC，这一发现反映了 Val 和 Met 纯合子中雌二醇相关的变化。 具体而言，与性腺功能减退症相比，Met 纯合子在雌二醇期间显示 DLPFC 激活显着增加，而 Val 纯合子则显示相反的模式，在雌二醇期间 DLPFC 激活显着降低，但在性腺功能减退或黄体酮替代条件下则不然。 杂合子中 DLPFC 的激活程度介于两个纯合子组之间。 这些数据与 COMT 基因型和月经周期阶段影响 PFC 中工作记忆相关激活的观察结果一致，并通过激素相互作用清楚地定义了 COMT 基因型。 因此，在缺乏生殖状态知识的情况下，无法推断基因型对女性 PFC 功能的影响。 这一观察结果背后的机制仍有待确定，但与雌二醇通过影响 DA 合成或代谢以及随之而来的 DLPFC 效率改变而影响 PFC 多巴胺调节的情况一致。 目前正在研究这种基因型与 PFC 功能的激素相互作用与经前抑郁症 (PMDD) 女性的相关性。 最后，尽管在几个认知领域（例如，视觉空间能力）中存在明确的性别差异，但很少有人类研究区分了循环性激素存在下明显的性别差异和雌二醇和睾酮循环水平相对缺乏时分别存在的性别差异（即，真正的性别差异反映了大脑功能的组织差异，与当前暴露于雌二醇或睾酮的差异无关） 睾酮）。我们评估了健康男性和女性在 GnRH 激动剂诱发性腺功能减退症之前（性腺功能正常）和期间的认知表现。尽管男性和女性的性腺功能都受到短期抑制，但我们在性腺功能正常的情况下观察到，男性在视觉空间表现方面的优势仍然存在。观察到性别（但不是激素状况或激素状况影响的性别）的显着主要影响：在性腺功能正常和性腺功能减退期间，男性在视觉空间任务（心理旋转、线条定向、金钱路线图、复杂图形绘制、嵌入图形和迷宫完成）方面比女性表现更好。 在任何其他认知测试领域均未观察到性别或激素状况的显着主要或交互影响。这些发现表明，在人类中，视觉空间表现的性别差异不需要循环性类固醇的存在，因此，不仅仅是雌二醇和睾酮相对暴露量的性别差异的反映。