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: 7969438
• 负责人: Peter Schmidt
• 金额: $ 88.77万
• 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/7969438
• 关键词: Accounting; Adrenal Glands; Affect; Affective; Age; Agonist; Amygdaloid structure; Androgens; Area; Back; Behavior; Biology; Brain; Brain region; Brain-Derived Neurotrophic Factor; Catechols; Cerebrovascular Circulation; Characteristics; Cognitive; Collaborations; Corpus striatum structure; Corticotropin-Releasing Hormone; Data; Deep Brain Stimulation; Development; Dexamethasone; Diagnostic; Disease; Dose; Early-life trauma; Emotions; Enantone; Endocrine; Estradiol; Expectancy; Failure; Feedback; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genes; Genetic; Goals; Gold; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Hippocampus (Brain); Hormonal; Hormones; Human; Hydrocortisone; Hypogonadism; Image; Imaging Techniques; Inferior; Inferior frontal gyrus; Lead; Left; Literature; Lobule; Magnetic Resonance Imaging; Measures; Medial; Menstrual cycle; Methodology; Midbrain structure; Mood Disorders; Moods; Nervous System Physiology; Neuraxis; Ovarian; Ovarian hormone; Parahippocampal Gyrus; Parietal; Patients; Pattern; Performance; Perimenopause; Perinatal; Phase; Physiological; Positioning Attribute; Positron-Emission Tomography; Predisposition; Prefrontal Cortex; Premenopause; Prevalence; Procedures; Process; Progesterone; Protocols documentation; Recruitment Activity; Regulation; Relative (related person); Reporting; Research; Research Personnel; Rest; Rewards; Rodent; Role; Scanning; Sex Characteristics; Short-Term Memory; Site; Steroids; Stress; System; Technology; Temporal Lobe; Testing; Therapeutic; Time; Transferase; Vasopressins; Woman; age effect; cingulate cortex; depression; disability; effectiveness trial; gonad function; hypothalamic-pituitary-adrenal axis; imaging modality; mortality; neural circuit; neuroimaging; neurophysiology; neurosteroids; novel therapeutics; preclinical study; proliferative phase Menstrual cycle; putamen; reproductive; reproductive hormone; response; serotonin transporter; treatment response

In our earlier studies of regional cerebral blood flow using PET, we reported for the first time in humans that induced hypogonadism was associated with the elimination of the normal pattern of cortical activation in the dorsolateral prefrontal cortex as well as in the posterior inferior temporal cortices and the inferior parietal lobule; whereas both estradiol and progesterone replacement restored the normal pattern of cortical activation during a working memory task. 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). We employ several different activational paradigms during the neuroimaging procedures that will allow us to both vary the cognitive load of the task (and possibly the level of stress involved in performing the task) and test neural circuits more relevant to the phenomenology of affective disorders (i.e., reward system). For example, using fMRI and parametrically varied working memory load (i.e., N-back test), we are testing the possibility that change in hormonal state causes a shift in the dose-response curve between cognitive load and neurophysiological response. Additionally, using the N-back task with two functional imaging methods (PET with repeated scans and fMRI), we are determining the activation pattern for each woman at each hormonal phase to test for variance in their sites of activation. Finally, using new analytical approaches, we are testing the hypothesis that the hormonally-induced alteration in function includes changes in interregional functional connectivity either in the resting state or during activation. Preliminary results from our O15 PET studies, demonstrate that estradiol significantly increased resting regional cerebral blood flow (rCBF) activity in the subgenual cingulate (BA25), medial prefrontal cortex (mPFC), posterior cingulate, and parahippocampal gyrus compared with the hypogonadal state; whereas, progesterone significantly increased resting rCBF in the mPFC and putamen compared with the hypogonadal state. The results of functional connectivity analyses investigating the effects of hormone condition on the covariance of BA25 with the default resting network are pending. Our findings that estradiol regulates activity within BA25 have implications for understanding the potential impact of estradiol on mood. The subgenual cingulate (BA25) has been implicated in the modulation of emotion and affective adaptation in humans. Neuroimaging studies have documented both structural and functional abnormalities in BA25 in depression, and differences in the activity of BA25 are proposed to underlie some of the therapeutic benefits of deep brain stimulation in depression. Finally, resting-state BA25 connectivity with the default resting network is significantly more robust in patients with mood disorders. Future initiatives will be determined by the results of our current studies examining the effects of gonadal steroids in isolation on regional cerebral blood flow and, by the successful importation of relevant emotion-imaging paradigms (e.g., reward paradigm) for investigating the neurocircuitry of reproductive endocrine-related mood disorders. Finally, recent data has documented the influence of genetic background on cognitive performance and affective adaptation. Thus the imaging studies performed in the GnRH agonist paradigm will provide a unique opportunity to examine the interactions between reproductive hormones and specific genes regulated by ovarian steroids (e.g., catechol-o-methyl transferase and brain-derived neurotrophic factor) on measures of cognitive performance, affective adaptation, and task-activated regional cerebral blood flow. Additionally, in a related project, we demonstrated changes in reward-related neurocircuitry across the normal menstrual cycle with increased activations during the expectancy of the reward during the follicular phase, when estradiol levels are high. These data demonstrate, for the first time in humans, that ovarian steroids modulate reward system function, with increased follicular phase activation of the orbitofrontal cortex and amygdala during reward anticipation and of the midbrain, striatum, and left ventrolateral prefrontal cortex (VLPFC) during reward delivery. We have further investigated these finding across the menstrual cycle by employing the reward paradigm in women who are participating in the GnRH agonist-induced hypogonadism study in which we examine the effects of estradiol and progesterone separately compared with a hypogonadal state. Preliminary findings demonstrate that both estradiol and progesterone modulate reward-related neurocircuitry. During the anticipation of reward, estradiol increased activity in the amygdala and orbitofrontal cortex compared with the hypogonadal state (consistent with our previous data across the menstrual cycle), and progesterone increased activity within the right inferior frontal gyrus compared with both estradiol and hypogonadism. These data suggest a substrate in which changes in gonadal steroids could modulate affective state, and are consistent with preclinical studies that document the modulatory effects of ovarian steroids on reward-related behaviors and brain regions, as well as a growing literature demonstrating the importance of the reward system in depression. We are awaiting completion of the analyses of possible diagnostic differences (i.e., PMD versus controls) in ovarian steroid-related alterations of reward neurocircuitry. In our previous studies of the effects of gonadal steroids on stress responsivity, we identified that progesterone rather than estradiol has a greater impact on HPA axis activation in humans, unlike in rodents, but the response to progesterone appears to differ in women with PMD and controls. We have begun conducting dexamethasone-corticotrophin releasing hormone (dex/CRH) testing in women with PMD and controls in both menstrual cycle and Lupron studies, as this measure is believed to be particularly sensitive to differences in vasopressin and is substantially less difficult to perform. We are awaiting the final results of our dex/CRH studies in women with PMD and asymptomatic controls, who have been tested during each of the three hormone conditions established in the Lupron paradigm. Preliminary data confirm a progesterone-related enhancement of cortisol secretion in both women with and without PMD (albeit largely reflecting an increased secretion in those without PMD), and the failure to suppress CRH-stimulated adrenocorticotrophic hormone (ACTH) secretion in women with PMD (but not controls) during both hypogonadism and estradiol replacement; whereas ACTH secretion is suppressed in both women with PMD and controls during progesterone replaced conditions. First, we intend to evaluate the role of early life trauma in these data, since women with PMD report high rates of early life trauma, and early life trauma accounts for a considerable amount of the variance in the elevated CRH-stimulated ACTH secretion observed in depression. Second, we will compare these data during the Lupron paradigm with dex/CRH tests performed across the menstrual cycle to examine the possible role of neurosteroids in the HPA axis responses in the women with PMD and controls. Finally, our preliminary data suggest an abnormality of HPA axis negative feedback regulation in PMD that could be normalized by progesterone.

在我们对使用PET区域脑血流的早期研究中，我们首次在人类中报道了诱导性性不足的人与消除背侧前额叶皮质中皮质激活的正常模式有关而雌二醇和孕酮的替代均恢复了在工作记忆任务中皮质激活的正常模式。 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）。 在神经影像学过程中，我们采用了几种不同的激活范例，这将使我们既可以改变任务的认知负荷（以及执行任务所涉及的压力水平），并测试与情感障碍现象学更相关的神经回路（即奖励系统）。 例如，使用fMRI和参数变化的工作记忆负载（即N-BACK测试），我们正在测试激素状态变化会导致认知负载和神经生理响应之间的剂量反应曲线的变化。 此外，使用两种功能成像方法（具有重复扫描和fMRI的PET）使用N-BACK任务，我们正在确定每个荷尔蒙阶段每个女性的激活模式，以测试其激活位点的方差。 最后，使用新的分析方法，我们正在测试以下假设：荷尔蒙引起的功能变化包括在静止状态或激活过程中的区域间功能连接的变化。 我们的O15 PET研究的初步结果表明，雌二醇在亚基因扣带回（BA25），内侧前额叶皮层（MPFC），后扣带和帕拉希峰乳房中的静脉静止脑血流（RCBF）活性显着增加。而与性交状态相比，孕酮在MPFC和壳虫中显着增加了RCBF。 功能连通性分析的结果研究了激素条件对BA25与默认休息网络的协方差的影响。 我们的雌二醇调节BA25活动活动的发现对了解雌二醇对情绪的潜在影响具有影响。 亚基因扣带（BA25）与人类情绪和情感适应的调节有关。 神经影像学研究已经证明了BA25的结构和功能异常，并提出BA25活性的差异是为了是抑郁症深脑刺激的某些治疗益处。 最后，对于情绪障碍患者，与默认静止网络与默认静止网络的静止状态BA25连接更加强大。 未来的举措将取决于我们目前的研究结果，研究了孤立的性腺类固醇对区域脑血流的影响，以及成功地进口相关的情绪成像范式（例如，奖励范式），以研究调查生殖性内分泌释放的情绪情绪分散的神经记录。 最后，最近的数据记录了遗传背景对认知表现和情感适应性的影响。 因此，在GNRH激动剂范式中进行的成像研究将提供一个独特的机会，以检查生殖激素与受卵巢类固醇调节的特定基因之间的相互作用（例如，结性激素 - 甲基转移酶和脑源性神经营养因子）对认知性能的测量，情感适应性造成的造成造成的造成的造成造成的造成的造成造成的造成的表现。 此外，在一个相关的项目中，我们证明了整个正常月经周期中与奖励相关的神经记录的变化，当雌二醇水平较高时，在卵泡期期望奖励期间的激活增加。 这些数据表明，在人类中，卵巢类固醇首次调节奖励系统功能，并在奖励预期期间增加了眶额皮层和杏仁核的卵泡相激活，并且在奖励交付过程中，中间脑，纹状体以及左侧脑外侧前额叶皮层（VLPFC）。 我们通过在参与GNRH激动剂诱导的性腺功能障碍研究的女性中采用奖励范式来进一步研究了整个月经周期的发现，在这些女性中，我们研究了雌二醇和孕酮与降低状态相比的影响。 初步发现表明，雌二醇和孕激素都调节了与奖励相关的神经记录。 在预期奖励期间，与性交状态相比，雌二醇增加了杏仁核和眶额皮层的活性（与我们先前的月经周期中的先前数据一致），与右下角右下角相比，孕酮的活性增加了，与雌二醇和低胆管化相比。 这些数据表明，在性腺类固醇中的变化可以调节情感状态，并且与临床前研究相一致，该研究记录了卵巢类固醇对奖励相关行为和大脑区域的调节作用，以及越来越多的文献证明了奖励系统在抑郁症中的重要性。 我们正在等待完成卵巢类固醇相关的奖励神经记录改变的可能诊断差异（即PMD与对照组）的分析。 在我们先前关于性腺类固醇对应激反应性作用的研究中，我们确定孕酮而不是雌二醇对人类的HPA轴激活有更大的影响，与啮齿动物不同，但对孕激素的反应在PMD和对照的女性中似乎有所不同。 我们已经开始在月经周期和卢普朗研究中进行PMD和对照的女性中的释放激素释放激素（DEX/CRH）测试，因为据信这种措施对加压素的差异特别敏感，并且很难进行。 我们正在等待在PMD和无症状对照女性中进行DEX/CRH研究的最终结果，这些妇女在Lupron范式中建立的三种激素条件中的每一个中都进行了测试。 初步数据证实了患有和没有PMD的女性皮质醇分泌的孕激素相关的增强（尽管在很大程度上反映了没有PMD的患者的分泌增加），并且未能抑制CRH刺激的肾上腺皮质营养性激素（ACTH）在PMD和PMD中的妇女分泌（但没有对照组）（但未在Hypogonad oppect中），并且没有抑制CRH的分泌。而在孕激素期间，患有PMD的女性和对照组都抑制了ACTH分泌。 首先，我们打算评估早期生命创伤在这些数据中的作用，因为PMD的女性报告了早期生命创伤的率很高，而早期生命创伤则是CRH刺激的ACTH升高的ACTH分泌物在抑郁症中观察到的差异。 其次，我们将在Lupron范式期间将这些数据与在月经周期进行的DEX/CRH测试进行比较，以检查神经类固醇在PMD和对照女性中HPA轴反应中的可能作用。 最后，我们的初步数据表明，PMD中HPA轴负反馈调节的异常，可以通过孕酮标准化。