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: 10929822
• 负责人: Peter Schmidt
• 金额: $ 33.73万
• 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/10929822
• 关键词: Acute; Affect; Affective; Agonist; Allopregnanolone; Amygdaloid structure; Back; Behavior; Bilateral; Biological; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cell Line; Cell Nucleus; Cells; Cerebrovascular Circulation; Child; Clinical Protocols; Cognition; Cognitive; Collaborations; Complex; Corpus striatum structure; Data; Development; Dopamine; Dose; Estradiol; Evaluation; Exposure to; Functional Magnetic Resonance Imaging; Functional disorder; Future; GABA-A Receptor; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Transcription; Genetic Variation; Genotype; Glutamates; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Hippocampus; Hormonal; Hormones; Human; Hypogonadism; Individual; Individual Differences; Left; Longitudinal Studies; Luteal Phase; Measures; Menopause; Menstrual cycle; Menstruation; Mental Depression; Mood Disorders; Motivation; Mus; Neurons; Neurotransmitters; Ovarian; Ovarian aging; Ovarian hormone; Oxygen; Pathway Analysis; Pathway interactions; Patients; Pattern; Perimenopause; Positron-Emission Tomography; Postpartum Depression; Prefrontal Cortex; Premenopause; Procedures; Progesterone; Proteins; Protocols documentation; Puberty; Regulation; Reporting; Rest; Rewards; Role; Sampling; Scanning; Signal Repression; Signal Transduction; Sorting; Stains; Steroid Receptors; Steroids; Stress; System; Techniques; Testing; Time; Tissues; Variant; Ventral Striatum; Water; Wisconsin; Withdrawal; Woman; Work; behavioral response; cingulate cortex; cognitive performance; density; differential expression; dopaminergic neuron; functional MRI scan; functional genomics; gamma-Aminobutyric Acid; genetic variant; genomic variation; hormone sensitivity; hypothalamic-pituitary-adrenal axis; induced pluripotent stem cell; lymphoblastoid cell line; nerve stem cell; neural circuit; neuroimaging; neurophysiology; neuropsychiatric disorder; neuropsychiatry; neurosteroids; older women; phenomenological models; pleiotropism; preclinical study; premenstrual dysphoric disorder; presynaptic; proliferative phase Menstrual cycle; putamen; response; trafficking; transcriptome; uptake; young woman

This report includes work arising from the following clinical protocols: NCT00026832, NCT00100360, NCT00001177, and NCT00001322. Evidence suggests that genomic variation in sex-steroid receptors or in the systems regulated by sex steroids may contribute to the ovarian hormone-sensitivity observed in PMDD. Thus, as a first step, we examined the effects of common genetic variations in women during each of the hormonal conditions established within the GnRH agonist-induced hypogonadism and ovarian steroid addback protocol. We have tested two specific, common functional variants (BDNF Val66Met and COMT Val158Met) that are both regulated by sex steroids and that are known to alter brain function in specific brain regions including the hippocampus and prefrontal cortex, respectively. In our studies, therefore, we employ these gene variants as probes for the impact of genetic substrates on the effects of ovarian steroids on womens brain function. A post hoc sensitivity analysis demonstrated that the effects of both BDNF and COMT genotypes were only evident in the presence of estradiol, and the differences in WM-related rCBF were brain region-specific: the effects of COMT genotype were only observed in the DLPFC regardless of the BDNF genotype, whereas the differences in rCBF between the BDNF genotype were confined to the hippocampus regardless of the COMT genotype. Overall, the findings from these studies demonstrate that in women, variations in genes putatively regulated by ovarian steroids impact functional neurocircuitry in a brain-region- and hormone-specific manner here, specifically, interactions between BDNF and COMT genotypes and estradiol on the activation of functional neurocircuitry in the hippocampus (where BDNF is highly expressed) and the DLPFC (where COMT has primacy for dopamine trafficking), respectively. Although sex steroids display pleiotropic effects within the CNS, their actions are often tissue-specific and reflect the effects of local tissue-specific regulators that facilitate sex steroid signaling in one tissue and inhibit or repress the signal in another tissue. Our findings demonstrate how genetic context could modulate the regulatory actions of sex steroids on the functions of specific brain regions involved in the pathophysiology of neuropsychiatric conditions, including the PFC and hippocampus. Additionally, these data suggest that effects of genes or hormones may not be identified if examined in isolation, given the impact of their interactions. Finally, we will probe the roles of variation in sex steroid-regulated genes on brain development across puberty, a time when the brain is re-exposed to sex steroids at gonadarche. In a separate study in which we examined presynaptic dopamine synthesis capacity in thirty-one healthy, regularly menstruating women, who underwent 18F-FDOPA PET scanning. Eleven women were scanned during the follicular phase and twenty women during the luteal phase. We documented increased 18F-FDOPA uptake in the follicular relative to luteal phase in bilateral striatum, including left putamen and right ventral striatum. Overall. we observed greater 18F-FDOPA uptake in women assessed during epochs of the menstrual cycle associated with relatively higher estradiol levels (follicular vs. luteal phase). These results align with prior preclinical and human studies demonstrating estradiols modulatory effects on DA function, and, if confirmed in longitudinal samples, may provide direction for future studies on neuropsychiatric disorders in women. Our functional genomic studies in cell lines from both women with and without PMDD and those with and without PPD have pursued our initial findings of altered function of the ESC/E(Z) gene complex in PMDD as follows: First, neuroprogenitor cells (NPCs) were successfully differentiated from induced pluripotent stem cells (iPSCs) made from women with PMDD and control women (confirmed by immunofluorescent staining and transcriptome analysis).Both LCLs and NPCs show signatures of differential gene silencing through similar mechanisms at baseline and in response to ovarian steroids. These findings in NPCs reveal neuronal differences between women with PMDD and controls both at baseline and after ovarian steroids, including ESC/E(Z) targets. Second, we examined the effects of a 24-hr dose of allopregnanolone (ALLO) on the GABAergic system gene expression in lymphoblastoid cell lines (LCLs) derived from patients with postpartum depression (PPD, n=8) and controls (n=6). Findings demonstrated differential expression of several genes including GABAR2, a GABA receptor, and GAD1, which synthesizes GABA. Pathway analysis revealed that the 24-hr ALLO exposure affected pathways involved in cell signaling, protein processing, and transcription. These data further inform our understanding of the potential mechanisms involved in the effects of brexanolone (ALLO) in mood disorders including PPD. We also are currently performing a study in which cultured iPSC lines from patients with PMDD and controls, that will be differentiated into neural stem cells (which will later be further differentiated into glutamatergic and dopaminergic neurons) to examine the effects of ALLO on these important neurotransmitter systems. In parallel, in the coming year, we will use single-nucleus sequencing to examine the effects of ALLO on gene expression in several regions of the mouse brain implicated in mood disorders and motivation (such as the striatum, hippocampus, amygdala, and prefrontal cortex). Finally, we have completed a high-density longitudinal study of women as they transition through the menopause. Our previous studies demonstrated the absence of an effect of acute loss of ovarian steroid exposure (i.e., hypogonadism) in younger premenopausal women. We now confirm a similar pattern of effects with no differences in cognitive performance in older women as they transition across the menopause. We will examine individual differences in menopause-related changes in cognition; however, the group as a whole demonstrates the lack of impact of the menopause transition in healthy, non-depressed women in the setting of ovarian aging.

本报告包括以下临床方案的工作：NCT00026832、NCT00100360、NCT00001177 和 NCT00001322。 有证据表明，性类固醇受体或性类固醇调节系统的基因组变异可能导致经前抑郁症中观察到的卵巢激素敏感性。因此，作为第一步，我们检查了在 GnRH 激动剂诱导的性腺功能减退症和卵巢类固醇加回方案中建立的每种激素条件下，女性常见遗传变异的影响。我们测试了两种特定的常见功能变体（BDNF Val66Met 和 COMT Val158Met），它们均受性类固醇调节，并且已知会分别改变特定大脑区域（包括海马体和前额皮质）的大脑功能。因此，在我们的研究中，我们利用这些基因变异作为探针，研究遗传底物对卵巢类固醇对女性大脑功能影响的影响。 事后敏感性分析表明，BDNF 和 COMT 基因型的影响仅在存在雌二醇的情况下才明显，并且 WM 相关 rCBF 的差异是脑区域特异性的：COMT 基因型的影响仅在 DLPFC 中观察到，无论是否存在。 BDNF 基因型的差异，而无论 COMT 基因型如何，BDNF 基因型之间 rCBF 的差异仅限于海马。总体而言，这些研究的结果表明，在女性中，假定由卵巢类固醇调节的基因变异以大脑区域和激素特异性方式影响功能性神经回路，特别是 BDNF 和 COMT 基因型与雌二醇之间的相互作用对激活分别位于海马体（BDNF 高度表达）和 DLPFC（COMT 在多巴胺运输中起主要作用）的功能神经回路。尽管性类固醇在中枢神经系统内表现出多效性，但它们的作用通常是组织特异性的，反映了局部组织特异性调节剂的作用，这些调节剂促进一个组织中的性类固醇信号传导并抑制或抑制另一组织中的信号。我们的研究结果表明，遗传背景如何调节性类固醇对参与神经精神疾病病理生理学的特定大脑区域（包括前额皮层和海马体）功能的调节作用。此外，这些数据表明，考虑到基因或激素相互作用的影响，如果单独检查，可能无法识别基因或激素的影响。最后，我们将探讨性类固醇调节基因的变异对青春期大脑发育的作用，青春期是大脑在性腺初现时重新暴露于性类固醇的时期。 在另一项研究中，我们检查了 31 名健康、月经规律的女性的突触前多巴胺合成能力，这些女性接受了 18F-FDOPA PET 扫描。十一名女性在卵泡期接受扫描，二十名女性在黄体期接受扫描。我们记录了双侧纹状体（包括左壳核和右腹侧纹状体）中卵泡相对于黄体期的 18F-FDOPA 摄取增加。全面的。我们观察到，在月经周期各个时期评估的女性中 18F-FDOPA 摄取量较高，与相对较高的雌二醇水平（卵泡期与黄体期）相关。 这些结果与先前的临床前和人体研究一致，证明雌二醇对 DA 功能具有调节作用，如果在纵向样本中得到证实，可能为未来关于女性神经精神疾病的研究提供方向。 我们对患有和不患有经前抑郁症 (PMDD) 以及患有和不患有产后抑郁症 (PPD) 的女性的细胞系进行功能基因组研究，初步发现 ESC/E(Z) 基因复合物在经前抑郁症 (PMDD) 中的功能改变如下：首先，神经祖细胞 (NPC)成功地从患有经前抑郁症 (PMDD) 女性和对照女性的诱导多能干细胞 (iPSC) 中分化出来（通过免疫荧光染色和转录组分析证实）。LCL 和 NPC 都显示差异基因的特征通过类似的机制在基线和对卵巢类固醇的反应中沉默。这些 NPC 的发现揭示了患有经前抑郁症 (PMDD) 的女性和对照组女性在基线和卵巢类固醇治疗后的神经元差异，包括 ESC/E(Z) 目标。其次，我们研究了 24 小时剂量的四氢孕酮 (ALLO) 对源自产后抑郁症患者 (PPD，n=8) 和对照 (n=6) 的类淋巴母细胞系 (LCL) 中 GABA 能系统基因表达的影响。研究结果证明了几个基因的差异表达，包括 GABAR2（一种 GABA 受体）和 GAD1（合成 GABA）。通路分析显示，24 小时 ALLO 暴露影响了细胞信号传导、蛋白质加工和转录相关的通路。这些数据进一步帮助我们了解 brexanolone (ALLO) 对包括 PPD 在内的情绪障碍的影响的潜在机制。 我们目前还正在进行一项研究，其中培养来自 PMDD 患者和对照的 iPSC 系，这些细胞将分化为神经干细胞（随后将进一步分化为谷氨酸能和多巴胺能神经元），以检查 ALLO 对这些重要神经递质的影响系统。与此同时，在接下来的一年中，我们将使用单核测序来检查 ALLO 对与情绪障碍和动机有关的小鼠大脑多个区域（例如纹状体、海马体、杏仁核和前额皮质）基因表达的影响）。 最后，我们完成了一项针对女性更年期过渡的高密度纵向研究。我们之前的研究表明，对于年轻的绝经前女性来说，卵巢类固醇暴露的急性丧失（即性腺功能减退症）不会产生影响。我们现在证实了类似的影响模式，老年女性在更年期过渡时的认知表现没有差异。我们将研究更年期相关认知变化的个体差异；然而，该群体作为一个整体表明，在卵巢老化的情况下，更年期过渡对健康、非抑郁的女性缺乏影响。