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: 10703929
• 负责人: Peter Schmidt
• 金额: $ 34.33万
• 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/10703929
• 关键词: Acute; Adrenergic Agents; Affect; Affective; Agonist; Amygdaloid structure; Behavior; Behavioral; Biological; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cell Line; Cells; Cerebrovascular Circulation; Child; Clinical Protocols; Cognition; Cognitive; Collaborations; Complex; Data; Development; Disease; Dopamine; Estradiol; Evaluation; Exposure to; Functional Magnetic Resonance Imaging; Functional disorder; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Variation; Genotype; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Hippocampus (Brain); Hormonal; Hormones; Human; Hypogonadism; Immune; Individual; Individual Differences; Longitudinal Studies; Measures; Menopause; Mental Depression; Mood Disorders; Neurobiology; Neurons; Ovarian; Ovarian aging; Ovarian hormone; Overlapping Genes; Oxygen; Pathway interactions; Pattern; Perimenopause; Phenotype; Positron-Emission Tomography; Prefrontal Cortex; Premenopause; Procedures; Progesterone; Protocols documentation; Puberty; Regulation; Reporting; Rest; Rewards; Role; Sex Differences; Signal Transduction; Stains; Steroid Receptors; Steroids; Stress; System; Techniques; Testing; Time; Tissues; Undifferentiated; Variant; Water; Wisconsin; Withdrawal; Woman; Work; behavioral response; cingulate cortex; clinically relevant; cognitive performance; density; disorder control; dopaminergic neuron; functional MRI scan; functional genomics; genetic variant; genomic variation; hormone sensitivity; hypothalamic-pituitary-adrenal axis; induced pluripotent stem cell; lymphoblastoid cell line; nerve stem cell; neural; neural circuit; neurogenetics; neuroimaging; neurophysiology; neuropsychiatric disorder; neuropsychiatry; neurosteroids; older women; phenomenological models; pleiotropism; precursor cell; premenstrual dysphoric disorder; reproductive hormone; response; trafficking; transcriptome; 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. These findings also have clinical relevance for understanding the neurobiological basis of individual differences in the cognitive/behavioral effects of ovarian steroids in women, and may provide a neurogenetic framework for understanding neuropsychiatric disorders related to reproductive hormones as well as illnesses with sex differences in disease expression. 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. Our functional genomic studies in cell lines from both women with and without PMDD 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). Overlapping gene expression between lymphoblastoid cell lines (LCLs) and NPCs reveals that several genes and gene pathways potentially important for PMDD pathophysiology are expressed in both. Indeed, 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 employed two stock neuronal cell lines: Luhmes Cells, which are immortalized neuronal precursor cell lines (both undifferentiated/neuronal precursors and differentiated/mature dopaminergic neurons), as well as SH-SY5Y, an immortalized neuroblastoid cell line characterized by an adrenergic and dopaminergic phenotype. Both stock neuronal cell lines contained evidence of ESC/E(Z) gene complex function and responsivity to ovarian steroids. Thus, these data provide strong supportive evidence of the neural relevance of our initial findings in lymphoblastoid cell lines (immune-origin tissue) in several more pathophysiologically-relevant tissues (i.e., human NPCs, two stock neuronal cell lines). We are completing 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.

该报告包括由以下临床方案产生的工作：NCT00026832，NCT00100360，NCT00001177和NCT0000001322。 有证据表明，性类固醇受体或性类固醇调节的系统的基因组变异可能有助于PMDD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和卵巢类固醇倒数型方案中，在每种激素中建立的激素中，女性常见遗传变异的影响。我们已经测试了两种由性类固醇调节的特定常见功能变异（BDNF Val66met和COMT Val158met），它们分别在包括海马和前额叶皮层在内的特定脑区域中改变了脑功能。因此，在我们的研究中，我们使用这些基因变异作为遗传底物对卵巢类固醇对女性脑功能的影响的影响的探针。 事后敏感性分析表明，BDNF和COMT基因型的影响仅在雌二醇的存在下才能明显，并且与WM相关的RCBF的差异是大脑区域特异性的：COMT基因型的效果仅在DLPFC中观察到BDNF Genotype resebene bed n eye bdnf ins bd n e rcbff ins y rcbff ins y rcbff。海马，无论COMT基因型如何。总体而言，这些研究的发现表明，在女性中，受卵巢类固醇受调节的基因的变化以大脑和激素特异性的方式影响功能性神经循环，特别是BDNF和COMT基因型与雌二醇之间的相互作用（特定于bdnf和COMT基因型之间的相互作用）（在herelcircitry in efterialcimialciratiate inl bdipciptrry of Hhelimocictry and bdipcoctif）（herimocircitry）（heripcircictry）（heripcircictry）（herimocircitry）（heripcircictry）（herimocictiratient inlipcocicitry） （COMT在多巴胺贩运方面具有至高无上的位置）。尽管性类固醇在中枢神经系统内表现出多效效应，但它们的作用通常是组织特异性的，并且反映了局部组织特异性调节剂的作用，这些调节剂促进了一种组织中的性类固醇信号传导，并抑制或抑制另一种组织中的信号。我们的发现表明，遗传环境如何调节性类固醇对参与神经精神疾病病理生理特定大脑区域功能的调节作用，包括PFC和Hippocampus。此外，这些数据表明，鉴于其相互作用的影响，如果隔离检查，基因或激素的影响可能不会被鉴定出来。这些发现也具有理解卵巢类固醇对女性认知/行为影响的神经生物学基础的临床相关性，并且可能会提供一个神经遗传框架，用于理解与生殖激素以及与疾病表达性别差异的疾病有关的神经精神疾病。最后，我们将探讨性类固醇调节基因在青春期的大脑发育中的变异，这是大脑在性腺上重新暴露于性类固醇的时代。 Our functional genomic studies in cell lines from both women with and without PMDD 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).淋巴母细胞系（LCLS）和NPC之间的重叠基因表达表明，两者中对PMDD病理生理学可能重要的几种基因和基因途径均表达。实际上，LCL和NPC均通过基线时的相似机制和对卵巢类固醇的反应均显示出差异基因沉默的特征。 NPC中的这些发现表明，基线和卵巢类固醇（包括ESC/E（Z）靶标），患有PMDD和对照的女性之间的神经元差异。其次，我们采用了两种库存的神经元细胞系：LUHMES细胞，它们是永生的神经元前体细胞系（均未分化/神经元前体和分化/成熟的多巴胺神经元），以及SH-SY5Y，以及由不朽的神经细胞系的SH-SY5Y，由Adenrennrennren crancren and andrennren ernrenigic and dopamigicatight and dopamigicatign earnciric and dopamigiat nigamigation。两种库存的神经元细胞系都有ESC/E（Z）基因复合功能和对卵巢类固醇的反应的证据。因此，这些数据提供了我们在淋巴细胞细胞系（免疫 - 原始组织）中最初发现的神经相关性的有力支持证据，在其他几种与病理生理学的组织（即人NPC，两个库存神经元细胞系）中的神经相关性。 我们正在完成对女性在更年期过渡时的高密度纵向研究。我们以前的研究表明，年轻的果皮前妇女缺乏卵巢类固醇暴露的急性损失（即性腺功能低下）。现在，我们证实了类似的影响模式，在更年期过渡时，老年妇女的认知表现没有差异。我们将研究与更年期相关的认知变化的个体差异。但是，整个小组表明，在卵巢衰老的情况下，更年期过渡的影响缺乏影响。