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.

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。这些发现对于理解女性卵巢类固醇认知/行为影响的个体差异的神经生物学基础也具有临床意义，并且可能为理解与生殖激素相关的神经精神疾病以及疾病表达中存在性别差异的疾病提供神经遗传学框架。 。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。 我们对患有和未患有经前抑郁症 (PMDD) 的女性的细胞系进行功能基因组研究，初步发现了 ESC/E(Z) 基因复合物在经前抑郁症 (PMDD) 中的功能改变：首先，神经祖细胞 (NPC) 成功地从诱导多能细胞中分化出来。由患有经前抑郁症 (PMDD) 的女性和对照女性制成的干细胞 (iPSC)（通过免疫荧光染色和转录组分析证实）。类淋巴母细胞系 (LCL) 和 NPC 之间的基因表达重叠表明，对 PMDD 病理生理学潜在重要的几个基因和基因通路在两者中均表达。事实上，LCL 和 NPC 都通过相似的基线机制和对卵巢类固醇的反应显示出差异基因沉默的特征。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，我们采用了两种库存神经元细胞系：Luhmes细胞，其是永生化神经元前体细胞系（未分化/神经元前体和分化/成熟多巴胺能神经元），以及SH-SY5Y，其是一种以肾上腺素能神经元为特征的永生化神经母细胞系。和多巴胺能表型。两种储备神经元细胞系均含有 ESC/E(Z) 基因复合体功能和对卵巢类固醇反应性的证据。因此，这些数据为我们在几种病理生理学相关组织（即人类 NPC，两种库存神经元细胞系）中的类淋巴母细胞系（免疫源组织）中的初步发现的神经相关性提供了强有力的支持证据。 我们正在完成一项针对更年期女性的高密度纵向研究。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。