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产生的工作：NCT 00026832、NCT 00100360、NCT 00001177和NCT 00001322。 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有助于在PMDD中观察到的卵巢激素敏感性。因此，作为第一步，我们研究了在GnRH激动剂诱导的性腺功能减退和卵巢类固醇添加方案中建立的每种激素条件下女性常见遗传变异的影响。我们已经测试了两种特定的，常见的功能变体（BDNF Val 66 Met和COMT Val 158 Met），它们都受到性类固醇的调节，并且已知它们分别改变特定大脑区域（包括海马和前额皮质）的大脑功能。因此，在我们的研究中，我们采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的影响。 事后敏感性分析表明，BDNF和COMT基因型的影响只在雌二醇的存在下是明显的，WM相关的rCBF的差异是脑区域特异性的：COMT基因型的影响只在DLPFC中观察到，而BDNF基因型之间的rCBF的差异仅限于海马，而不管COMT基因型。总的来说，这些研究的结果表明，在女性中，由卵巢类固醇调节的基因p53的变化以脑区域和海马特异性的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海马功能性神经回路的激活（其中BDNF高度表达）和DLPFC（其中COMT对多巴胺运输具有首要作用）。虽然性类固醇在CNS内显示多效性作用，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，抑制或抑制另一个组织中的信号传导。我们的研究结果表明，遗传背景如何调节性类固醇对神经精神疾病的病理生理学所涉及的特定脑区（包括PFC和海马）功能的调节作用。此外，这些数据表明，基因或激素的影响可能无法确定，如果孤立地检查，考虑到它们的相互作用的影响。这些发现也有临床意义，了解卵巢类固醇对女性认知/行为影响的个体差异的神经生物学基础，并可能提供一个神经遗传学框架，了解与生殖激素相关的神经精神疾病以及疾病表达的性别差异。最后，我们将探讨性类固醇调节基因的变化对整个青春期大脑发育的作用，青春期大脑在性腺初显时再次暴露于性类固醇。 我们在患有和不患有PMDD的女性的细胞系中进行的功能基因组研究已经追踪了我们在PMDD中ESC/E（Z）基因复合物功能改变的初步发现，如下：首先，神经祖细胞（NPC）成功地从患有PMDD的女性和对照女性的诱导多能干细胞（iPSC）分化（通过免疫荧光染色和转录组分析证实）。淋巴母细胞样细胞系（LCL）和NPC之间的重叠基因表达揭示了几个基因和基因通路PMDD病理生理学的潜在重要性都在两者中表达。事实上，LCL和NPC在基线和对卵巢类固醇的反应中通过相似的机制显示差异基因沉默的特征。NPC的这些发现揭示了PMDD患者和对照组在基线和卵巢类固醇治疗后的神经元差异，包括ESC/E（Z）靶点。其次，我们采用了两种储备神经元细胞系：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-SY 5 Y，一种以肾上腺素能和多巴胺能表型为特征的永生化神经母细胞系。两种储备神经元细胞系都含有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，这些数据提供了我们在淋巴母细胞样细胞系（免疫源性组织）中的初步发现在几种更多的病理生理学相关组织（即，人NPC，两种储备神经元细胞系）。 我们正在完成一项高密度的纵向研究妇女，因为他们通过更年期过渡。我们以前的研究表明，没有卵巢类固醇暴露的急性损失的影响（即，性腺功能减退）。我们现在证实了一个类似的模式的影响，没有差异的认知表现，老年妇女，因为他们过渡到更年期。我们将研究认知中与更年期相关的变化的个体差异;然而，整个研究表明，在卵巢衰老的背景下，健康、非抑郁的女性更年期过渡缺乏影响。