Animal Models of Sex-Specific HPA Axis Development

性别特异性 HPA 轴发育的动物模型

• 批准号: 8101016
• 负责人: JILL M GOLDSTEIN
• 金额: $ 23.68万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101016
• 关键词: ARNT2 gene; Adrenal Glands; Adult; Affect; Agonist; Animal Model; Behavioral; Biological Assay; Brain region; Brain-Derived Neurotrophic Factor; Cell Death; Cell Nucleus; Cells; Cessation of life; Characteristics; Companions; Data; Date of birth; Depressive disorder; Development; Developmental Process; Disease; Economics; Embryo; Employee Strikes; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Etiology; Exposure to; Female; Functional disorder; Generations; Genes; Genetic; Glucocorticoids; Hand; Hormones; Human; Hypothalamic Diseases; Hypothalamic structure; Immigration; In Vitro; Knock-out; Knockout Mice; Label; Lead; Life; Link; Location; Major Depressive Disorder; Mediating; Mental Depression; Modeling; Movement; Mus; National Institute of Mental Health; Neurons; Neurosecretory Systems; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type I; Nuclear; Output; Pathway interactions; Pattern; Peptides; Phase; Phenotype; Pituitary Gland; Play; Population; Positioning Attribute; Predisposition; Research; Research Personnel; Risk; Role; Secondary to; Sex Characteristics; Site; Staging; Structure; System; Testing; Time; Video Microscopy; base; behavior test; calbindin; capsule; cell motility; depressive symptoms; fetal; gamma-Aminobutyric Acid; hypothalamic-pituitary-adrenal axis; in vivo; knockout gene; male; migration; mouse model; neurogenesis; paraventricular nucleus; prenatal exposure; programs; promoter; protein expression; receptor; research study; selective expression; sex; sry Genes; synergism; tool; transcription factor

Almost 10 percent of the adult US population have been suggested to suffer from a depressive illness with large economic consequences in addition to human suffering. A growing number of studies have pointed to the involvement of disorders of the hypothalamic-pituitary-adrenal (HPA) axis in the etiology and symptomatology of major depressive disorders. This proposal focuses on the paraventricular nucleus of the hypothalamus (PVN) as the key final common integration site and output pathway of the HPA axis. The PVN is a key nucleus for regulating homeostatic, neuroendocrine, and behavioral functions. Nuclear development, similar to other brain regions, proceeds through several key developmental phases that can be characterized simply by the generation of neurons, the migration of neurons to proper positions, the choice of life or death for new neurons, the establishment of cell phenotypes, and finally the establishment of functional connections. Our current and proposed research plan tests hypotheses for each of these facets of PVN development as they may contribute as fetal antecedents to adult dysfunction that may include susceptibility to major depressive disorder. PVN formation and function depends upon the expression of a number of transcription factors on one hand and selected effector molecules on the other. There are two basic hypotheses for mechanisms by which this influence is mediated. One suggests that these transcription factors are critical for the terminal differentiation of PVN neurons that remain in their normal locations. By contrast, we hypothesize that there are alterations in PVN differentiation that are secondary to alterations in the positions of PVN neurons and that a number of factors are critical for determining normal neuronal migration in the region of the PVN. Our specific aims will test several hypotheses concerning the role of several effector molecules in different stages of PVN development. We will ask what is the pattern of cell migration to the PVN and then how nitric oxide, gamma-aminobutyric acid (GABA), and brain-derived neurotrophic factor (BDNF) may play specific roles in nuclear organization. We will ask these questions in the context of potential differences between males and females to determine how sex differences in the developing HPA axis might contribute to the greater risk of depression in females.

已有几乎10％的美国人口被认为患有抑郁疾病 除了人类苦难之外，还会造成巨大的经济后果。越来越多的研究指出 下丘脑 - 垂体 - 肾上腺（HPA）轴的疾病参与病因学和 主要抑郁症的症状。该提议着重于 下丘脑（PVN）是HPA轴的关键最终共同整合位点和输出途径。 PVN 是调节稳态，神经内分泌和行为功能的关键核。核 类似于其他大脑区域的发展贯穿了几个关键的发展阶段 仅仅以神经元的产生，神经元向适当位置的迁移，特征 选择新神经元的生与死，建立细胞表型，最后是机构 功能连接。我们目前和拟议的研究计划测试这些方面的假设 PVN发育的发展可能会成为成人功能障碍的胎儿先例，其中可能包括 对重度抑郁症的敏感性。 PVN的形成和功能取决于A的表达 一方面的转录因子的数量，另一方面是选定的效应分子。有两个 对这种影响介导的机制的基本假设。有人建议这些转录 因素对于保留在正常位置的PVN神经元的终末分化至关重要。经过 对比，我们假设PVN分化发生了变化，这是继此次改变的变化 PVN神经元的位置，许多因素对于确定正常神经元至关重要 PVN区域的迁移。我们的具体目的将检验一些有关作用的假设 在PVN发育的不同阶段，有几个效应分子。我们会问什么是单元格的模式 迁移到PVN，然后迁移到一氧化氮，γ-氨基丁酸（GABA）和脑衍生 神经营养因子（BDNF）可能在核组织中起特殊的作用。我们将在 男性和女性之间潜在差异的背景，以确定性别差异如何 开发HPA轴可能会导致女性抑郁症的更大风险。