Animal Models of Sex-Specific HPA Axis Development

性别特异性 HPA 轴发育的动物模型

基本信息

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
项目类别：
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

项目摘要

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.

近 10% 的美国成年人被认为患有抑郁症除了人类苦难之外，还造成了巨大的经济后果。越来越多的研究指出下丘脑-垂体-肾上腺（HPA）轴疾病参与病因学和重度抑郁症的症状学。该提案的重点是室旁核下丘脑 (PVN) 作为 HPA 轴的关键最终共同整合位点和输出途径。 PVN 是调节体内平衡、神经内分泌和行为功能的关键核。核与其他大脑区域类似，发育也经历了几个关键的发育阶段，这些阶段可以简单地通过神经元的产生、神经元迁移到适当的位置、新神经元的生死选择，细胞表型的建立，最后的建立的功能连接。我们当前和拟议的研究计划测试了每个方面的假设 PVN 发育的影响，因为它们可能作为胎儿先兆导致成人功能障碍，其中可能包括对重度抑郁症的易感性。 PVN 的形成和功能取决于 a 的表达一方面是转录因子的数量，另一方面是选定的效应分子。有两个介导这种影响的机制的基本假设。有人认为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。经过相反，我们假设 PVN 分化的改变继发于 PVN 神经元的位置以及许多因素对于确定正常神经元至关重要 PVN 地区的迁移。我们的具体目标将测试有关角色作用的几个假设 PVN 发育不同阶段的几种效应分子。我们会问细胞的图案是什么迁移到 PVN，然后一氧化氮、γ-氨基丁酸 (GABA) 和脑源性如何神经营养因子（BDNF）可能在核组织中发挥特定作用。我们将在中提出这些问题男性和女性之间潜在差异的背景，以确定性别差异如何 HPA 轴的发育可能会增加女性患抑郁症的风险。