Animal Models of Sex-Specific HPA Axis Development

近10%的美国成年人口被认为患有抑郁症， 除了人类的苦难，还有巨大的经济后果。越来越多的研究指出 下丘脑-垂体-肾上腺轴(HPA)紊乱在病因和发病机制中的作用 主要抑郁障碍的症状学。这一建议侧重于脑室旁核。 下丘脑(PVN)是HPA轴的最终共同整合部位和输出通路。PVN 是调节体内平衡、神经内分泌和行为功能的关键核心。核子 发育，类似于其他大脑区域，经历了几个关键的发育阶段，这些阶段可以 简单地说就是神经元的生成，神经元的迁移到适当的位置， 新神经元的生死选择，细胞表型的建立，最后是建立 功能连接。我们当前和提议的研究计划测试了这些方面的假设 PVN的发展，因为它们可能是成人功能障碍的胎儿先兆，可能包括 易患严重抑郁障碍。PVN的形成和功能取决于a基因的表达 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 关于这种影响的调节机制的基本假设。其中一项建议是这些转录 这些因素对于保留在正常位置的PVN神经元的终末分化是至关重要的。通过 相反，我们假设PVN分化中存在继发于 PVN神经元的位置以及一些因素对确定正常神经元是至关重要的 在PVN区域内的迁移。我们的具体目标将检验几个关于 在PVN发育的不同阶段的几个效应分子。我们会问细胞的模式是什么 迁移到PVN，然后一氧化氮，γ-氨基丁酸(GABA)和大脑来源 神经营养因子(BDNF)可能在核组织中发挥特定的作用。我们将在以下时间提出这些问题 男女之间的潜在差异的背景决定了性别差异在 HPA轴的发育可能导致女性患抑郁症的风险更大。

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.