Project 3: Functional Studies of Novel Candidate Genes in the Rat (pgs. 239-258)

项目 3：大鼠新候选基因的功能研究（第 239-258 页）

• 批准号: 6850575
• 负责人: William E BUNNEY
• 金额: $ 28.81万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6850575
• 关键词: antidepressants; anxiety; behavioral /social science research tag; bipolar depression; brain morphology; disease /disorder etiology; emotions; fibroblast growth factor; gene expression; growth factor receptors; hippocampus; laboratory rat; major depression; microarray technology; neurogenetics; neuropathology; neuropharmacology; phenotype; psychobiology; stress; stressor

The goal of this project is to use rat models of emotional reactivity and social stress to test the function of novel candidate genes that arise from microarray studies in human postmortem brains of subjects who suffered from severe mood disorders (major depression and bipolar illness). In this proposal, we develop a specific hypothesis and describe the strategy that will be used to implicate a family of novel candidates in mood and affect. The human microarray studies (described in the Overview and in Project 1) pointed to the family of fibroblast growth factors (FGF's) and their receptors as being altered in frontal cortical regions of severely depressed patients relative to control subjects. This change in gene expression was not seen in the brain of bipolar subjects. The FGF family has been implicated in the control of development and differentiation of the brain and in neurogenesis. However, there was little evidence implicating this family in the control of emotional reactivity, stress responsiveness or mood disorders. The array findings have led us to the specific hypothesis that the FGF family is involved either in the etiology or the expression of severe depression. In order to test this hypothesis, we plan to use rats that have been screened for differential responsiveness to stress and anxiety-like situations (High Responders and Low Responders). This allows us to investigate the connection between individual differences in emotionality and anxiety-lake behavior and this gene family. In addition, these animals will either be handled (controls) or subjected to social defeat conditions (stress), which we have shown to activate the same neural pathways engaged by depression in humans. Using this animal model, we plan to address the following questions: 1) Do high responders and low responders differ in the expression of FGF-related genes, either basally or following social defeat? 2) Do various classes of antidepressants have any effects on the expression of the FGF genes, either in control or in socially defeated animals? 3) If we administer members of the FGF family to newborn rats, can we implicate them in hippocampal morphology and alterations in neurogenesis, and can we link these potential alterations to change in emotionality or stress reactivity? Together, these studies serve as a prototype for testing the potential function of genes that were not previously implicated in the severe mood disorders but whose expression is significantly altered in the brain of depressed or bipolar individuals. This will allow us to extend our understanding of the fundamental molecular and neuralmechanisms associated with mood disorders and to develop novel targets for treatment and prevention of these devastating illnesses.

该项目的目标是使用情绪反应和社会压力的大鼠模型来测试从患有严重情绪障碍（重度抑郁症和双相情感障碍）的人类死后大脑的微阵列研究中产生的新型候选基因的功能。在这一建议中，我们提出了一个具体的假设，并描述了将用于在情绪和情感中暗示一系列新候选人的策略。人类微阵列研究（在概述和项目1中描述）指出，与对照组相比，严重抑郁症患者的额叶皮质区域的成纤维细胞生长因子家族及其受体发生了改变。这种基因表达的变化在双相情感障碍患者的大脑中没有发现。FGF家族与大脑发育和分化的控制以及神经发生有关。然而，几乎没有证据表明这个家族在控制情绪反应、压力反应或情绪障碍方面有作用。这一系列发现使我们提出了一个特定的假设，即FGF家族参与了严重抑郁症的病因学或表达。为了验证这一假设，我们计划使用对压力和焦虑样情况的不同反应进行筛选的大鼠（高反应者和低反应者）。这使我们能够研究情绪和焦虑湖行为的个体差异与该基因家族之间的联系。此外，这些动物要么被处理（控制），要么遭受社会失败