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

这个项目的目标是使用大鼠的情绪反应和社会压力模型来测试新的候选基因的功能，这些候选基因来自于患有严重情绪障碍(严重抑郁症和双相情感障碍)的受试者死后大脑中的微阵列研究。在这个建议中，我们发展了一个特定的假设，并描述了将被用来在情绪和情感上牵连一群新奇候选人的策略。人类微阵列研究(在综述和项目1中描述)指出，与对照受试者相比，严重抑郁症患者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变化。这种基因表达的变化在双相情感受试者的大脑中看不到。成纤维细胞生长因子家族参与了大脑发育和分化的控制以及神经发生。然而，几乎没有证据表明这个家庭与情绪反应、压力反应或情绪障碍的控制有关。这一系列的发现使我们得出了一个具体的假设，即成纤维细胞生长因子家族与严重抑郁症的病因或表达有关。为了验证这一假设，我们计划使用对压力和类似焦虑的情况(高响应者和低响应者)进行差异反应筛选的大鼠。这使我们能够调查情绪和焦虑湖行为的个体差异与这个基因家族之间的联系。此外，这些动物要么会受到控制，要么会遭到社会的挫败 条件(压力)，我们已经证明可以激活与人类抑郁症相同的神经通路。利用这个动物模型，我们计划解决以下问题：1)高反应者和低反应者在基础上或在社会失败后，成纤维细胞生长因子相关基因的表达是否存在差异？2)在对照动物或社会失败者中，不同类别的抗抑郁药对成纤维细胞生长因子基因的表达有影响吗？3)如果我们给新生大鼠注射成纤维细胞生长因子家族的成员，我们能否将它们与海马体形态和神经发生的变化联系起来，我们能否将这些潜在的变化联系起来，以改变情绪性或应激反应性？总而言之，这些研究是 测试基因的潜在功能，这些基因以前与严重的情绪障碍无关，但其表达在抑郁或躁郁症患者的大脑中发生了显着变化。这将使我们能够扩大我们对与情绪障碍相关的基本分子和神经机制的理解，并开发治疗和预防这些毁灭性疾病的新靶点。

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.