FOREBRAIN OVEREXPRESSION OF A STRESS-RELATED GENE

前脑中与压力相关的基因过度表达

• 批准号: 7389843
• 负责人: HUDA AKIL
• 金额: $ 25.06万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-25 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7389843
• 关键词: Adolescence; Adolescent; Adult; Animals; Anxiety; Behavior; Behavioral; Brain; Chronic; Cocaine; Cognitive; Condition; Development; Drug abuse; Early treatment; Emotional; Equilibrium; Exhibits; Exposure to; Family; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Gene Expression; Gene Targeting; Genes; Glucocorticoid Receptor; Growth Factor; Growth Factor Gene; Hippocampus (Brain); Human; Life; Ligands; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Target; Morphology; Mus; Neonatal; Neuronal Plasticity; Nucleus Accumbens; Outcome; Pattern; Pharmaceutical Preparations; Phenotype; Predisposition; Process; Prosencephalon; Protein Overexpression; Protocols documentation; Psychotropic Drugs; Purpose; Rattus; Research Personnel; Rewards; Role; Shapes; Staging; Stress; Substance abuse problem; Switch Genes; Synapses; Testing; Time; Tissues; Transact; Transgenic Animals; Transgenic Mice; Transgenic Model; Transgenic Organisms; Weaning; biological adaptation to stress; critical developmental period; drug of abuse; drug reward; genetic manipulation; mouse model; neonatal exposure; neurogenesis; preference; psychostimulant; receptor expression; relating to nervous system; response; social stress

Forebrain Overexpression of a Stress-Related Gene: Impact on Reactivity to Cocaine This project tests the hypothesis that the level of activity of a stress-related gene in the brain, the glucocorticoid receptor (GR) represents a molecular antecedent for increased susceptibility to drugs of abuse. Since the glucocorticoid receptor is a ligand-activated transacting factor that modulates many target genes implicated in emotional behavior and drug reward, and since it is known to mediate stress responsiveness and impact on mechanisms of neural plasticity, it represents a potential key molecular target for modulation of abuse liability. The proposed studies rely on two related mouse transgenic models we have developed: a) a constitutive GR overexpressor (GRov) with increased GR expression in the forebrain only. This animal shows altered emotional reactivity and increased sensitization to cocaine. It also shows significant alterations in the expression of genes implicated in substance abuse as well as neural plasticity genes such as growth factors; b) a new inducible/tissue-specific GR overexpressor (iGRov) in which GR overexpression in the forebrain can be controlled at various stages of development. We plan to determine whether the GRov animals, compared to their wild type littermates, exhibit alterations in hippocampal neurogenesis and morphology and/or changes in expression of neuroplasticity genes basally and after exposure to chronic cocaine. The same panel of genes used in the other three projects will be tested. Using iGRov, 'we plan to ascertain whether there are critical periods in development, includingpre- weaning and adolescence, during which lifelong responsiveness to cocaine can be altered. Finally we will ask whether a single neonatal exposure to fibroblast growth factor 2 (FGF2), which is known to enhance neurogenesis, can counteract the impact of GR overexpression on responsiveness to cocaine under control or social stress conditions. We will ascertain the neural changes associated with this manipulation in the wild type and transgenic animals. These studies will provide a mechanistic examination of the antecedents of substance abuse and will test specifically whether a balance of stress-related genes and growth factor-related genes determines susceptibility to psychoactive drugs and whether there are key developmental windows that impact on it.

压力相关基因的前脑过度表达：对可卡因反应性的影响 该项目测试了这样的假设：大脑中与压力相关的基因的活动水平 糖皮质激素受体（GR）代表了对药物敏感性增加的分子前因 虐待。由于糖皮质激素受体是一种配体激活的反式作用因子，可调节许多靶标 与情绪行为和药物奖励有关的基因，并且已知它可以调节压力 反应性和对神经可塑性机制的影响，它代表了潜在的关键分子靶标 用于调节滥用责任。拟议的研究依赖于我们拥有的两个相关的小鼠转基因模型 发达： a) 组成型 GR 过表达蛋白 (GRov)，仅在前脑中增加 GR 表达。这 动物表现出情绪反应的改变和对可卡因的敏感性增加。也显示出显着的 与药物滥用有关的基因以及神经可塑性基因的表达变化 作为生长因子； b) 一种新的诱导型/组织特异性 GR 过表达蛋白 (iGRov)，其中 GR 过表达在 前脑可以在发育的各个阶段受到控制。 我们计划确定 GRov 动物与其野生型同窝动物相比是否表现出 海马神经发生和形态的改变和/或神经可塑性表达的改变 基因基础上和长期接触可卡因后。其他三个中使用相同的基因组 项目将接受测试。 使用 iGRov，“我们计划确定开发中是否存在关键时期，包括预 断奶和青春期，在此期间对可卡因的终生反应可能会改变。最后我们将 询问单次新生儿是否接触成纤维细胞生长因子 2 (FGF2)，已知该因子可增强 神经发生，可以抵消 GR 过度表达对受控可卡因反应的影响 或社会压力条件。我们将确定与这种野外操作相关的神经变化 型和转基因动物。 这些研究将对药物滥用的前因进行机械检查，并将 具体测试压力相关基因和生长因子相关基因的平衡是否决定 对精神药物的敏感性以及是否有影响它的关键发育窗口。