Project 1: Impact of BDNF Genotype on Learning and Brain Development

项目1 越来越多的文献表明，脑源性神经营养因子(BDNF)在 神经系统的发育，以及依赖活动的学习和可塑性。脑源性神经营养因子水平 增长超过发展，并在青春期达到顶峰，然后开始稳步下降，并持续到 成人期。脑源性神经营养因子水平的这种变化模式表明，行为和神经解剖学上的差异 在发育过程中，BDNF型之间的差异可能会有所不同。这个项目考察了 独特的人类BDNF Val66Met多态调节上下文、线索和反转学习(灭绝)。 初步成像研究证实，研究中的学习形式在一定程度上取决于 海马体(Amso等人，2005年)、杏仁核(Hare等人，2005年)和腹内侧额前皮质 (包括眶前叶皮质)。这些地区已被证明对环境因素很敏感。 (压力)，在患有临床疾病的儿童中可能受到损害(Thomas等人，2001年)。我们将使用这些 结合结构和功能磁共振成像的行为学习分析 检查与BDNF基因相关的变化的技术。我们将具体研究是否 随着年龄的增长，不同基因类型之间的差异会随着BDNF水平的变化而发生变化 (居中目标1)。我们还将确定是否经历了轻微至中度的环境风险因素 在典型的发展过程中，而不是项目II和项目II中审查的严重早期应激源 3、增强BDNF基因类型之间的差异(中心目标2)。这个项目是直接 由项目III补充，该项目将在人类脑源性神经营养因子基因敲入小鼠模型中使用类似的分析方法 Val66Met突变限制了来自组织学和细胞水平的人类发现 分析。项目I将确定BDNF在不同形式的 并将为解释BDNF基因环境提供坚实的基础 在经历了严重的早期生活压力的青少年群体中的相互作用 机构/孤儿院养育(项目二)。分析和数据管理核心和统计 遗传学核心将支持行为、成像和遗传数据的数据处理和分析。

Project 1 A growing body of literature shows that brain-derived neurotrophic factor (BDNF) plays a significant role in the development of the nervous system, as well as in activity-dependent learning and plasticity. BDNF levels increase over development and peak at adolescence, before beginning a steady decline that continues into adulthood. This pattern of change in BDNF levels suggests that behavioral and neuroanatomical differences between BDNF genotypes may vary across the course of development. This project examines how the uniquely-human BDNF Val66Met polymorphism mediates contextual, cued and reversal learning (extinction). Preliminary imaging studies confirm that the forms of learning under investigation are in part dependent on the hippocampus (Amso et al., 2005), amygdala (Hare et al., 2005) and ventromedial prefrontal cortex (including orbitofrontal cortex). These regions have been shown to be sensitive to environmental factors (stress) and may be compromised in children with clinical disorders (Thomas et al., 2001). We will use these behavioral learning assays in combination with structural and functional magnetic resonance imaging techniques to examine changes associated with BDNF genotype. We will specifically examine whether differences between genotypes change with age as a function of variations in BDNF levels overdevelopment (Center Aim 1). We will also determine whether mild to moderate environmental risk factors experienced over the course of typical development, as opposed to severe early stressors examined in Projects II and III, serve to potentiate differences between BDNF genotypes (Center Aim 2). This project is directly complemented by Project III, which will use similar assays in a BDNF knock-in mouse model of the human Val66Met mutation to constrain human findings with evidence from histological and cellular levels of analysis. Project I will establish the role of BDNF in the typical developmental trajectory of different forms of learning and will provide a solid foundation on which to base interpretations of BDNF gene-environment interactions in a population of adolescents who experienced severe early-life stress in the form of institutional/orphanage rearing (Project II). Both the Analytic and Data Management Core and Statistical Genetics Core will support data processing and analysis of behavioral, imaging and genetic data.