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）在神经系统疾病中起着重要作用。 神经系统的发育，以及活动依赖性学习和可塑性。BDNF水平 随着发育而增加，在青春期达到顶峰，然后开始稳步下降，持续到 成年BDNF水平的这种变化模式表明，行为和神经解剖学差异 BDNF基因型之间的差异可能在整个发育过程中有所不同。这个项目研究了 人类BDNF Val 66 Met多态性介导背景、线索和逆转学习（灭绝） 初步的成像研究证实，正在调查的学习形式部分取决于 海马体（Amso等，2005）、杏仁核（Hare等人，2005）和腹内侧前额叶皮层 （包括眶额皮质）。这些地区已被证明是敏感的环境因素 （压力）并且可能在患有临床病症的儿童中受损（托马斯等人，2001年）。我们将会用这些 结合结构和功能磁共振成像的行为学习测定 技术来检查与BDNF基因型相关的变化。我们将具体研究 基因型之间的差异随着年龄的变化而变化，这是BDNF水平过度发育的函数 （中心目标1）。我们还将确定是否经历了轻度至中度的环境风险因素， 在典型的发展过程中，与项目II中检查的严重早期压力源相反， III，用于增强BDNF基因型之间的差异（中心目标2）。该项目直接 补充项目III，这将使用类似的测定在BDNF基因敲入小鼠模型的人类 Val 66 Met突变限制人类发现，来自组织学和细胞水平的证据表明， 分析.项目I将建立BDNF在不同形式的脑血管病的典型发展轨迹中的作用。 学习，并将提供一个坚实的基础上解释BDNF基因环境 在青少年的人口谁经历了严重的早期生活压力的形式， 机构/孤儿院养育（项目二）。分析和数据管理核心以及统计 Genetics Core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.