Impact of BDNF Genotypes and Stress on Learning and Brain Development

总体中心摘要 此应用程序是响应程序公告（PA）编号PAR-06-053跨学科发展中心心理健康（IDSC）：成熟中心（P50）。拟议的中心代表了一群杰出科学家的独特人才，他们在认知和情感发展以及系统级神经科学，儿科成像，分子生物学，小鼠模型和生物统计分析方面具有专业知识。我们将使用内表型方法来检查脑源性神经营养因子（BDNF）和经验事件（例如，压力和丰富）跨越发展的三种形式的学习（上下文，线索，灭绝）及其相关的神经回路。这些学习系统的破坏是许多形式的精神疾病的核心，使我们能够检查脆弱性和抵抗精神病理学作为压力和基因型的函数。这一建议的优势在于对人类和动物项目进行了优雅的绘图，这样转基因小鼠模型将为人类发育中的基因-环境相互作用提供一个受约束的解释。该中心由3个高度相互依赖的项目和2个核心（行政和数据管理核心和统计遗传学核心）组成，旨在为每个项目提供资源和支持。中心有三个首要目标。首先，使用人类成像和动物模型，我们将跟踪参与学习的脑系统的发育轨迹作为BDNF基因型的函数（项目I和III）。第二，我们将描述不同形式的压力的影响，包括早期的严重压力 （项目II和III）和当前，轻度应激（项目I）对这些脑系统在发展过程中作为BDNF基因型的功能。第三，我们将测试作为BDNF基因型功能的内表型差异在多大程度上可以被遗传或环境拯救（项目I，II和III）。拟议的研究将共同测试三组关于BDNF背景下基因-环境相互作用在学习和发展中的作用的假设。这些假说包括有关以下方面的预测：1）学习的行为和神经解剖学测量的变化作为BDNF基因型和BDNF水平的发育变化的函数; 2）BDNF基因型如何调节逆境对学习和相关电路的影响;以及3）通过环境和/或遗传操作拯救BDNF表型。

OVERALL CENTER ABSTRACT This application is in response to Program Announcement (PA) Number PAR-06-053 Interdisciplinary Developmental Centers for Mental Health (IDSC): Mature Centers (P50). The proposed Center represents a unique marshaling of the talents of a distinguished group of scientists with expertise in cognitive and affective development and systems-level neuroscience, pediatric imaging, molecular biology, mouse models, and biostatistical analysis. We will use an endophenotype approach to examine the impact of brain-derived neurotrophic factor (BDNF) and experiential events (e.g., stress and enrichment) across development on three forms of learning (contextual, cued, extinction) and their associated neural circuitry. Disruption of these learning systems is at the core of many forms of psychiatric disorders, allowing us to examine vulnerability and resistance to psychopathology as a function of stress and genotype. The strength of this proposal is the elegant mapping of human and animal projects, such that transgenic mouse models will provide a constrained interpretation of gene-environment interactions in developing humans. The Center is comprised of 3 highly interdependent projects and 2 cores (Administrative and Data Management Core and Statistical Genetics Cores) designed to provide resources and support for each of the projects. There are three overarching Center aims. First, using both human imaging and animal models, we will track the developmental trajectory of brain systems involved in learning as a function of BDNF genotype (Projects I and III). Second, we will characterize the impact of different forms of stress, including early, severe stress (Projects II and III) and current, mild stress (Project I) on these brain systems during development as a function of BDNF genotype. Third, we will test the extent to which the endophenotypic differences as a function of BDNF genotype can be rescued genetically or environmentally (Project I, II, and III). The proposed studies will collectively test three sets of hypotheses about the role of gene-environment interactions in learning and development in the context of BDNF. These hypotheses include predictions pertaining to: 1) changes in behavioral and neuroanatomical measures of learning as a function of both BDNF genotype and developmental changes in BDNF levels; 2) how BDNF genotype modulates the impact adversity on learning and associated circuitry; and 3) rescue of BDNF phenotype through environmental and/or genetic manipulations.