Impact of BDNF Genotypes and Stress on Learning and Brain Development

整体中心摘要 本申请是对项目公告(PA)编号PAR-06-053精神健康跨学科发展中心(IDSC)：成熟中心(P50)的回应。拟议的中心代表着一批杰出的科学家的独特人才集结，这些科学家在认知和情感发展以及系统水平的神经科学、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长。我们将使用内表型方法来研究脑源性神经营养因子(BDNF)和跨越发展的经验事件(例如，压力和丰富)对三种形式的学习(背景学习、线索学习、消亡学习)及其相关神经回路的影响。这些学习系统的中断是许多形式精神障碍的核心，使我们能够检查作为压力和基因功能的精神病理学的脆弱性和抵抗力。这一提议的优势在于完美地绘制了人类和动物项目的图谱，这样转基因小鼠模型将为发育中的人类的基因与环境相互作用提供一种受限的解释。该中心由3个高度相互依存的项目和2个核心(行政和数据管理核心以及统计遗传学核心)组成，旨在为每个项目提供资源和支助。有三个首要的中心目标。首先，使用人类成像和动物模型，我们将跟踪参与学习的大脑系统作为BDNF基因功能的发展轨迹(项目I和III)。其次，我们将描述不同形式的压力的影响，包括早期压力、严重压力 (项目II和项目III)和当前的轻度应激(项目I)在这些大脑系统的发育过程中作为BDNF基因的功能。第三，我们将测试作为BDNF基因功能的内表型差异可以在多大程度上从遗传或环境方面得到挽救(项目I、II和III)。拟议的研究将在BDNF的背景下共同测试关于基因-环境相互作用在学习和发展中的作用的三套假说。这些假说包括以下几个方面的预测：1)学习的行为和神经解剖学测量作为BDNF基因和BDNF水平发育变化的函数的变化；2)BDNF基因如何调节逆境对学习及其相关回路的影响；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.