Project 3: Impact of Stress and Enrichment on a Mouse Model of the BDNF Val66Met

项目三 脑源性神经营养因子（BDNF）在脊椎动物神经系统发育中起重要作用。 最近，BDNF基因中的一个单核苷酸多态性（SNP），一个缬氨酸（瓦尔）到甲硫氨酸（Met） 在前结构域（BDNFMet t）中的取代，已显示导致人类中的 海马依赖性记忆、海马体积减小与神经精神病易感性 紊乱利用表达BDNF湿SNP的新型转基因敲入小鼠进行的初步研究， 这使我们假设在成人中枢神经系统中观察到的BDNFMet的生物学后果 系统是由于开发过程中BDNF可用性降低。在这个项目中，我们建议使用 DNFMet敲入小鼠以建立海马（He）的典型发育轨迹， 前额叶皮层（PFC）和杏仁核（AMG），作为BDNF基因型的函数。我们将利用任务， 与项目I中人类研究中提出的几乎相同，以探索不同基因型之间的差异。 发展（中心目标1）。在初步研究中，我们已经确定BDNFMet基因型具有 对He、PFC和AMG的神经解剖学以及它们的相关行为有显著影响。在 随后的研究，环境（压力，富集），以及遗传（BDNF过表达） 干预措施将用于确定BDNF水平变化对整个发展的确切影响。 这些研究将与项目2平行，调查早期生活逆境（孤儿院）的影响， 随后被安置到收养家庭作为基因型因素。项目三的具体目标是 1）确定BDNFMet变体对He、PFC和AMG功能的生物学后果， 2）确定BDNF中压力和基因型之间的相互作用 通过评估He、PFC和AMG功能，以及3）确定 在整个发育过程中对BDNFMet小鼠的He、PFC和AMG功能的影响。

Project III Brain derived neurotrophic factor (BDNF) plays a critical role in vertebrate nervous system development. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene, a valine (Val) to methionine (Met) substitution in the prodomain (BDNFMet t), has been shown to result in impairments in humans in hippocampal dependent memory, decreased hippocampal volume, and susceptibility to neuropsychiatric disorders. Preliminary studies utilizing a novel transgenic knock-in mouse expressing the BDNFwet SNP have led us to hypothesize that the biological consequences of BDNFMet observed in the adult central nervous system are due to reduced BDNF availability during development. In this project, we propose to use the DNFMet knock-in mouse to establish the typical developmental trajectory of the hippocampus (He), prefrontal cortex (PFC), and amygdala (AMG), as a function of BDNF genotype. We will exploit tasks that are nearly identical to those proposed in human studies in Project I, to probe genotypic differences across development (Center Aim 1). In preliminary studies, we have determined that the BDNFMet genotype has significant effects on neuroanatomy of the He, PFC, and AMG, as well as their associated behaviors. In subsequent studies, environmental (stress, enrichment), as well as genetic (BDNF overexpression) interventions will be used to determine the precise impact of changing levels of BDNF across development. These studies will parallel work in Project 2, investigating the impact of early life adversity (orphanage) and subsequent placement into an adoptive home as a factor of genotype. The Specific Aims of Project III are to 1) determine the biological consequences of the variant BDNFMet on He, PFC, and AMG function across development, 2) determine the interaction between stress and genotype across development in BDNF mice through the assessment of He, PFC, and AMG function, and 3) Determine the effect of BDNF gain of function on He, PFC, and AMG function of the BDNFMet mouse across development.