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

项目III 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，脑源性神经营养因子基因的一个单核苷酸多态(SNP)，一个由缬氨酸(Val)转变为蛋氨酸(Met)的基因 原结构域的替换(BDNFMet T)，已被证明会导致人类在 海马区依赖记忆、海马区体积减少以及对神经精神病学的易感性 精神错乱。利用一种新型的表达BDNFwt SNP的转基因敲入鼠的初步研究 这让我们假设，BDNFMet在成年中枢神经系统观察到的生物学后果 这是由于开发期间BDNF可获得性降低。在此项目中，我们建议使用 DNFMet敲入小鼠建立典型的海马区发育轨迹， 前额叶皮质(PFC)和杏仁核(AMG)，作为BDNF基因的一个功能。我们将利用以下任务 与项目I的人类研究中提出的几乎相同，以探索不同基因类型的差异 发展(中心目标1)。在初步研究中，我们已经确定BDNFMet基因有 对He、PFC和AMG及其相关行为的神经解剖学有显著影响。在……里面 随后的研究，环境(压力，富集物)，以及遗传(BDNF过表达) 干预措施将被用来确定在整个发展过程中BDNF水平变化的确切影响。 这些研究将在项目2中并行工作，调查早期生活逆境(孤儿院)和 随后被安置到领养家庭作为一个基因因素。项目III的具体目标是 1)确定BDNFMet变异对HE、PFC和AMG功能的生物学影响 发育，2)确定BDNF在发育过程中应激和基因型之间的交互作用 通过评估小鼠的HE、PFC和AMG功能，以及3)确定BDNF获得的影响 对BDNFMet小鼠的HE、PFC和AMG功能的跨开发。

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.