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

项目 3：应激和富集对 BDNF Val66Met 小鼠模型的影响

基本信息

批准号：
8379158
负责人：
CASEY/LEE
金额：
$ 33.15万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8379158
关键词：
Adolescence Adult Alleles Amygdaloid structure Anatomy Anxiety Behavior Behavioral Behavioral Assay Biological Brain Brain region Brain-Derived Neurotrophic Factor Clinical Pathology Codon Nucleotides Cognitive Development Disease Event Functional disorder Gene Dosage Gene Frequency Genes Genetic Genotype Hippocampus (Brain)Home environment Human Impaired cognition Impairment In Vitro Intervention Knock-in Mouse Lead Learning Life Link Mediating Memory Memory impairment Methionine Modality Molecular Morphology Mus Neuraxis Neuroanatomy Neurons Orphanages Phenotype Play Population Positioning Attribute Predisposition Prefrontal Cortex Process Proteins Research Design Research Proposals Role Single Nucleotide Polymorphism Stress Structure Symptoms Transgenic Organisms Valine Variant Work biological adaptation to stress environmental enrichment for laboratory animals gain of function genetic variant in vivo mouse development mouse model nervous system development neurodevelopment neuropsychiatry neurotrophic factor novel overexpression postnatal

项目摘要

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.

项目第三