Genetic and environmental factors that alter stress resilience and behavior

改变压力恢复能力和行为的遗传和环境因素

• 批准号: 8715070
• 负责人: Jason D Gray
• 金额: $ 5.51万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8715070
• 关键词: Adult; Affect; Affinity Chromatography; Alleles; Animal Model; Animals; Anxiety; Bacterial Artificial Chromosomes; Behavior; Behavioral; Brain; Brain-Derived Neurotrophic Factor; Childhood; Chromosome Mapping; Chronic; Chronic stress; Clinical; Codon Nucleotides; Cognition; Data; Development; Environment; Environmental Risk Factor; Exhibits; Failure; Future; Gene Expression; Gene Expression Profile; Gene Mutation; Gene Targeting; Generations; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Hippocampus (Brain); Human; Individual; Lead; Life Stress; Link; Maps; Mental Depression; Methionine; Modeling; Molecular; Molecular Profiling; Mood Disorders; Moods; Mus; Mutation; Neuronal Plasticity; Neurons; Pattern; Performance; Phenotype; Physiological; Population; Predisposition; RNA; RNA Sequence Analysis; RNA Sequences; Recovery; Reporter; Research; Research Personnel; Resources; Risk; Rodent Model; Signal Transduction; Stress; Stressful Event; Technology; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Translating; Valine; Vertebral column; Wild Type Mouse; biological adaptation to stress; cognitive function; density; gene function; high throughput analysis; improved; in vivo; insight; mature animal; meetings; mouse model; novel; physical conditioning; promoter; public health relevance; research study; resilience; response; restraint stress; stress disorder; stress resilience; transcriptome sequencing

DESCRIPTION (provided by applicant): Stress in the environment can lead to the development of a mood disorder. Yet, not everyone exposed to a stressful event develops a mood disorder. This suggests that mood disorders result from a unique confluence of genetic and environmental factors. While some factors have been identified that can increase susceptibility to mood disorders, the mechanisms underlying normal recovery after stress (resilience) or failure to recover (loss of resilience) remain unknown. This proposal will use rodent models of chronic restraint stress (CRS) and early life stress (ELS), which have been shown to alter mood-related behaviors and induce morphological and functional changes in the hippocampus to study recovery from stress as a model of susceptibility to mood disorders. The CA3 region of hippocampus is particularly sensitive to the effects of both CRS and ELS, therefore a novel transgenic reporter mouse in which EGFP has been fused to the L10a ribosomal subunit under control of a CA3-specific promoter (Gprin3) will be used to isolate in vivo translating RNA from CA3 neurons. Use of RNA-sequencing technology will allow for high-throughput analysis of gene expression changes implicated in neuroplasticity after CRS, recovery from CRS, and ELS in this highly dynamic subpopulation of neurons. These results will provide a map of altered gene function in normal resilience and impaired resilience, identifying genes that normally recover after CRS, but fail to recover when CRS is combined with ELS. Changes in expression will be correlated with the altered behavioral endpoints expected after ELS. Additionally, this proposal will use a genetic model of increased susceptibility to stress and mood disorders, the BDNF-Val66Met mouse, to study impaired resilience. This mutation in brain derived neurotrophic factor (BDNF) results in the substitution of a valine for a methionine in codon 66 (Val66Met). In clinical populations, carriers of the Met allele exhibit decreased hippocampal function and increased risk of mood disorders. Further, Met allele carriers exposed to ELS have reduced hippocampal volumes and altered BDNF levels as adults. The mouse model of this mutation exhibits anxiety and depression-like behaviors believed to recapitulate the human phenotype and is more vulnerable to CRS, but the effects of ELS on Val66Met mice have not been investigated. This study will use the Val66Met mice in combination with the CA3-reporter mice previously described to investigate the impact of a genetic predisposition to mood disorders on gene expression in CA3. Double transgenic mice will be subjected to ELS and CRS, combining genetic and environmental susceptibilities, to study their impact on gene expression in CA3 neurons as well as the still uncharacterized behavioral effects of ELS on BDNF-Val66Met mice. These experiments will identify genes that fail to recover after CRS, as a result of this highly prevalent genetic mutation, when compared with expression patterns from normal recovery. These gene expression profiles will provide new insight into BDNF's function in stress-induced neuroplasticity and identify new targets for the treatment of mood disorders.

描述（由申请人提供）：环境中的压力会导致情绪障碍的发展。但是，并不是每个人都面临压力大事会发展出情绪障碍。这表明情绪障碍是由于遗传和环境因素的独特融合而引起的。尽管已经确定了一些可以增加对情绪障碍敏感性的因素，但压力（弹性）或未能恢复（恢复能力丧失）后正常恢复的机制仍然未知。该建议将使用慢性约束应力（CRS）和早期生命压力（ELS）的啮齿动物模型，这些模型已证明会改变与情绪相关的行为，并在海马中诱导形态学和功能变化，以研究从压力中恢复作为对情绪障碍易感性的模型的恢复。海马的CA3区域对CRS和EL的作用尤其敏感，因此，在CA3特异性启动子（GPRIN3）控制的L10A核糖体亚基（GPRIN3）下，EGFP已与L10A核糖体亚基融合在一起，将用于分离Ca3神经元的Vivo转换RNA。 RNA序列技术的使用将允许对CRS后神经可塑性的基因表达变化进行高通量分析，在这种高度动态的神经元亚群中，从CRS之后的神经可塑性和ELS进行了高通量分析。这些结果将提供正常弹性和弹性受损的基因功能改变的图，鉴定通常在CRS之后恢复但与EL相结合时无法恢复的基因。表达变化将与EL后预期的行为终点改变相关。此外，该提案将使用增加压力易感性和 情绪障碍，BDNF-VAL66MEM小鼠，以研究弹性受损。大脑衍生的神经营养因子（BDNF）中的这种突变导致在密码子66中替代甲氨酸甲氨酸（Val66met）。在临床人群中，MET等位基因的载体表现出降低的海马功能和情绪障碍风险的增加。此外，接触ELS的MED等位基因载体减少了海马体积和成年人的BDNF水平改变。该突变的小鼠模型表现出焦虑和抑郁样的行为，被认为可以概括人类表型，并且更容易受到CRS的影响，但是尚未研究EL对Val666met小鼠的影响。这项研究将使用Val66met小鼠与先前描述的CA3 reporter小鼠结合使用，以研究遗传易感性对情绪障碍对CA3基因表达的影响。双转基因小鼠将对遗传和环境敏感性结合使用ELS和CR，以研究其对CA3神经元中基因表达的影响，以及ELS对BDNF-VAL666MET小鼠的ELS的未表征的行为影响。与正常恢复的表达模式相比，这些实验将确定由于这种高度普遍的基因突变而无法恢复的基因。这些基因表达谱将为BDNF在压力诱导的神经塑性中的功能提供新的见解，并确定治疗情绪障碍的新目标。