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: 9127804
• 负责人: Jason D Gray
• 金额: $ 6.2万
• 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/9127804
• 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; DNA Sequence Alteration; Data; Development; Environment; Environmental Risk Factor; Exhibits; Failure; Future; Gene Expression; Gene Expression Profile; Gene Targeting; Generations; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Health; 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; 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; research study; resilience; response; restraint stress; stress disorder; stress reactivity; 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）：环境中的压力可能导致情绪障碍的发生。然而，并不是所有接触压力事件的人都会出现情绪障碍。这表明情绪障碍是遗传和环境因素独特结合的结果。虽然已经确定了一些可能增加情绪障碍易感性的因素，但压力后正常恢复（恢复力）或恢复失败（恢复力丧失）的机制仍然未知。该提案将使用慢性束缚应激（CRS）和早期生活应激（ELS）的啮齿动物模型，这些模型已被证明可以改变与情绪相关的行为并诱导海马体的形态和功能变化，以作为易感性模型来研究从压力中恢复情绪障碍。海马的 CA3 区域对 CRS 和 ELS 的影响特别敏感，因此将使用一种新型转基因报告小鼠来分离 CRS 和 ELS，其中 EGFP 已与 CA3 特异性启动子 (Gprin3) 控制下的 L10a 核糖体亚基融合。体内翻译来自 CA3 神经元的 RNA。 RNA测序技术的使用将允许对这种高度动态的神经元亚群中与CRS后的神经可塑性、CRS恢复和ELS相关的基因表达变化进行高通量分析。这些结果将提供正常弹性和受损弹性中基因功能改变的图谱，识别在 CRS 后通常恢复但在 CRS 与 ELS 结合时无法恢复的基因。表达的变化将与 ELS 后预期的行为终点改变相关。此外，该提案将使用对压力和压力敏感度增加的遗传模型。 情绪障碍，BDNF-Val66Met 小鼠，用于研究受损的恢复力。脑源性神经营养因子 (BDNF) 的这种突变导致密码子 66 (Val66Met) 中的缬氨酸取代甲硫氨酸。在临床人群中，Met 等位基因携带者表现出海马功能下降和情绪障碍风险增加。此外，暴露于 ELS 的 Met 等位基因携带者成年后海马体积减小并改变了 BDNF 水平。这种突变的小鼠模型表现出焦虑和抑郁样行为，据信重现了人类表型，并且更容易受到 CRS 的影响，但 ELS 对 Val66Met 小鼠的影响尚未得到研究。本研究将使用 Val66Met 小鼠与先前描述的 CA3 报告小鼠结合使用，以研究情绪障碍的遗传倾向对 CA3 基因表达的影响。双转基因小鼠将接受 ELS 和 CRS，结合遗传和环境敏感性，研究它们对 CA3 神经元基因表达的影响，以及 ELS 对 BDNF-Val66Met 小鼠尚未表征的行为影响。与正常恢复的表达模式相比，这些实验将识别由于这种高度普遍的基因突变而在 CRS 后无法恢复的基因。这些基因表达谱将为 BDNF 在压力诱导的神经可塑性中的功能提供新的见解，并确定治疗情绪障碍的新靶点。