Effects of early-life experience:role of CRH

早期生活经历的影响：CRH 的作用

• 批准号: 8249914
• 负责人: Tallie Z. Baram
• 金额: $ 37.03万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249914
• 关键词: 6-Cyano-7-nitroquinoxaline-2,3-dione; Address; Adult; Affect; Animal Model; Attenuated; Award; Binding; Binding Sites; CREB1 gene; Caring; Cells; Child; Childhood; Chromatin; Clinical; Cognitive; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; DNA; DNA Sequence; Deacetylation; Defect; Disease; Elements; Emotional; Enabling Factors; Epigenetic Process; Event; Gene Expression; Genes; Glucocorticoid Receptor; Glutamate Receptor; Glutamates; Goals; Health; Hippocampus (Brain); Histones; Hormonal; Human; Hypothalamic structure; Immune Sera; In Vitro; Individual; Intervention; Knowledge; Learning; Life; Life Experience; MK801; Maintenance; Mediating; Memory; Mental Depression; Methyl-CpG-Binding Protein 2; Methylation; Modeling; Modification; Molecular; Molecular Target; N-Methylaspartate; Nature; Neuronal Plasticity; Neurons; Nuclear; Nucleic Acid Regulatory Sequences; Phenotype; Post-Traumatic Stress Disorders; Process; Proteins; Rattus; Receptor Signaling; Recruitment Activity; Repression; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Sensory; Signal Transduction; Stress; Synapses; System; Testing; Tissues; Transcription Repressor/Corepressor; Transcriptional Silencer Elements; Up-Regulation; Vertebral column; Western Blotting; abuse neglect; attenuation; base; biological adaptation to stress; blocking factor; chromatin immunoprecipitation; clinically significant; cohort; early experience; experience; gene environment interaction; gene interaction; neural initiation; neurobiological mechanism; paraventricular nucleus; postnatal; prevent; programs; public health relevance; relating to nervous system; research study; resilience; response; stress related disorder; stress resilience; transcription factor

DESCRIPTION (provided by applicant): This proposal focuses on understanding the neurobiological mechanisms of resilience to stress-related disorders. Because stress-related disorders--including depression, post-traumatic stress disorder and childhood cognitive and emotional defects that follow neglect and abuse--affect a significant proportion of children and adults and exact a huge human potential and financial toll, understanding the processes that engender resilience to these disorders carries profound impact. Vulnerability and resilience to disease are governed by the interaction of genes and environment / experience. Importantly, experience during early postnatal life influences the expression of stress-related genes, which may promote resilience or vulnerability to stress-related disorders. However, little is known about how these important effects take place. Augmenting early life experience by enhancing maternal care in the rat results in persistent alterations of stress-related genes: reduced expression of hypothalamic corticotropin releasing hormone (CRH) was found by the applicant already by the end of the enriched-experience period on postnatal day 9, preceding attenuation of stress responses and increased expression of hippocampal glucocorticoid receptor (GR). In addition, reducing CRH-CRH-receptor signaling in immature non-enriched rats was sufficient to up-regulate hippocampal GR persistently and to confer enduring resilience to stress. These findings indicate that repression of hypothalamic Crh gene expression is an early and crucial step in the molecular cascade bridging enriched maternal-derived early-life experience and the enduring neuroplasticity of the stress system that promotes resilience to stress-related disorders. The current proposal addresses important gaps in our understanding of the process by which augmented sensory input from maternal care promotes resilience to stress-related disorders: how are maternal-derived signals converted to information that 'commands' hypothalamic neurons to repress Crh gene expression? What molecular mechanisms initiate this repression? Maintain it throughout life? The aims of the proposed research are to (1) Test the hypothesis that augmented early-life maternal-care initiates epigenetic programming of the Crh gene via increased expression of the transcriptional repressor Neural Restrictive Silencing Factor (NRSF) and increased NRSF binding to a cognate binding site (NRSE) in the regulatory region of Crh. (2) Test the hypothesis that NRSF binding to NRSE is required for repression of Crh gene expression in hypothalamic neurons from experience-enriched rats. (3) Employ controlled, in vitro systems to test the hypothesis that NRSF upregulation and Crh repression in hypothalamic neurons are a result of reduced excitatory synaptic input to these neurons. (4) Examine the mechanisms that may be responsible for the maintenance of the suppressed expression of CRH and consequent attenuated stress responses and resilience to stress-related disorders. In summary, resilience to stress-related disorders is of major clinical significance. The paramount contribution of early-life experience to this resilience can be studied in suitable animal models, and information is now available regarding the molecular and functional changes of the 'stress system' that contribute to resilience. The proposed research will define how these molecular changes are initiated and maintained, and identify potential targets for translational clinical use, with profound impact on human health. PUBLIC HEALTH RELEVANCE: Some people are more resilient to stressful situations that can provoke depression or learning and memory problems in other individuals. There is some evidence that having a good experience early in life might promote this resilience. Here we hope to use animal models to discover exactly how this resilience happens. The resulting information would enable us to use the same mechanisms as a basis for therapy in people who have not had the same type of optimal childhood experience.

描述（由申请人提供）：该提案的重点是了解对压力相关疾病的恢复能力的神经生物学机制。因为与压力相关的疾病——包括抑郁症、创伤后应激障碍以及忽视和虐待导致的儿童认知和情感缺陷——影响了很大一部分儿童和成人，并造成巨大的人类潜力和经济损失，了解这些疾病的过程增强对这些疾病的抵御能力具有深远的影响。对疾病的脆弱性和恢复力是由基因和环境/经验的相互作用决定的。重要的是，产后早期的经历会影响与压力相关的基因的表达，这可能会增强对压力相关疾病的恢复力或脆弱性。然而，人们对这些重要影响是如何发生的知之甚少。通过加强大鼠的母性护理来增强早期生活体验会导致压力相关基因的持续改变：申请人在出生后第 9 天的丰富体验期结束时就发现下丘脑促肾上腺皮质激素释放激素 (CRH) 的表达减少，提前减弱应激反应并增加海马糖皮质激素受体（GR）的表达。此外，减少未成熟非富集大鼠中的 CRH-CRH 受体信号转导足以持续上调海马 GR，并赋予持久的压力恢复能力。这些发现表明，抑制下丘脑 Crh 基因表达是分子级联桥接丰富的母源性早期生活经历和应激系统的持久神经可塑性（促进应激相关疾病的恢复力）的早期且关键的一步。当前的提案解决了我们对孕产妇护理增强感觉输入促进对压力相关疾病的恢复力的过程的理解中的重要差距：来自孕产妇的信号如何转换为“命令”下丘脑神经元抑制 Crh 基因表达的信息？哪些分子机制引发了这种抑制？终生维持吗？拟议研究的目的是 (1) 检验这一假设，即增强的早期孕产妇护理通过增加转录抑制神经限制性沉默因子 (NRSF) 的表达以及增加 NRSF 与同源基因的结合来启动 Crh 基因的表观遗传编程。 Crh 调控区的结合位点 (NRSE)。 (2) 检验以下假设：NRSF 与 NRSE 结合是抑制经验丰富的大鼠下丘脑神经元 Crh 基因表达所必需的。 (3) 采用受控体外系统来检验以下假设：下丘脑神经元中 NRSF 上调和 Crh 抑制是这些神经元的兴奋性突触输入减少的结果。 (4) 检查可能负责维持 CRH 表达抑制以及随之而来的应激反应减弱和对应激相关疾病的恢复力的机制。总之，对压力相关疾病的恢复力具有重要的临床意义。早期生活经历对这种复原力的最重要贡献可以在合适的动物模型中进行研究，并且现在可以获得有关有助于复原力的“压力系统”的分子和功能变化的信息。拟议的研究将定义这些分子变化是如何启动和维持的，并确定转化临床应用的潜在目标，对人类健康产生深远影响。 公共卫生相关性：有些人对压力环境的适应能力更强，这些压力环境可能会引发抑郁症或其他人的学习和记忆问题。有一些证据表明，早年获得良好的经历可能会增强这种适应力。在这里，我们希望利用动物模型来揭示这种恢复能力到底是如何发生的。由此产生的信息将使我们能够使用相同的机制作为治疗那些没有相同类型的最佳童年经历的人的基础。