Childhood Maltreatment: Epigenetic Modulation of the Glucocorticoid Receptor

描述(由申请人提供)：早期生活压力(ELS)史是成人精神病理学的重要危险因素，包括严重的抑郁症、焦虑症和药物滥用。对啮齿动物和非人类灵长类动物的临床前研究表明，早期的护理经验在参与调节应激反应、情感和行为的大脑回路的发展中发挥着关键作用。压力敏感性和HPA轴功能的变化可能是压力和精神障碍风险之间的联系的基础。来自临床前和临床研究的一系列证据表明，暴露于过高的糖皮质激素浓度会损害海马区的神经保护和神经发生，并增强杏仁核中的树突分支，这些效应与抑郁和焦虑的发病机制有关。最近的研究已经确定了几个风险基因，这些基因似乎可以缓和儿童虐待等应激源对精神病理风险的影响。人类这种相互作用的确切机制尚不清楚，但一系列关于表观遗传学的临床前工作表明，基因和应激经历之间存在复杂的相互作用，环境扰动导致基因表达的变化，从而导致糖皮质激素分泌增加以及应激的行为后遗症。特别是，啮齿动物的低水平母爱与糖皮质激素受体基因甲基化增加有关，此外还与对压力的荷尔蒙和行为反应夸大有关。最近的研究已经开始研究早期应激是否会导致人类糖皮质激素受体基因的表观遗传修饰。本提案的目的是确定与没有虐待史的成年人相比，有儿童期虐待史的成年人是否有糖皮质激素受体基因的表观遗传修饰。此外，我们的目标是研究该基因甲基化与神经内分泌对心理社会和神经生物学挑战测试的反应之间的关系。这项研究的结果可能会提供关于儿童期虐待与精神障碍风险之间的联系的机制，以及早期生活应激对应激反应和HPA轴功能变化的影响的信息。针对表观遗传修饰或以其他方式减轻高危个体的应激反应的治疗干预措施，最终可能在治疗和预防与虐待有关的精神病理学方面发挥作用。 公共卫生相关性：这项拟议的研究试图在有和没有儿童期虐待史的成年人样本中检查糖皮质激素受体基因的表观遗传修饰。此外，这项研究旨在确定这种变化是否与皮质醇和ACTH对心理社会和神经生物应激测试的反应改变有关。这项研究的结果可能为儿童虐待抑郁症和焦虑症的高危个体提供神经生物学标记物和疾病机制的洞察。这些信息可能有助于未来应激相关疾病的治疗和预防工作。

DESCRIPTION (provided by applicant): A history of early-life stress (ELS) is an important risk factor for adult psychopathology, including major depression, anxiety disorders, and substance abuse. Preclinical studies of rodents and non-human primates demonstrate that early care-giving experiences play a critical role in the development of brain circuits involved in the regulation of stress-reactivity, affect and behavior. Changes in stress sensitivity and functioning of the HPA axis may underlie the association between stress and risk for psychiatric disorders. Converging lines of evidence from preclinical and clinical studies indicate that exposure to excessive glucocorticoid concentrations impairs neuroprotection and neurogenesis in the hippocampus and enhances dendritic branching in the amygdala, effects linked to the pathogenesis of depression and anxiety. Recent studies have identified several risk genes which appear to moderate the effects of stressors such as childhood maltreatment on risk for psychopathology. The precise mechanism of such interactions in humans is not known, but an elegant body of preclinical work on epigenetics shows complex interactions between genes and stressful experiences, with environmental perturbations causing changes in gene expression which leads to increased glucocorticoid secretion as well as behavioral sequelae of stress. In particular, low levels of maternal care in rodents have been linked to increased methylation of the glucocorticoid receptor gene in addition to exaggerated hormonal and behavioral responses to stress. Recent studies have begun to examine whether early-life stress leads to epigenetic modifications of the glucocorticoid receptor gene in humans. The goal of the present proposal is to determine whether adults with a history of childhood maltreatment have epigenetic modifications of the glucocorticoid receptor gene in comparison to adults without a history of maltreatment. Further, we aim to study the relationship between methylation of this gene and neuroendocrine responses to psychosocial and neurobiological challenge tests. The results of this study may yield information about the mechanism of the association between childhood maltreatment and risk for psychiatric disorders as well as the effect of early-life stress on alterations in stress reactivity and HPA axis function. Therapeutic interventions that target epigenetic modifications or otherwise mitigate stress responsivity in at-risk individuals may eventually have a role in the treatment and prevention of psychopathology related to maltreatment. PUBLIC HEALTH RELEVANCE: The proposed study seeks to examine epigenetic modifications of the glucocorticoid receptor gene in a sample of adults with and without a history of childhood maltreatment. In addition, the study aims to determine whether such changes are associated with altered cortisol and ACTH responses to psychosocial and neurobiological stress challenge tests. Results of this study may provide insight into the neurobiological markers and mechanisms of illness in individuals at-risk for depressive and anxiety disorders by virtue of childhood maltreatment. This information may contribute to future treatment and prevention efforts for stress- related disorders.