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风险因素，包括重度抑郁症、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，早期护理经验在参与压力反应、情感和行为调节的大脑回路的发展中起着关键作用。压力敏感性和HPA轴功能的变化可能是压力和精神疾病风险之间联系的基础。来自临床前和临床研究的证据表明，暴露于过量的糖皮质激素浓度会损害海马体中的神经保护和神经发生，并增强杏仁核中的树突分支，这与抑郁症和焦虑症的发病机制有关。最近的研究已经确定了几个风险基因，这些基因似乎可以减轻压力源的影响，例如童年虐待对精神病理学风险的影响。这种相互作用在人类中的确切机制尚不清楚，但关于表观遗传学的临床前研究表明，基因和压力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压力的行为后遗症。特别是，啮齿类动物中的低水平孕产妇护理与糖皮质激素受体基因甲基化增加以及对压力的过度激素和行为反应有关。最近的研究已经开始检查早期生活压力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具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的甲基化和神经内分泌反应的心理社会和神经生物学的挑战测试之间的关系。这项研究的结果可能会产生信息的机制之间的关联儿童虐待和精神疾病的风险，以及早期生活压力的影响，在压力反应性和HPA轴功能的改变。针对表观遗传修饰或以其他方式减轻风险个体的压力反应的治疗干预可能最终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：这项拟议中的研究旨在检查糖皮质激素受体基因的表观遗传修饰，在一个有和没有儿童虐待史的成年人样本中。此外，该研究旨在确定这些变化是否与皮质醇和ACTH对心理社会和神经生物学应激试验的反应改变有关。这项研究的结果可能会提供深入了解的神经生物学标志物和疾病的个人在抑郁症和焦虑症的风险凭借童年虐待的机制。这一信息可能有助于未来治疗和预防压力相关疾病的努力。

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.