Childhood Maltreatment:Biomarkers of Risk and Resilience

描述（由申请人提供）：虐待和忽视形式的儿童虐待是一个重大的公共卫生问题。受虐待的儿童具有较高的内化精神病理率，并且具有广泛的不良后果的高风险。婴儿和幼儿受到虐待的风险最大，也可能是遭受虐待最严重的。由于对虐待的初级预防往往不可行的情况下，查明对受虐待儿童产生积极影响的因素至关重要。遗传风险和保护因素似乎在儿童虐待的行为尖叫中起重要作用。最近的一些研究已经确定了与童年逆境相互作用的特定基因，这些基因会在成人和儿童中产生严重抑郁和焦虑相关特征的风险。这些基因包括调节单胺神经传递和神经内分泌功能的基因。基因-环境相互作用的一种可能机制是，风险基因可能通过改变下丘脑轴的功能而赋予对压力的敏感性。大量证据表明，早期逆境动物模型中下丘脑轴功能失调。越来越多对有早期虐待史的儿童和成人的研究提供了这种压力系统功能障碍的证据（这可能反映在皮质醇反应的夸大或减弱上）。来自临床前和临床研究的越来越多的证据表明，过度激活下丘脑轴可能是有毒的，并导致与重度抑郁症和其他疾病有关的大脑结构和回路功能的改变。除了早期生活压力对神经内分泌的持久影响外，这种HPA轴的过度活跃可能部分源于参与调节该压力轴的基因变异。本应用的目的是鉴定受虐待的学龄前儿童行为问题和精神病理的遗传和神经内分泌预测因子。调节单胺或HPA轴功能的基因将根据与这些行为问题有关的神经通路的参与以及与内化障碍和虐待的先前经验关联进行检查。此外，我们试图确定下丘脑轴功能的改变是否介导了这些关系。后续评估将检查这些生物标志物与行为结果之间的潜在关系，以及神经内分泌活动与行为关联的稳定性。这些结果应该为受虐待儿童情感和行为问题的发展提供有价值的信息，可以指导治疗和预防工作以及未来临床研究工作的方向。

DESCRIPTION (provided by applicant): Childhood maltreatment, in the form of abuse and neglect, is a major public health problem. Maltreated children have elevated rates of internalizing psychopathology and are at high risk for a broad range of adverse outcomes. Infants and young children are at the greatest risk of maltreatment and may have the most severe squeal of maltreatment. Insofar as primary prevention of maltreatment is often not feasible, the identification of factors that influence positive outcomes in maltreated children is critically important. Genetic risk and protective factors appear to play an important role in the behavioral squeal of childhood maltreatment. A number of recent studies have identified specific genes that interact with childhood adversity to produce risk for major depression and anxiety-related traits in adults and children. These include genes that regulate monoamine neurotransmission and neuroendocrine function. One likely mechanism of gene-environment interactions is that risk genes may confer sensitivity to stress, possibly through altered functioning of the HPA axis. A substantial body of evidence documents dysregulation of HPA axis function in animal models of early adversity. A growing body of research in children and adults with a history of early maltreatment provides evidence of dysfunction of this stress system (which may be reflected in exaggerated or attenuated cortisol responses). Converging lines of evidence from preclinical and clinical studies indicate that excessive activation of the HPA axis may be toxic and result in alterations of brain structure and function in circuitry involved in major depression and other disorders. In addition to enduring neuroendocrine effects of early-life stress, such HPA axis hyperactivity may in part result from gene variants involved in the regulation of this stress axis. The goal of the present application is to identify genetic and neuroendocrine predictors of behavior problems and psychopathology in maltreated preschoolers. Genes that regulate monoamine or HPA axis function will be examined based on involvement in neural pathways implicated in these behavioral problems as well as prior empirical associations with internalizing disorders and maltreatment. Further, we seek to determine whether alterations in HPA axis function mediate these relationships. A follow-up assessment will examine prospective relationships between these biomarkers and behavioral outcomes as well as the stability of associations of neuroendocrine activity with behavior. These results should provide valuable information regarding the development of affective and behavioral problems in maltreated children that could guide treatment and prevention efforts as well as direction for future clinical research efforts. PUBLIC HEALTH RELEVANCE: The proposed study seeks to elucidate neurobiological and social risk and protective factors for behavior problems in maltreated children. Results of this study may provide insight into the neurobiological markers and mechanisms of psychopathology in these vulnerable children. Such information may contribute to future treatment and prevention efforts.