Childhood Maltreatment:Biomarkers of Risk and Resilience

描述（由申请人提供）：儿童虐待，以虐待和忽视的形式，是一个主要的公共卫生问题。受虐待的儿童具有较高的内在精神病理学发病率，并且具有广泛的不良后果的高风险。婴儿和幼儿遭受虐待的风险最大，可能会发出最严重的虐待尖叫。由于对虐待行为的初级预防往往不可行，因此，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期虐待的行为尖叫中起着重要作用。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，这些基因在成人和儿童中产生了严重抑郁症和焦虑相关特征的风险。这些包括调节单胺神经传递和神经内分泌功能的基因。基因-环境相互作用的一个可能机制是风险基因可能赋予对压力的敏感性，可能是通过改变HPA轴的功能。大量的证据表明，在早期逆境的动物模型中，HPA轴功能失调。越来越多的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）。临床前和临床研究的证据表明，HPA轴的过度激活可能是有毒的，并导致大脑结构和功能的改变，涉及严重抑郁症和其他疾病的电路。除了早期生活压力的持久神经内分泌效应之外，这种HPA轴过度活跃可能部分地由参与该压力轴调节的基因变体引起。本申请的目的是鉴定受虐待学龄前儿童的行为问题和精神病理学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参与这些行为问题中涉及的神经通路以及先前与内化障碍和虐待的经验关联进行检查。此外，我们试图确定HPA轴功能的改变是否介导这些关系。后续评估将检查这些生物标志物和行为结果之间的前瞻性关系，以及神经内分泌活动与行为相关性的稳定性。这些结果应该提供有价值的信息，在虐待儿童的情感和行为问题的发展，可以指导治疗和预防工作，以及未来的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.