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Susceptibility and Resilience to Adverse Childhood Experiences: A Role for Perineuronal Nets

对童年不良经历的敏感性和恢复力：神经周围网络的作用

基本信息

批准号：
10221013
负责人：
BERNARD G. SCHREURS
金额：
$ 37.24万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10221013
关键词：
Accidents Address Adolescent and Young Adult Adult Adverse event Affect Age Amnesia Amygdaloid structure Animal Model Antibiotics Area Behavior Therapy Behavioral Brain Cerebellar Nuclei Child Childhood Chondroitin ABC Lyase Chondroitin Sulfate Proteoglycan Conditioned Stimulus Cues Data Development Diagnosis Distress Doxycycline Emotional Event Exposure to Extinction (Psychology)Goals Growth Impairment Incidence Injury Interpersonal Violence Laws Learning Memory Modeling Neurons Pharmaceutical Preparations Pharmacological Treatment Play Predisposition Prevalence Procedures Process Psychopathology Publishing Rattus Role Series Sexual abuse Stimulus Stress Stressful Event Structure Techniques Testing United States War adverse childhood events age related base classical conditioning critical period experience experimental study forgetting infancy juvenile animal mature animal neurochemistry neuromechanism pup relating to nervous system resilience response stress reactivity stress resilience traumatic event treatment strategy young adult

项目摘要

SUMMARY: Over 60% of children experience severe stress and are exposed to traumatic events including interpersonal violence, sexual abuse, accidents and injuries – adverse childhood experiences – but there is a mismatch between their exposure to these experiences and the prevalence of subsequent psychopathology. This mismatch, in which most children who experience traumatic events do not show psychopathology, may result from resilience to the events, a lack of diagnosis, or forgetting about the experiences. Resilience to adverse events involves responding with minimal distress or an early and effective return to normal levels of function. Forgetting about traumatic events in the very young – referred to as infantile amnesia – has been associated with critical periods in development involving the formation and strengthening of perineuronal nets surrounding neurons in specific areas of the brain related to memory formation for highly stressful events. Disrupting these perineuronal nets may extend or renew critical periods and help allow the memory of adverse experiences to be erased. Using a new model of hyperarousal in young rats to model adverse childhood experiences, we will determine the ontogeny, mechanisms, and treatment of hyperarousal. Our overarching goal is to understand the hyperarousal that results from stressful events. We will test the hypothesis that resilience to and forgetting about learning-induced hyperarousal is a function of perineuronal nets that form and strengthen during development around neurons in the circuits underlying associative learning. To test this hypothesis, we focus on three specific aims: (1) Characterize the ontogeny of hyperarousal and determine the underlying neural mechanisms, (2) Determine behavioral strategies to “treat” or mitigate hyperarousal in young rats and delineate the neural mechanisms involved, and (3) Determine the role of perineuronal nets in hyperarousal and its treatment. We will conduct a series of experiments in which we characterize hyperarousal in young rats, determine treatments, and then manipulate perineuronal nets before acquisition or extinction of aversive associative learning to determine whether we can manipulate critical periods to impair the development or facilitate the forgetting of hyperarousal as well as the conditioned emotional responding to cues associated with adverse events. The proposed experiments constitute a concerted effort to fill an important gap in our understanding of the developmental trajectory of hyperarousal that occurs in children following adverse events – an area of growing concern as the incidence of interpersonal violence, accidents and injuries to children continues to escalate both in the United States and abroad. We will focus on mechanistic studies that reveal the underlying neural processes, the role of perineuronal nets, and elucidate age-specific behavioral and pharmacological treatment strategies.

摘要：超过60%的儿童承受着严重的压力，并暴露在包括人际关系在内的创伤事件中暴力、性虐待、事故和伤害--不利的童年经历--但存在错配他们接触这些经历和随后的精神病理流行之间的关系。这错配可能会导致大多数经历过创伤事件的儿童没有表现出精神病态从恢复力到事件，缺乏诊断，或忘记经历。对逆境的适应能力事件包括以最小的痛苦或尽早有效地恢复正常功能水平作出反应。在很小的时候就忘记创伤性事件--被称为婴儿健忘症--与处于发育的关键时期，涉及周围神经网的形成和加强大脑特定区域的神经元与高压力事件的记忆形成有关。打乱了这些神经周网络可以延长或更新临界期，并有助于允许对不利经历的记忆被删除了。使用一种新的幼鼠高唤醒模型来模拟不良的童年经历，我们将确定高觉醒的个体发生、机制和治疗。我们的首要目标是了解由紧张事件引起的极度兴奋。我们将检验这样一种假设，即对遗忘的弹性关于学习诱导的高度觉醒是在学习过程中形成和加强的神经周网络的功能在联想学习的基础回路中围绕神经元的发育。为了检验这一假设，我们将重点放在关于三个具体目标：(1)描述高觉醒的个体发生和确定潜在的神经机制，(2)确定“治疗”或减轻幼年大鼠高觉醒的行为策略，并描述所涉及的神经机制，以及(3)确定神经周围网络在高觉醒中的作用及其治疗。我们将进行一系列实验，在这些实验中，我们将描述幼鼠的高度觉醒，确定治疗方法，然后在获得或消除厌恶情绪之前操纵神经周网络联想学习，以确定我们是否可以操纵关键时期来损害发育或促进忘记过度唤醒以及对与以下因素相关的提示的条件性情绪反应不良事件。拟议的实验是一项协调一致的努力，以填补我们在对不良事件后儿童高觉醒发展轨迹的理解 -一个日益令人关切的领域，因为人际暴力、事故和对儿童的伤害的发生率在美国和国外都在继续升级。我们将专注于揭示潜在的神经过程，周围神经网络的作用，并阐明特定年龄的行为和药物治疗策略。