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：
10667529
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/10667529
关键词：
Accidents Address Adolescent and Young Adult Adult Adverse event Affect Age Amnesia Amygdaloid structure Animal Model Antibiotics Area Association Learning 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 Goals Growth Impairment Incidence Injury Interpersonal Violence Laws Learning Memory Modeling Neuroanatomy 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 critical period experience experimental study forgetting infancy juvenile animal mature animal neural neurochemistry neuromechanism pup 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.

概括：超过 60% 的儿童承受着严重的压力，并遭受过包括人际关系在内的创伤性事件暴力、性虐待、事故和伤害——不良的童年经历——但存在不匹配他们接触这些经历与随后的精神病理学的流行之间的关系。不匹配，即大多数经历创伤事件的儿童没有表现出精神病理学，可能会导致来自对事件的适应力、缺乏诊断或忘记经历。事件涉及以最小的痛苦做出反应或尽早有效地恢复到正常的功能水平。遗忘很小的创伤事件（称为婴儿失忆症）与此相关发育的关键时期涉及周围神经网络的形成和强化大脑特定区域的神经元与高压力事件的记忆形成有关。神经周围网可以延长或更新关键时期，并有助于让不良经历的记忆得以恢复。使用幼鼠的新的过度兴奋模型来模拟不良的童年经历，我们将确定过度觉醒的个体发育、机制和治疗方法我们的首要目标是了解。我们将检验由压力事件引起的过度兴奋的假设，即恢复力和遗忘。关于学习引起的过度兴奋是神经周围网络的功能，该网络在学习过程中形成和加强为了验证这一假设，我们重点关注关联学习回路中神经元的发育。三个具体目标：（1）表征过度唤醒的个体发育并确定潜在的神经机制机制，（2）确定“治疗”或减轻幼年大鼠过度兴奋的行为策略，并描绘所涉及的神经机制，以及（3）确定神经周围网络在过度唤醒及其相关性中的作用我们将进行一系列实验来表征幼鼠的过度兴奋，确定治疗方法，然后在厌恶情绪获得或消失之前操纵神经周围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展或促进忘记过度唤醒以及对与相关线索相关的条件性情绪反应所提出的实验是填补我们的重要空白的共同努力。了解不良事件后儿童发生过度警觉的发展轨迹 – 人际暴力、事故和儿童受伤的发生率日益受到关注在美国和国外，这种情况持续升级，我们将重点关注揭示这一现象的机制研究。潜在的神经过程、神经周围网络的作用，并阐明年龄特异性的行为和药物治疗策略。