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

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

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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，并暴露于创伤事件，包括人际关系暴力，性虐待，事故和伤害 - 不利的童年经历 - 但存在不匹配在他们对这些经历的暴露与随后的心理病理学的流行之间。这不匹配的大多数经历创伤事件的孩子都不表现出心理病理学，可能会导致从韧性到事件，缺乏诊断或忘记经历。对逆境的韧性事件涉及响应最小的困扰或早期有效的恢复正常的功能水平。忘记了年轻的创伤事件（称为基础设施失忆症）已经关联了随着开发的关键时期涉及周围的周围神经元网的形成和加强大脑特定区域的神经元与高度压力事件的记忆形成有关。破坏这些会内神经元网可能会延长或续签关键时期，并有助于使不良经历的记忆成为擦除。在年轻的大鼠中使用新的高阳光模型来建模广告童年的体验，我们将确定过度阳极的个体发育，机制和治疗。我们的总体目标是了解由压力事件引起的高阳性。我们将检验以下假设的韧性和忘记关于学习引起的超阳极的函数是会内神经元网，并在在关联学习的基础电路中神经元周围的发展。为了检验这一假设，我们集中于在三个特定目标上：（1）表征超阳极的个体发育并确定基础中性机制，（2）确定行为策略以“治疗”或减轻年轻大鼠的高伴侣并划定涉及的神经机制，以及（3）确定会内神经元网中的作用治疗。我们将进行一系列实验，在这些实验中，我们表征了年轻大鼠的高伴侣，确定治疗方法，然后在获取或扩展厌恶之前操纵神经元网协会学习以确定我们是否可以操纵关键时期以损害发展或促进忘记超值以及对与之相关的线索的条件情感反应不利事件。拟议的实验构成了一致的努力，以填补我们的重要空白了解不良事件后儿童发生的高阳光的发育轨迹 - 作为人际暴力，事故和儿童伤害的事件，人们越来越关注的领域在美国和国外继续升级。我们将专注于揭示的机械研究根本的神经过程，会内神经元网的作用以及阐明特定年龄的行为和药理治疗策略。