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

总结： 超过60%的儿童经历严重的压力，并暴露于创伤性事件，包括人际关系 暴力、性虐待、事故和伤害-不良的童年经历-但存在着不匹配 他们暴露于这些经历和随后精神病理学的流行之间的联系。这 不匹配，其中大多数经历创伤事件的儿童没有表现出精神病理学，可能导致 从对事件的适应能力，缺乏诊断，或者忘记经历。对不利影响的恢复力 事件涉及以最小的痛苦或早期和有效地恢复到正常功能水平的反应。 在很小的时候就忘记创伤性事件--被称为婴儿健忘症--与 在发育的关键时期，包括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应激事件的记忆形成有关。破坏这些 神经束网可以延长或更新关键期，并有助于使不良经历的记忆 被抹去了使用一种新的年轻大鼠过度觉醒模型来模拟不良的童年经历，我们将 确定个体发育，机制，和过度觉醒的治疗。我们的首要目标是了解 压力事件导致的过度兴奋我们将检验一个假设， 关于学习引起的过度觉醒是一个神经元周围网络的功能， 在神经元周围的神经元的发展，潜在的联想学习。为了验证这一假设，我们将重点 三个具体目标：（1）描述个体发育的过度觉醒，并确定潜在的神经 机制，（2）确定行为策略，以“治疗”或减轻年轻大鼠的过度觉醒，并描述 涉及的神经机制，（3）确定神经元周围网络在过度觉醒及其 治疗我们将进行一系列的实验，在这些实验中，我们描述了年轻大鼠的过度觉醒， 确定治疗方法，然后在获得或消除厌恶之前操纵神经元周围的网络。 联想学习，以确定我们是否可以操纵关键时期，以损害发展， 促进对过度觉醒的遗忘以及对与以下相关的线索的条件性情绪反应 不良事件。拟议的实验构成了一项协调一致的努力，以填补我们的一个重要空白， 了解不良事件后儿童过度觉醒的发展轨迹 - 这是一个日益令人关注的领域，因为儿童遭受的人际暴力、事故和伤害的发生率 在美国和国外都在继续升级。我们将重点关注揭示了 潜在的神经过程，神经元周围网络的作用，并阐明特定年龄的行为和 药物治疗策略。

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.