Sleep-dependent negative overgeneralization in peri-pubertal anxiety

项目摘要 高达50%的青春期青年焦虑的临床需求未得到满足，使这些青年处于高风险状态， 自杀、抑郁和滥用药物。根据NIMH战略计划的雅阁，我们的目标是 深化对青春期敏感期焦虑的机制性认识， 治疗和减少健康风险。这一建议的重点是消极的过度概括，这是一个核心 焦虑的一个维度，人们对它的了解很少，它指的是一种倾向，即把厌恶的反应概括起来 从一个上下文（房屋火灾）到共享特征的其他上下文（篝火）。杏仁核活动，由 提高情绪唤醒，增强可塑性的联想学习机制，促进绑定 在记忆中的上下文特征只是松散的相关。我们认为睡眠在 消极的过度概括。具体来说，我们从基础神经科学中提出了一个模型， 清醒时杏仁核的反应性增强，这是由情绪唤起的增加引起的， 睡眠中的负面记忆。这种便利的重放导致稳定和整合 （巩固）的负面记忆到长期记忆网络通过慢波振荡事件， NREM睡眠。我们进一步提出，在睡眠期间促进负面记忆的重放， 通过影响潜在的神经计算机制（即，模式补全- a 使神经表征相似的计算过程）。最后，我们提出，睡眠依赖 巩固是可塑性的，例如睡眠期间积极记忆的目标记忆再激活（TMR） 可以竞争性地取代负面记忆的巩固，减少负面的过度概括。的 当前的提议使用结合神经成像的新颖的多方法方法来测试该模型， 多导睡眠图，以及一项记忆任务，该任务捕捉行为泛化及其潜在的神经 模式完成（pattern completion）。目标1对200名青春期青年（年龄10-13岁）进行了全面检查， 在随机睡眠（n=140）与清醒（n=60）设计中连续的焦虑症状，以证明 睡眠对负性过度概括的行为和神经机制的影响。目标2重点 对140名处于睡眠状态的青少年进行杏仁核编码反应性和睡眠神经生理学评价 在编码后睡眠中作为焦虑和消极过度概括之间的中介。Aim 3使用 与睡眠条件相同的设计，但招募了一个新的焦虑升高的青年样本（n=60）参加 一项随机试验，在睡眠中提示积极记忆（TMR，n=30），或提供假提示 在睡眠期间（n=30），检查消极过度概括的睡眠依赖机制的延展性。 该项目将为开发控制睡眠的新干预措施的长期目标奠定基础 (e.g.通过TMR）不仅可以改善现有症状，还可以积极塑造神经发育， 在青春期敏感期降低风险。

PROJECT SUMMARY Up to 50% of peripubertal youth with anxiety have unmet clinical needs, leaving these youth at high risk for suicide, depression and substance abuse across adolescence. In accord with the NIMH strategic plan, we aim to deepen mechanistic understanding of anxiety during the sensitive period of peripuberty to inform novel treatments and reduce health risks. This proposal focuses on negative overgeneralization, which is a core dimension of anxiety that is poorly understood, and refers to the tendency to generalize aversive responses from one context (house fire) to other contexts (camp-fire) that share features. Amygdala activity, induced by heightened emotional arousal, enhances plasticity in associative learning mechanisms, facilitating the binding of contextual features in memory that are only loosely related. We posit that sleep plays a critical role in negative overgeneralization. Specifically, we draw from basic neuroscience to propose a model by which heightened amygdala reactivity during wakefulness, induced by increased emotional arousal, facilitates replay of negative memories during sleep. This facilitated replay leads to the stabilization and integration (consolidation) of negative memories into long-term memory networks via slow wave oscillatory events during NREM sleep. We further propose that facilitated replay of negative memories during sleep promotes generalization by influencing underlying neurocomputational mechanisms (i.e., pattern completion – a computational process that makes neural representations similar). Finally, we propose that sleep-dependent consolidation is malleable, such that Targeted Memory Reactivation (TMR) of positive memories during sleep can competitively displace consolidation of negative memories, and reduce negative overgeneralization. The current proposal tests this model using a novel multi-method approach combining neuroimaging, polysomnography, and a memory task that captures behavioral generalization and its underlying neural mechanisms (i.e. pattern completion). Aim 1 examines 200 peripubertal youth (ages 10-13 years) across a full continuum of anxious symptoms in a randomized sleep (n=140) versus wake (n=60) design to demonstrate sleep-dependent effects on behavioral and neural mechanisms of negative overgeneralization. Aim 2 focuses on the 140 youth in the sleep condition to evaluate amygdala reactivity at encoding and sleep neurophysiology during post-encoding sleep as mediators between anxiety and negative overgeneralization. Aim 3 uses the same design as the sleep condition but recruits a new sample of youth with elevated anxiety (n=60) to enroll in a randomized trial in which positive memories are cued during sleep (TMR, n=30), or sham cues are presented during sleep (n=30), to examine malleability of sleep-dependent mechanisms of negative overgeneralization. This project will set the stage for the long-term goal of developing novel interventions that manipulate sleep (e.g. via TMR) not only to improve existing symptoms, but also to positively shape neurodevelopment and reduce risk in the sensitive period of peripuberty.