Combining human and nonhuman primate studies to understand the pathophysiology of childhood anxiety disorders

项目摘要 焦虑症（AD）是儿童和青少年中最常见的精神疾病。童年 AD严重损害发育，并赋予后期精神病理学的高风险，包括持续性 焦虑抑郁和药物滥用共病鉴于高流行率和长期的负面影响 因此，在发育早期成功治疗AD至关重要。不幸的是，许多孩子 这些疾病或者对治疗没有完全反应或者复发。了解儿童广告的生物学 对于开发早期干预措施至关重要，有可能减少慢性和合并症 与儿童期发病有关。大脑行为关系的跨物种保护提供了一个独特的 有机会将非人类灵长类动物的基础神经科学与儿童AD的临床神经科学联系起来， 识别儿童焦虑的神经基础。拟议项目将利用这一特殊的 通过使用两种集成方法的优势：1）多站点多模式成像研究， 基础科学发现，在非人类灵长类动物的大样本的青春期前与广告和2）分子 一项将儿童AD的神经发现转化为非人灵长类动物基因表达研究的研究， 我们的非人类灵长类动物脑库集中在神经可塑性转录物的改变上。 我们的非人灵长类动物研究结果强调了识别神经基质的重要性， 有助于AD之间的共享方差，以及与AD相关的特定神经基质。 特定的焦虑表型这种方法与证据的共同和具体特点， 儿童AD：大多数AD儿童存在症状和治疗反应的混合物， 不同的诊断相似，表明有共同的神经基质;然而，症状和 提示神经基质异质性。研究将集中于三个具体目标：（1）确定 儿童广泛性焦虑症、社交焦虑症和 分离焦虑症;（2）确定与特定焦虑相关RDoC相关的神经改变 结构（即急性，潜在和持续的威胁，以及条件恐惧的泛化）;以及（3） 在儿童AD研究的指导下，研究儿童AD核心脑区的分子改变 在目标1和2中，特别关注神经可塑性相关的改变。研究AD的大样本 儿童对于解析儿童广告中常见的异质性至关重要;为了实现这一目标，我们 集合了三个具有焦虑专业知识的网站（非人类灵长类动物焦虑模型，儿童焦虑， 发展心理学）和先进的方法（基因表达，神经成像和统计学）。最终 我们的目标是阐明儿童AD的神经生物学机制，以确定新的脑靶点 包括儿童AD的共享和表型特异性神经相关性。

Project Summary Anxiety disorders (ADs) are the most prevalent psychiatric ailments in children and adolescents. Childhood ADs substantially impair development and confer high risk for later psychopathology including persistent anxiety, depression and comorbid substance abuse. Given the high prevalence and long-term negative impact of childhood ADs, it is critical to successfully treat ADs early in development. Unfortunately, many children with these disorders either fail to fully respond to treatment or relapse. Understanding the biology of childhood ADs is crucial for developing early interventions with the potential to reduce the chronicity and comorbidity associated childhood onset. Cross-species conservation of brain-behavior relationships provides a unique opportunity to link basic neuroscience in nonhuman primates with clinical neuroscience in childhood ADs to identify the neural substrates of childhood anxiety. The proposed project will capitalize on this exceptional advantage by using two integrated approaches: 1) a multisite multimodal imaging study that extends promising basic science findings in nonhuman primates to a large sample of preadolescents with ADs and 2) a molecular study that translates neural findings in childhood ADs to gene expression studies in nonhuman primates using our fully-phenotyped nonhuman primate brain bank focused on alterations in neuroplasticity transcripts. Findings from our nonhuman primate studies highlight the importance of identifying neural substrates that contribute to shared variance across ADs, as well as specific neural substrates that are associated with particular anxiety phenotypes. This approach is consistent with evidence of shared and specific features of childhood ADs: most children with ADs present with an admixture of symptoms and treatment responses are similar across diagnoses suggesting shared neural substrates; however, substantial variation in symptoms and presentation suggest heterogeneous neural substrates. The study will focus on three specific aims: (1) Identify neural alterations that are shared among childhood generalized anxiety disorder, social anxiety disorder, and separation anxiety disorder; (2) determine neural alterations linked to specific anxiety-relevant RDoC constructs (i.e. acute, potential, and sustained threat, and generalization of conditioned fear); and (3) Investigate molecular alterations in brain regions central to childhood ADs, guided by the childhood AD studies in Aims 1 and 2, with a particular focus on neuroplasticity-related alterations. Studying a large sample of AD children is critical to parse the heterogeneity common in childhood ADs; to achieve this goal, we have assembled three sites with expertise in anxiety (nonhuman primate models of anxiety, childhood anxiety, developmental psychology) and advanced methods (gene expression, neuroimaging, and statistics). Ultimately we aim to elucidate the neurobiological mechanisms underlying childhood ADs to identify novel brain targets for treatment, including shared and phenotype-specific neural correlates of childhood ADs.