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

项目摘要 焦虑症(ADS)是儿童和青少年最常见的精神疾病。童年 广告在很大程度上损害了发育，并为后来的精神病理包括持续性疾病提供了高风险 焦虑、抑郁和共病的药物滥用。鉴于高流行率和长期的负面影响 在儿童广告中，成功地对待早期发展的广告是至关重要的。不幸的是，许多患有 这些疾病要么对治疗没有完全反应，要么复发。理解儿童广告的生物学 对于开发早期干预措施具有减少慢性病和合并症的潜力至关重要 相关的儿童期发病。大脑-行为关系的跨物种保护提供了一种独特的 将非人类灵长类动物的基础神经科学与儿童广告中的临床神经科学联系起来的机会 找出儿童焦虑的神经基础。拟议中的项目将利用这一特殊情况 使用两种综合方法的优势：1)多站点多模式成像研究，扩展了有希望的 非人灵长类动物的基础科学发现与患有ADS和2)分子的青春期前儿童的大样本 一项将儿童广告中的神经发现转化为非人类灵长类动物基因表达研究的研究 我们的完全表型的非人类灵长类脑库专注于神经可塑性转录的变化。 我们对非人类灵长类动物的研究结果突显了识别神经底物的重要性 有助于广告之间的共同差异，以及与以下各项相关的特定神经底物 特殊的焦虑表型。这种方法与有共同和特定特征的证据是一致的 儿童ADS：大多数ADS儿童的症状和治疗反应混合在一起 相似的诊断表明有共同的神经基础；然而，症状和 表现表明是异质的神经基质。这项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 分离性焦虑症；(2)确定与特定焦虑相关的RDoC相关的神经改变 结构(即急性、潜在和持续的威胁，以及条件性恐惧的泛化)；以及(3) 在儿童期AD研究的指导下，研究儿童期ADS中枢脑区的分子变化 在目标1和目标2中，特别关注与神经可塑性相关的改变。研究AD的大样本 儿童是分析儿童广告中常见的异质性的关键；为了实现这一目标，我们有 收集了三个具有焦虑方面专业知识的网站(焦虑的非人类灵长类模型，儿童焦虑， 发展心理学)和高级方法(基因表达、神经成像和统计学)。最终 我们的目标是阐明儿童广告背后的神经生物学机制，以确定新的大脑靶点。 用于治疗，包括共同的和表型特定的儿童ADS的神经相关性。

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.