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

结合人类和非人类灵长类动物研究来了解儿童焦虑症的病理生理学

基本信息

批准号：
10414803
负责人：
JENNIFER URBANO BLACKFORD
金额：
$ 37.63万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10414803
关键词：
Acute Admixture Adolescent Affect Amygdaloid structure Animals Anterior Anxiety Anxiety Disorders Basic Science Behavioral Biology Brain Brain region Cell Nucleus Child Childhood Chronic Clinical Cognitive Data Development Diagnosis Diagnostic Diffusion Magnetic Resonance Imaging Dimensions Disease Early Intervention Early treatment Emotions Freezing Functional disorder Gene Expression Gene Mutation Generalized Anxiety Disorder Genes Genetic Variation Goals Height Heterogeneity High Prevalence Hippocampus (Brain)Human Image Impairment Individual Differences Insula of Reil Life Link Measures Mental Depression Methods Modeling Molecular Monkeys Multimodal Imaging Mutation National Institute of Mental Health Neuronal Plasticity Neurophysiology - biologic function Neurosciences Phenotype Physiological Primates Process Psychopathology RNA Regulation Relapse Research Domain Criteria Rest Risk Rodent Sampling Scanning Separation Anxiety Disorder Site Small Nuclear RNA Social Anxiety Disorder Structure Substance abuse problem Symptoms Tissues Transcript Translating Treatment Failure Uncertainty Variant Work anxious base brain behavior brain metabolism brain tissue cell type childhood anxiety clinical diagnosis comorbid depression comorbidity conditioned fear developmental psychology diagnostic strategy differential expression effective therapy generalized anxiety high risk imaging study improved outcome individual variation innovation insight multimodal neuroimaging neural circuit neural correlate neurobiological mechanism neuroimaging nonhuman primate novel prevent relating to nervous system response social anxiety statistics symptom treatment transcriptome sequencing translational approach translational study treatment of anxiety disorders treatment response

项目摘要

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.

项目摘要焦虑症（AD）是儿童和青少年最普遍的精神病。童年广告大大损害了发展的发展，并赋予了以后的心理病理的高风险焦虑，抑郁和合并药物滥用。鉴于高流行和长期负面影响关于童年广告，至关重要的是在开发早期成功处理广告至关重要。不幸的是，许多孩子这些疾病要么无法完全应对治疗或复发。了解童年广告的生物学对于制定早期干预措施至关重要，并有可能降低慢性和合并症相关的童年发作。跨物种的脑行为关系保存提供了独特的将非人类灵长类动物的基本神经科学与儿童时期临床神经科学联系起来的机会确定儿童焦虑的神经底物。拟议的项目将利用这一特殊的通过使用两种集成方法的优势：1）多站点多模态成像研究扩展了有希望的非人类灵长类动物的基础科学发现，大量具有AD的前核心和2）分子将儿童广告中的神经发现转化为非人类灵长类动物的基因表达研究的研究我们的全型非人类灵长类动物脑库的重点是神经塑性转录的改变。我们非人类灵长类研究的发现突出了鉴定神经底物的重要性有助于跨广告的共享差异，以及与之相关的特定神经底物特定的焦虑表型。这种方法与共享和特定特征的证据一致童年广告：大多数患有症状和治疗反应混合的广告的儿童是在诊断中相似，表明共有神经基质；但是，症状和演示表明异质神经底物。该研究将重点关注三个具体目标：（1）确定在儿童期广泛性焦虑症，社交焦虑症和分离焦虑症；（2）确定与特定焦虑相关的RDOC相关的神经改变构造（即急性，潜在和持续的威胁，以及条件恐惧的概括）；（3）在儿童时期研究的指导下，研究了儿童期广告中心的大脑区域的分子改变在目标1和2中，特别关注与神经塑性相关的改变。研究大量AD样本儿童对于解析儿童期广告中常见的异质性至关重要。为了实现这一目标，我们有组装了三个具有焦虑专业知识的地点（非人类灵长类动物焦虑，儿童焦虑，发育心理学）和高级方法（基因表达，神经影像学和统计）。最终我们旨在阐明儿童期广告的神经生物学机制，以鉴定新的大脑目标用于治疗，包括儿童广告的共享和表型特异性神经相关性。