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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.

项目总结